IPRCC Meeting - 11/16/2018

Introduction

On November 16, 2018, at 8:30 a.m., a meeting of the Interagency Pain Research Coordinating Committee (IPRCC) convened on the National Institutes of Health (NIH) campus in Bethesda, Maryland. In accordance with Public Law 92-463, the meeting was open to the public. Walter Koroshetz, MD, Director of the National Institute of Neurological Disorders and Stroke (NINDS), presided as chair.

The following members of the IPRCC were in attendance:

Federal Members: David Clark, MD, PhD; Charles G. Helmick, II, MD; Sharon Hertz, MD; Walter Koroshetz, MD; Martha J. Somerman, DDS, PhD,  

Scientific Members: Daniel B. Carr, MD; Robert D. Kerns, PhD

Public Members: George Carter; Janet Chambers; Katherine Hammitt; Gwenn Herman; Cindy Steinberg; Catherine Underwood, MBA

Ex-Officio Members: Helene M. Langevin, MD, CM (Ex-Officio); Ann Cashion, PhD, RN, FAAN

Designated Federal Official: Linda L. Porter, PhD

Call to Order and Welcome

Welcome and Introduction of Committee Members and Updated IPRCC Mandate

Dr. Walter Koroshetz, Director, NINDS; Chair, IPRCC

Dr. Koroshetz welcomed participants to the meeting and asked the IPRCC’s new members, listed below, to briefly introduce themselves:

Dr. David Clark serves as the Vice Chair of Research at the Department of Anesthesiology at Stanford University and the Director of the Pain Clinic at The Department of Veterans Affairs Palo Alto Health Care System.

Ms. Katherine Hammitt serves as the Vice President of Medical and Scientific Affairs for the Sjögren’s Syndrome Foundation and is a Sjögren’s patient.

Ms. Gwenn Herman serves as the Clinical Director of Pain Connection, a program of the U.S. Pain Foundation.

Mr. George Carter is a sickle cell disease patient and advocate who serves as the Executive Director for Statewide Sickle Cell Chapters of Virginia.

Dr. Robert Kerns is a Clinical Psychologist and Professor of Psychiatry at Yale University School of Medicine who worked for the U.S. Department of Veterans Affairs (VA) for more than 37 years, serving as the National Director for Pain Management from 2005 to 2013.

Dr. Helene Langevin is the incoming Director of the National Center for Complementary and Integrative Health (NCCIH). She previously served as Director of the Osher Center for Integrative Medicine at Harvard Medical School.

Following the above introductions, Dr. Koroshetz invited the remaining members of the IPRCC and other attendees (not listed below), to introduce themselves:

Dr. Martha Somerman serves as Director of the National Institute of Dental and Craniofacial Research.

Mr. Kevin Galloway, who serves as the Deputy Director, Strategic Communications and Policy at the Defense and Veterans Center for Integrative Pain Management, attended for Colonel Chester “Trip” Buckenmaier, III, MD, (IPRCC representative for DoD) who was unable to attend.

Dr. Wilson Compton, who serves as the Deputy Director of NIDA, attended for Nora Volkow, MD (Ex-Officio member who was unable to attend). Dr. Compton noted that he recently co-chaired the committee that wrote a “Draft Report of the Fast Track Action Committee on Health Science and Technology Response to the Opioid Crisis,” which was commissioned by the White House Office of Science and Technology Policy. This report will be open for public comment until December 5, and Dr. Compton will distribute the comment link to IPRCC members to solicit their input.

Ms. Catherine Underwood, now retired, formerly served as the Chief Executive Officer of the American Pain Society.

Dr. Chad Helmick serves as a medical epidemiologist at the Centers for Disease Control and Prevention (CDC).

Dr. Daniel Carr serves as Professor of Public Health and Community Medicine at the Tufts University School of Medicine.

Dr. Sharon Hertz serves as the Director of the Division for Anesthesia, Analgesia, and Addiction Products of the Food and Drug Administration (FDA).

Ms. Cindy Steinberg serves as the National Director of Policy and Advocacy at the U.S. Pain Foundation, the Policy Chair for the Massachusetts Pain Initiative, and a member of the HHS Pain Management Best Practices Inter-Agency Task Force.

Ms. Janet Chambers, who joined the meeting remotely, serves as the President of the National Fibromyalgia and Chronic Pain Association.

Dr. Koroshetz provided a brief summary of the meeting agenda and reviewed the recent language changes to the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act. The new congressional language expands the following charges to the IPRCC mandate:

• “Develop a summary of advances in pain care research supported or conducted by the Federal agencies relevant to the diagnosis, prevention, treatment, and management of pain and diseases and disorders associated with pain, including information on best practices for the utilization of non-pharmacologic treatments, non-addictive medical products, and other drugs or devices approved or cleared by the FDA [U.S. Food and Drug Administration].”
• “Identify critical gaps in basic and clinical research on (1) the symptoms and causes of pain, including the identification of relevant biomarkers and screening models and the epidemiology of acute and chronic pain; (2) the diagnosis, prevention, treatment, and management of acute and chronic pain, including with respect to non-pharmacologic treatments, non-addictive medical products, and other drugs or devices approved or cleared by the FDA; and (3) risk factors for, and early warning signs of, substance use disorders in populations with acute and chronic pain.”
• “Make recommendations to the Director of NIH (1) to ensure that the activities of NIH and other Federal agencies are free of unnecessary duplication of effort; (2) on how best to disseminate information on pain care and epidemiological data related to acute and chronic pain; and (3) on how to expand partnerships between public entities and private entities to expand collaborative, cross-cutting research.”

In addition, the congressional language stipulates that “the [Department of Health and Human Services (HHS)] Secretary shall ensure that recommendations and actions taken by the [NIH] Director with respect to the topics discussed [at IPRCC meetings] are included in appropriate reports to Congress.” Thus, attention will increasingly fall upon the IPRCC and its activities.

Approval of the Minutes of the July 9, 2018, IPRCC Meeting

Dr. Linda Porter, Director of Pain Policy and Planning, NINDS; Designated Federal Official, IPRCC

The IPRCC approved the July 9, 2018, teleconference meeting minutes, with no corrections.

Updates from IPRCC Members

NIH-DoD-VA Collaboratory

Dr. David Shurtleff, Outgoing Ad Hoc IPRCC Member

Dr. Shurtleff reported that, in February 2015, the NCCIH Advisory Council recommended that NCCIH assess the feasibility of conducting large-scale collaborative studies among NIH, the Department of Defense (DoD), and VA to investigate integrative approaches to pain management within military and veteran patient populations. Rates of opioid use and chronic pain are significantly greater among U.S. military personnel after combat deployment than they are among the general public. The NIH-DoD-VA Pain Management Collaboratory (PMC), a funding initiative that aims to develop capacity to implement cost-effective, large-scale, clinical research embedded in military and veteran health care delivery systems, focuses on nonpharmacological approaches to pain management and related comorbidities.

The PMC currently contains 11 Pragmatic Trial Demonstration Projects (6 NIH-funded, 4 DoD-funded, and 1 VA-funded) that are nearing the end of their 2-year planning phase, and that will soon be evaluated according to certain planning-phase milestones to determine whether to transition each of them to a 2- to 4-year implementation phase. During the implementation phase, the Demonstration Project teams will cooperate with their respective funding agency representative and the PMC Coordinating Center (PMC³), which will determine resource needs and monitor progress toward agreed-upon project milestones.

Throughout the 2-year planning phase, the PMC³ has helped the 11 projects develop their clinical trial protocols and prepare for all facets of implementation. To facilitate focused and productive discussion as well as data sharing and policy harmonization among projects, the PMC³ has established and managed the following Working Groups: Electronic Health Records, Stakeholder Engagement, Phenotypes/Outcomes, Study Design/Biostatistics, Data Sharing, Ethical/Regulatory, and Implementation Science. Working Groups consist of chairs appointed by the PMC³ as well as individuals from the Demonstration Projects and staff from NIH, DoD, and VA. Presiding over all aspects of the PMC is the Executive Committee, which provides quarterly updates to funding and co-funding agency leads from NIH, DoD, and VA. In addition, Executive Committee co-chairs will make funding decisions regarding program continuance and expansion with input from other agency co-funders.

Discussion

Dr. Koroshetz asked about PMC’s plans to release data. Dr. Shurtleff explained that data collection will begin soon after the implementation phase begins for the various projects, which is expected to occur in fall 2019. The first data releases will likely occur approximately 1 year after that. As part of the Helping to End Addiction Long-term (HEAL) Initiative, NIH hopes to establish a data infrastructure that will link data from many studies and consortia; future discussions may focus on integrating PMC data into such a data resource.

Dr. Shurtleff explained that a key driver of PMC’s success thus far has been its structure. The Demonstration Projects are conducted by the Working Groups, which are managed by the PMC³. Each of these organizational units has been staffed with individuals with expertise in different aspects of PMC’s work. This action has facilitated iterative stages of planning, learning, and adjustment, resulting in constant progress across the various projects. Biostatisticians, clinical trialists, and other key specialist have been placed on the appropriate Working Groups to accelerate progress.

Healthy People 2030, MMWR on High Impact Chronic Pain, Annals of Internal Medicine on Chronic Pain in Suicide Decedents

Dr. Charles Helmick, CDC IPRCC Member

Dr. Helmick explained that the Office of Disease Prevention and Health Promotion’s Healthy People 2020 initiative includes four “developmental” objectives (i.e., those that lack associated baseline data and targets) relating to high impact chronic pain (HICP): (1) decrease the prevalence of adults having HICP, (2) increase self-management of HICP, (3) decrease the impact of HICP on families and significant others, and (4) increase public awareness/knowledge of HICP. Healthy People 2030 (anticipated release, late 2019) will transfer Objective 1 from “developmental” to “informational” (indicating that it has at least two measurable data points associated with it, but no specific targets), maintain Objectives 2 and 3 as developmental, and remove Objective 4 for lack of a reliable data source.

By adding pain-related questions to the 2016 and 2017 National Health Interview Survey (NHIS), investigators were able to operationalize definitions for chronic pain and HICP, and to measure their prevalence. According to 2016 survey data, published in Morbidity and Mortality Weekly Report (MMWR), approximately 20 percent of adults experience chronic pain while 8 percent experience HICP. In addition, the NHIS has proposed a “pain module” consisting of 20 pain-related questions, to be included in surveys every odd-numbered year beginning in 2019. The data generated by these questions will help to support Healthy People 2030 HICP objectives.

In addition, Petrosky and colleagues have utilized CDC’s National Violent Death Reporting System (NVDRS) to investigate relationships between suicide decedents and chronic pain. By establishing criteria that would qualify decedents as having suffered chronic pain and analyzing NVDRS abstracts for related keywords, investigators found that approximately 9 percent of suicide decedents suffered chronic pain associated with a variety of conditions, including musculoskeletal injuries, cancer, and arthritis. In addition, the rate increased from approximately 7 percent in 2003 to approximately 10 percent in 2014. The highest prevalence was among older males, with firearms accounting for greater than 50 percent of completed suicides associated with chronic pain.

Discussion

Dr. Thomas noted that the finding that only 9 percent of suicide decedents suffered chronic pain seems lower than expected. Dr. Helmick explained that this number may be lower than the actual figure because the criteria used to designate suicide decedents as sufferers of chronic pain were based on relatively conservative definitions. In addition, obtaining accurate numbers is difficult because investigators cannot administer questionnaires to the deceased. Ms. Steinberg added that the HHS Pain Management Best Practices Inter-Agency Task Force, before even releasing its report, has received more than 3,000 public comments: 25 percent mention suicide.

Clinical Decision Support for Chronic Pain

Dr. Linda Porter on behalf of Dr. Ric Ricciardi, AHRQ IPRCC retiring member

Dr. Ricciardi was unable to attend the meeting. Dr. Koroshetz informed the IPRCC that Dr. Ricciardi will leave the Agency for Healthcare Research and Quality (AHRQ) for a faculty position at the Georgetown University School of Nursing and Health Studies. Dr. Porter provided a brief summary of Dr. Ricciardi’s presentation on his behalf.

AHRQ’s Clinical Decision Support (CDS) program has been augmented with an electronic tool aimed at health care providers to specifically address chronic pain in accordance with the CDC prescribing guidelines, which promote non-opioid pain therapies. The tool helps providers by guiding their conversations with patients regarding pain management, offering recommendations and guidelines for assessment, and providing reference materials and evidence-based guidelines for treatment in a user-friendly format.

Discussion

Dr. Somerman highlighted the importance of integrating treatment recommendations for dental and oral pain conditions, which are sometimes neglected in electronic medical records (EMRs), into such tools. Dr. Carr noted that the Massachusetts Department of Public Health recently published a document establishing standard competencies that all medical and dental school graduates in the state must demonstrate upon graduation, which could be a useful resource. Dr. Carr will provide IPRCC members with instructions for accessing this document.

Dr. Hogans commented that the presented screenshots of the CDS tool do not contain options or prompts for nonpharmacological pain treatments, though they should. Ms. Underwood noted that Dr. Kathleen Sluka at the University of Iowa is currently engaged in work to integrate nonpharmacological treatment guidelines for chronic pain into EMRs such as Epic.

Dr. Koroshetz noted that the IPRCC has displayed an interest in discussing AHRQ’s CDS tool in more detail, and assured members that a new IPRCC member from AHRQ will be selected soon.

National Academy of Sciences, Planning for Pain Practice Guidelines

Dr. Sharon Hertz, FDA IPRCC Member

Dr. Hertz described FDA’s efforts to develop a rational and evidence-based set of clinical practice guidelines for prescribing opioids with the aim “to reduce overall exposure to opioids, while preserving access for those patients who will benefit.” FDA has conducted a study on post-surgical opioid use to investigate the relationship between amounts of opioids prescribed and used. Investigators found that across many surgery types, including some classified as “high” and others as “low” opioid need, median opioid consumption ranged from 3 to 67 percent of the prescribed quantity. In addition, 24 percent of patients overall took no opioids after surgery. The fact that so many prescribed opioids are not consumed following surgery suggests that non-secure storage and lack of disposal could present significant risks of later opioid misuse and abuse, including through third-party access or accidental exposure to prescribed opioids. Indeed, survey data from the Substance Abuse and Mental Health Services Administration has indicated that approximately 35 percent of misused pain relievers are accessed through legitimate prescriptions from a single doctor. However, data from the National Survey on Drug Use and Health (NSDUH, 2017) indicate that the vast majority (approximately 63 percent) of pain reliever misuse is aimed at relieving physical pain.

The SUPPORT for Patients and Communities Act, which became law in October 2018, further stimulated FDA’s efforts by charging it with a mandate to “develop evidence-based opioid analgesic prescribing guidelines for the indication-specific treatment of acute pain where such guidelines do not exist.” In response, FDA is currently engaged in a joint project with the National Academies of Sciences, Engineering, and Medicine titled “Evidence-Based Clinical Practice Guidelines for Prescribing Opioids for Acute Pain.” An ad hoc committee will develop a framework to evaluate existing clinical practice guidelines (CPGs) for prescribing opioids for acute pain indications and will recommend indications for which new evidence-based guidelines should be developed.

Discussion

Dr. Shurtleff and Dr. Langevin noted several alternative explanations for the gaps between amounts of opioids prescribed and consumed, including that providers may have prescribed other medications in addition to opioids or that patients may have decided on their own to relieve their pain through a different yet unreported therapy. Dr. Hertz acknowledged that the numbers presented reflect only available data and cannot on their own rule out such possibilities.

Several participants cited a recent paper, published by Dr. Erin Krebs and colleagues in JAMA, which presented data indicating that non-opioid medications successfully treated chronic back, hip, or knee pain across a 12-month randomized clinical trial (n = 240). Dr. Carr emphasized the need to interpret the Krebs results in relation to the specific cohort tested, and to not overgeneralize its conclusions. Dr. Hertz agreed, adding that FDA’s aim is to develop general CPGs that can help providers to develop individualized patient care plans.

Other Updates

National Physician Survey to Assess Incorporation of Opioid and Pain Management Guidelines into Clinical Practice

Dr. Richard Nahin, Lead Epidemiologist, NCCIH

Dr. Nahin reported that crosstalk among various National Pain Strategy (NPS) Implementation working groups, resulted in the launch of a project to use physician surveys to assess how opioid and pain management guidelines (including but not limited to those issued by CDC) are integrated into clinical practice. This initiative is expected to provide data that will help to address many of the goals outlined in the NPS. Over the past 10 years, many evidence-based CPGs have been released by professional organizations and at various levels of government. However, scant data exist on whether physicians are aware of these guidelines or on how and whether they are being applied in clinical practice. Moreover, those data that do exist are ambiguous (e.g., they are correlations that do not include comparison populations) and focus either (1) exclusively on CDC guidelines or (2) on specific states. Thus, the new survey project is intended to create a nationally representative, publicly available dataset that assesses (1) physician awareness and knowledge of pain and opioid management guidelines and (2) whether and how these guidelines are used in the care of patients suffering from pain.

This project will officially begin in January 2019. During the project’s initial phase, which has been fully funded by NCCIH, and which will last approximately 2 years, the project team will develop a draft questionnaire that will undergo iterative pilot testing and modification rounds. At the end of this phase, the survey will receive Office of Management and Budget and Institutional Review Board approval, at which point it will become publicly available. During phase 2, set to begin January 2021 (and which, along with phase 3, has not yet been funded), the survey will be administered to 1,000 physicians. During phase 3, set to begin January 2022, the survey dataset will become publicly available, and corresponding EMR data will be collected for linkage to the survey data.

The data set that will result from this project is expected to support assessment of guideline compliance over time and suggestions of educational initiatives for physicians and other health care providers. In addition, it may allow researchers and policymakers to identify barriers to awareness and use of CPGs, and to propose appropriate solutions. As a result, the prevalence of physicians who are aware of opioid and pain management CPGs may increase, leading to better and more consistent outcomes for patients and their families.

Discussion

Dr. Carr asked whether the project scope includes any external validation to check against physician self-report (e.g., to determine whether physicians who believe they are following CPGs are truly doing so). Dr. Nahin explained that such validation is outside the project scope, adding, however, that the final dataset could be validated by other researchers using the EMR data collected during phase 3.

The Pain Management Best Practices Task Force

Dr. Vanila Singh, Chief Medical Officer, OASH; Chair, Pain Management Best Practices Task Force

Dr. Singh stated that the Pain Management Best Practices Inter-Agency Task Force (“the Task Force”), authorized by the Comprehensive Addiction and Recovery Act of 2016, consists of representatives from HHS, DoD, VA, the Office of National Drug Control Policy, and several nonfederal members. The Task Force will publish its initial draft report within the next several weeks, which will then be subject to a 90-day public comment period, to which IPRCC members are strongly encouraged to contribute their input. However, the Task Force has already received approximately 3,000 public comments, including 30 from professional medical organizations, and many others from patients and patient advocacy groups. The Task Force has used machine learning to analyze the comments to gather information on their content, yielding information on what topics were addressed by what proportion of comments, such as the following: chronic pain (80 percent), access to treatment (78 percent), decreased functionality (60 percent), provider disincentives and fear (40 percent), stigma (27 percent), and CDC guidelines (explicit mentions, 13 percent). In addition, public comments have reflected the growing concern regarding the association between chronic pain and suicide as reflected in the NVDRS.

The initial draft report, which is being finalized, reviews a wide variety of treatment modalities (e.g., pharmaceuticals, psychological and behavioral interventions, and many others) including comprehensive and integrative care. In order to facilitate the understanding and implementation of such treatment modalities and guidelines, the report also addresses stigma, risk assessment (e.g., drug histories and prescription drug monitoring programs), access to care (including insurance coverage and telemedicine), education for both patients and providers, and societal awareness regarding the more than 50 million Americans living with daily chronic pain, which includes the 19.6 million living with HICP. In addition to the general public health crisis associated with chronic pain, the report also highlights the critical need for individualized patient care, as well as the needs of special populations such as women, geriatrics, and Alaska natives. The report also covers health disparities among minority populations, such as African Americans and Native Americans, as well as various conditions that underlie much of the chronic pain experienced by specific populations around the country, such as sickle cell disease.

Dr. Singh will provide Dr. Porter with a link to the draft report’s public comment page for distribution to IPRCC members for their input.

Patient’s Perspective on the Pain Management Best Practices Task Force

Ms. Cindy Steinberg, Pain Management Best Practices Task Force Member

Ms. Steinberg stated that, in addition to the tremendous suffering endured by those living with chronic pain, much human potential is wasted because of its debilitating effects. However, now is a hopeful time for pain research, as the scale and scope of neurobiological research focused on pathological pain and its underlying mechanisms have been substantially expanded. In addition, data now capture, better than ever before, the prevalence of chronic pain and HICP in the United States. For years, chronic pain sufferers have often been suspected—or even accused—of being mere drug-seekers. As knowledge of the causes and treatment options for pain has grown, patients are receiving more individualized and sophisticated interventions for their chronic pain. Lessening the burden shouldered by chronic pain sufferers is the primary aim of the Task Force’s draft report, which reflects a patient-centered approach, largely owing to the substantial number of public comments submitted by pain patients and their advocates. Crucially, the report’s recommendations will only have an impact if adopted and implemented by the responsible stakeholders, including government agencies. Therefore, Ms. Steinberg issued a plea to the agencies represented in the present meeting to provide advice and support for the Task Force’s recommendations within their respective organizations.

Discussion

Dr. Kerns made two points that received general approval: (1) stakeholders should consciously replace the goal of “curing” pain with the goal of “managing” pain and (2) researchers and policymakers should place more focus on the social determinants of pain, such as poverty, lack of education, and other forms of chronic disadvantage that are associated with pain conditions and various comorbidities, including those related to stress and mental health.

The NIH HEAL Initiative

Overview of Pain Research Projects and Concepts of the NIH HEAL Initiative

Dr. Walter Koroshetz, Director, NINDS; Chair, IPRCC

Dr. Koroshetz explained that, under the banner of the Helping to End Addiction Long-term (HEAL) Initiative, NIH has established a variety of research programs aimed at improving pain management. HEAL programs intersect with the Federal Pain Research Strategy (FPRS) and strive to both (1) lessen the burden of pain across the United States and (2) ameliorate the opioid crisis. The U.S. Congress has committed $500 million per year to improve prevention and treatment strategies for opioid misuse and addition, both in clinical and real-world settings, and these efforts include research programs to enhance pain management, which encompass the following general goals:

• Understand the biological underpinnings of chronic pain.
• Accelerate the discovery and preclinical development of nonaddictive treatments.
• Advance new nonaddictive treatments through the clinical pipeline.
• Inform best practices for effective pain management while minimizing risk of addiction.

HEAL research efforts dovetail with the work of the NIH Pain Consortium, which consists of collaborative, coordinated research programs among NIH Institutes involved in pain research. With the HEAL Initiative, NIH can fund pain research across the entire spectrum of research-to-care, from discovery to preclinical development, clinical trials, and implementation and dissemination of novel therapies. The main advantage of this full-spectrum funding strategy is to eliminate funding gaps that could stall the delivery of innovative pain management therapies to patients.

Regarding basic research, the HEAL Initiative aims to better understand the neurobiology of chronic pain and “to discover objective biosignatures that can help to identify susceptibility or resilience to chronic pain.” The search for mechanisms and novel therapeutic targets will entail following patients with acute pain onset from trauma or surgery, and having them undergo standardized phenotyping, genotyping, sensory testing, and imaging, along with various -omics analyses that can be integrated across a multi-site research network. Such efforts will require considerable infrastructure, including a Clinical Coordination Center, Multi-Site Clinical Centers, -Omics Data Generation Centers, and a Data Integration and Resource Center. In addition, this work intersects with the FPRS priority to conduct “prospective studies for susceptibility and resilience factors underlying the transition from acute to chronic pain.”

Other HEAL Initiative research efforts that cover the research-to-care spectrum will intersect with other FPRS priorities, including to (1) explore novel biological targets, (2) develop safer analgesics and the first generation of disease-modifying agents, (3) identify the most sensitive and specific preclinical models of pain, (4) discover and evaluate biomarker information, and (5) evaluate the efficacy, safety, and interactions of new therapies. These efforts will seek to develop means of manipulating pain circuitry independently of reward circuitry, potentially leading to nonaddictive yet effective pain therapies. In addition, the HEAL Initiative proposes an early-phase pain investigation clinical network, which could help to improve the quality, consistency, and efficiency of pain-related clinical trials, including those that use deep-phenotyping to facilitate development of individualized pain treatments, particularly for well-defined pain conditions with “high unmet need.”

Discussion

Ms. Hammitt sought clarification about the term “high unmet need.” Dr. Koroshetz explained that some pain sufferers may become desperate and contemplate suicide if available therapies do not effectively relieve their pain. Their “high unmet need” lives in tension with a general need for a very high standard for approving pain medications that will be taken by millions of pain patients around the country. It makes sense to accelerate the process of developing and approving novel therapies to provide relief to patients with high unmet need, who may view the cost-benefit analysis quite differently.  

Dr. Clark asked about the funding and structure of the clinical network. Dr. Koroshetz explained that the structure is modeled on the Next Generation Networks for Neuroscience, where each clinical site obtains ongoing funding for a coordinator and a primary investigator to participate in the network, and then additional funds are appropriated for specific clinical trials as they arise. In addition, each of the approximately 10 clinical centers will serve as a hub that will grant the network access to patients from their affiliated hospitals, which will greatly enhance the reach of the network, making it feasible to recruit patients with a variety of pain conditions of interest into the appropriate clinical trials. However, one critical element for the success of this clinical trial network is the staffing of each site with the relevant medical experts for that specific trial.

The Federal Pain Research Strategy

Annual Update

Dr. Linda Porter, Director of Pain Policy and Planning, NINDS; Designated Federal Official, IPRCC

Dr. Porter explained that a set of topic-specific working groups (i.e., Prevention of Acute and Chronic Pain; Acute Pain and Acute Pain Management; Transition from Acute to Chronic Pain; Chronic Pain and Chronic Pain Management; Disparities) comprised of many external experts and stakeholders, under the IPRCC’s oversight, developed and released the FPRS. The working groups were asked to identify gaps in the existing federal pain research portfolio, develop lists of research areas that cut across the various working group topics, and prioritize the items on these lists according to their potential benefit to pain patients. Dr. Porter highlighted how many of the proposed research projects under the HEAL Initiative, such as those covered by Dr. Koroshetz will serve to fill the research gaps identified by the FPRS working groups.

The HEAL Initiative will help to address another FPRS priority to identify effective approaches to delivering evidence-based effective acute or chronic pain management programs. Research that fulfills this aim must incorporate evidence from real-world settings and include representative samples of patients. Thus, NIH has proposed, under the HEAL Initiative, to launch pragmatic and implementation studies of pain management interventions to reduce opioid prescribing. The HEAL Initiative’s proposal to create a Back-Pain Research Consortium (BACPAC) also aligns with the FPRS priority to develop approaches incorporating the principles of precision medicine to prevent and treat chronic pain.

Further FPRS priorities will be addressed by leveraging existing NIH initiatives, including the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) and the Stimulating Peripheral Activity to Relieve Conditions (SPARC) programs. Such FPRS priorities include (1) develop safer analgesics through drug and device discovery efforts that target endogenous resolution mechanisms; (2) evaluate the efficacy, safety, and interactions of new therapies; and (3) characterize the heterogeneity of the circuitry involved in pain sensation and modulation.

Still, many of the top FPRS priorities are not covered by existing NIH initiatives, including HEAL. These priorities will be revisited in the future as the NIH pain research portfolio evolves.

Discussion

Dr. Porter explained that, to facilitate the value of data produced by the HEAL Initiative and the clinical trial network, a unified biorepository will hold all collected biosamples. Regarding data collection, coordination is currently under way to ensure that primary and secondary measures are standardized across projects and across study sites. NIH is committed to making data collection consistent across these research networks to maximize the value of the resulting data for future studies.

CDC Opioid Prescribing Guideline Update

Plans and Process

Dr. Christopher Jones, Senior Consultant

Dr. Debbie Dowell, Chief Medical Officer, National Center for Injury Prevention and Control, CDC

The CDC Guideline for Prescribing Opioids for Chronic Pain aligns with the President’s Initiative to Stop Opioid Abuse and Reduce Drug Supply and Demand (“the CDC guideline”) and with HHS’s 5-Point Opioid Strategy. The twofold goal of the CDC guideline is to reduce opioid-related harm and to improve pain care. Recently, CDC issued a report titled “Quality Improvement and Care Coordination” as a resource to help health care systems integrate the CDC guideline into their clinical practice. Currently, CDC is collaborating with a working group composed of non-CDC personnel to improve documentation regarding opioid prescribing practices for various health conditions, and to apply the insights gained from this documentation to improve such prescribing practices. CDC is also conducting a systematic review of evidence relating to pain treatments (including opioids, non-opioid pharmaceuticals, and nonpharmaceutical treatments) that has emerged since the CDC guideline was published to help develop novel clinical tools and to determine whether updates to the CDC guideline are needed. In addition, although the original CDC guideline focused on chronic pain, a review is currently under way to evaluate the effectiveness of opioids and non-opioid treatments for acute pain.

Discussion

Dr. Hertz noted that, although the CDC guideline was not intended to establish hard cutoffs regarding opioid prescribing, some state governments, municipalities, and health care systems have started to implement the CDC guideline’s recommendations too stringently. However, while CDC is working to disseminate the guideline and to ensure its appropriate interpretation, there is currently no specific effort to contact bodies that have adopted strict cutoffs or limitations for their medical communities. Dr. Clark suggested that CDC publish a letter-to-the-editor in a high-impact journal that clarifies the intent of the CDC guideline to draw attention to its misuse.

Mr. Carter emphasized that the CDC guideline has effectively frightened many physicians into not prescribing opioids for sickle cell and other pain patients who are increasingly desperate for relief. Mr. Carter asked whether CDC plans to rectify this situation. Dr. Dowell assured Mr. Carter that the CDC guideline was not intended to erect barriers for those in genuine need of pain relief, adding that CDC is working to clarify the CDC guideline to include more condition-specific suggestions, including for sickle cell disease.

Participants raised a concern related to the development of the CDC guideline, that is, that evidence of effectiveness was only considered if the efficacy phase of the clinical trial lasted for at least 1 year. This effectively ruled out much of the efficacy data from clinical trials that lasted for shorter periods of time, which are common because of the difficulty of retaining participants for longer periods, especially in efficacy trials that are properly designed and controlled.

Dr. Hertz and Dr. Dowell agreed that, as CDC works to update and improve its guideline, it would be fruitful for FDA and CDC to collaborate in a public manner. In addition, Ms. Steinberg and Ms. Herman strongly recommended that CDC engage with advocates and patients, who have been negatively impacted by the unintended consequences of the CDC guideline.  Ms. Steinberg specifically suggested that CDC host a meeting for patients and patient advocates to ensure that their perspectives are seriously considered throughout the process of improving the CDC guideline.

Low Back Pain

Non-Pharmacological Approaches to Low Back Pain

Dr. Helene Langevin, Director, Designee NCCIH

Dr. Langevin stated that 10-20 percent of Americans experience back pain, and nonpharmacological approaches to treatment are receiving renewed focus because of the opioid epidemic, although prevalence varies by age. However, many questions regarding what treatments are most effective, and for which patients, remain unanswered. Furthermore, the understanding of clinical back pain itself contains important gaps. Prior to 1990, the clinical consensus was that structural spinal issues caused back pain. After 1990, researchers and medical practitioners realized that back pain is more complex and initiated studies of the central and peripheral nervous system sensitization. However, the shift toward thinking of back pain primarily as a central nervous system (CNS) problem has become over-exaggerated, leading to a lack of attention to peripheral tissues, such as those in the musculoskeletal system, and pain-generating factors such as microtrauma, inflammation, fibrosis, and low tissue pH. Increasingly, investigators are exploring the potential of nonpharmacological therapies that have their effects via interactions between the CNS and peripheral tissue systems—such as acupuncture—to help alleviate back pain.

During acupuncture therapy, a needle is inserted into skeletal muscle tissue and manipulated by probing and twisting it to mechanically stimulate the muscle. Such muscular stimulation can also induce changes in the CNS, including pain relief, and can provoke long-term changes to certain brain regions, such as the cingulate and amygdala. Investigators have long-known that certain brain areas initiate descending pain inhibition via the spinal cord, which could help to explain the analgesic effects of acupunctural muscle stimulation. However, work published in 2002 by Langevin and colleagues found that acupuncture achieves its analgesic effects when loose connective tissue becomes tightly wound around the probing and twisting needle. Investigators initially hypothesized that this effect could be explained by positing that the affected connective tissue had mechanically stimulated nearby sensory nerves, somehow causing an analgesic effect. However, further experiments showed that acupuncture had dramatic effects, not on nearby sensory neurons, but on collagen fibers within the connective tissues themselves. When connective tissue from mice was stimulated by twisting acupuncture needles ex vivo, the collagen-producing fibroblasts immediately surrounding the penetration site changed shape and expanded dramatically after approximately 30 minutes. Moreover, this pattern of fibroblast changes subsequently spread out across several centimeters of tissue.

Thereafter, further research found that fibroblast expansion could be inhibited by introducing substances such as suramin, apyrase, or Rho kinase inhibitors, all of which interfere with the extracellular signaling carried out by adenosine (in the form of adenosine triphosphate [ATP]). These results, in combination with experiments showing that stretching muscle tissue results in the sustained release of ATP by fibroblasts, led to the hypothesis that when fibroblasts are mechanically stimulated, they continuously release ATP into extracellular space, which then binds to P2Y receptors on their surface, and on the surface of other nearby fibroblasts, causing them to expand and change shape. Moreover, as the ATP is broken down in extracellular space, the resulting adenosine can bind to Adenosine A1 receptors on the surface of proximate peripheral sensory neurons in adjacent tissue regions.

Regarding back pain, researchers now believe that layers of connective tissue in the back become abnormally entangled or fused with each other in response to even minor tissue injuries. This prevents the tissue layers from sliding independently of one another, which is crucial for normal motion and for activities such as stretching. Although the exact character of this fusion or entanglement of tissue layers is not fully understood, investigators have hypothesized that acute inflammation can fail to resolve, leading to chronic inflammation and fibrosis that might persist over time and reduce tissue mobility, which in turn keeps inflammation from subsiding. This may produce a vicious cycle, wherein peripheral and CNS sensitization leads to psychological strategies for keeping the effected regions immobilized, thereby further reducing tissue mobility (e.g., through lack of stretching). However, if this hypothesis is correct, it suggests several possible methods of intervening to break, and potentially reverse, this vicious cycle. Thus, continued research must adopt a multimodal approach to studying treatments for pain, which should be based upon an integrative understanding of pain pathophysiology and should investigate the full gamut of viable nonpharmacological interventions.

The Back Pain Initiative

Dr. Susana Sztein, Associate Director for Strategic Initiatives, NIAMS

Dr. Sztein explained that back pain is among the most common forms of chronic pain among adults worldwide. In the United States, 20 percent of adults report “frequent” back pain and 28 percent report having experienced low back pain that lasted 1 day or more during the past 3 months, according to data from the NHIS. Moreover, back pain is over-represented among women and in people of low socioeconomic status. Children are also affected. A recent study indicated that the prevalence of low back pain in adolescents increases with age, and reaches the levels observed in adults by age 18. Considering these facts and following up on recommendations made by an NIH Pain Consortium Research Task Force, established in 2013, NIH is considering establishing a Back Pain Consortium (BACPAC) research program to help address the FPRS priority to develop approaches incorporating the principles of precision medicine to prevent and treat chronic pain. Presently, relatively few clinical trials have focused on testing pharmaceuticals intended to treat low back pain. BACPAC would help to initiate further clinical trials to understand optimal selection of treatments, effective combinations and sequencing of treatments, effectiveness of treatments for radicular low back pain, and effectiveness on outcomes other than pain and function. Safety and efficacy data produced by these trials would allow novel therapies to enter Phase 3 trials.

BACPAC is being conceived as a patient-centric translational research initiative that will address the need for effective and personalized therapies for chronic low back pain. In pursuit of such personalized therapies, it will be crucial to extensively phenotype patients with low back pain so that abundant phenotypic information can be used to develop more targeted treatment strategies, and so that treatment response data can be mapped to phenotype data. Other general goals of BACPAC would be to (1) expand the number of therapeutic options to improve pain and function, (2) understand the mechanisms of low back pain, (3) use novel technologies to identify new druggable disease mechanisms, (4) develop precise diagnostic and treatment algorithms, and (5) test new therapies. Data generated through BACPAC’s research activities would be shared and integrated by a Data Integration, Algorithm Development, and Program Management Center, which would also conduct systems-level data analysis to produce an integrated model of low back pain. Such an approach would take advantage of cohorts and technologies developed at different institutions.

NIH-CMS Collaboration on Low Back Pain

Dr. Shari Ling, Deputy Chief Medical Officer for the Centers for Medicare & Medicaid Services

Dr. Ling reported that the Centers for Medicare & Medicaid Services (CMS) remains the largest purchaser of health care services globally. However, CMS aims to pay for value for its beneficiaries, rather than for volume. Providing maximum value presents an important challenge as the population that CMS serves is becoming increasingly varied and complex. Thus, CMS requires evidence that can help to support coverage policies that will include the heterogeneous population of beneficiaries who qualify for CMS services, whether by age, disability, or other criteria. For example, aging populations, particularly those who suffer with pain, include individuals with a wide range of physical, cognitive, and behavioral health comorbidities. Ensuring that CMS coverage policies properly serve such a heterogeneous population requires evidence based upon reliable measurements and robust outcomes. Moreover, such evidence should meet standards that allow patients and their providers to decide upon appropriate, individualized treatment plans.

Recently, NIH released a Notice of Intent to Publish a Funding Opportunity Announcement (FOA) for Pragmatic Randomized Controlled Trial of Acupuncture for Management of Chronic Low Back Pain in Older Adults. This announcement signals a prime opportunity for NIH to partner with CMS to generate policy-supporting evidence relevant to treatment of patients suffering from chronic pain. This FOA also aligns with the 2018 CMS Roadmap to Address the Opioid Epidemic, which includes three key focus areas: (1) prevention, (2) treatment, and (3) data. Because a lack of evidence for a treatment can result in a national noncoverage policy by CMS that cannot be overridden by state or local contractors (as occurred with acupuncture), it is critically important to build a robust evidence base in advance of offering CMS coverage.

Discussion

Referencing Dr. Ling’s emphasis on the need for robust evidence to cover new treatments, Dr. Kerns and Ms. Underwood inquired as to whether any formal review process investigates treatments that are currently covered by CMS, but for which existing evidence is relatively thin. Dr. Ling noted that CMS works closely with other federal partners to conduct such reviews, but that CMS does not have its own internal, formal review process to deal with such questions. Dr. Ling further stated that CMS has less authority to revoke coverage for pharmaceuticals that are already FDA approved. Dr. Clark asked whether CMS had considered delisting specific treatments or services, citing epidural injections as an example. Dr. Ling explained that such considerations can be submitted to CMS by interested parties as suggestions.

Dr. Porter asked Dr. Ling to confirm that CMS seeks public comment through monthly announcement of treatments and services that are under active consideration for coverage. Dr. Ling stated that CMS releases such announcements, but not necessarily on a fixed schedule. Dr. Porter and Dr. Ling agreed that it would be valuable to establish a practice whereby CMS could inform the IPRCC of each announcement to solicit input.

National Survey of Coverage for Low Back Pain

Dr. Caleb Alexander, Associate Professor, Johns Hopkins Bloomberg School of Public Health

Dr. Alexander explained that, with HHS support from NIH, CDC, and the Office of the Assistant Secretary for Planning and Evaluation, investigators recently conducted a survey of national-level, health care payer coverage for low back pain. The motivation for this work sprung from the recognition, contrary to popular belief, that there is no conflict between reducing opioid use and improving quality of pain care. However, improving quality of care while reducing dependence on opioids requires active participation from payers, both public and private. Thus, this survey examined 45 payer plans (15 commercial, 15 Medicaid, and 15 Medicare Advantage) using low back pain as a model and evaluating coverage policies for both pharmacological and nonpharmacological treatment modalities. All 45 plans were actively seeking ways to develop coverage policies to help address the opioid epidemic, indicating that the IPRCC has an opportunity to leverage this moment of heightened focus on pain to help payers improve coverage policies for treating chronic pain.

However, regarding coverage for pharmaceutical treatments, including opioids, most payers focused on identifying high-risk prescribers and high-risk patients, rather than on developing broader coverage policies and programs to target improved overall quality of care for chronic pain patients. Step therapy was seldom advised. Regarding nonpharmaceutical treatments, investigators found near-universal coverage for certain treatments, such as physical therapy, and highly variable coverage for other treatments, such as acupuncture, even when such treatments had a robust evidence base (e.g., cognitive behavioral therapy). Given these results, Dr. Alexander emphasized the importance of considering nonpharmacological treatments for pain across all stages of policy design, implementation, and evaluation.

In addition, the survey found that evidentiary criteria for covering nonpharmaceutical pain treatments were highly variable (e.g., the criteria for determining the number of covered visits, the length of coverage, and out-of-pocket costs). This high variability might be explained by a lack of agreement about a model policy, by disincentives for payers to implement whatever model policies exist, or both. Investigators also found it difficult to locate coverage information, suggesting that patients experience such difficulties as well. In addition, access to nonpharmacological pain treatments are likely more limited than the survey itself might suggest, because the survey did not examine such factors as provider-network density or limited access to care facilities for rural residents.

Going forward, it is crucially important that payers be proactive in developing, implementing, and evaluating pain care policies, and that they be held accountable for the rationales for, and for the ramifications of, those policies, to ensure that they reflect best practices and standards for the double aim of improving pain management and reducing the overuse of opioids.

Discussion

Regarding step therapy, which requires that patients fail to respond adequately to a less expensive or lower-risk treatment before advancing to a more expensive or riskier treatment, Dr. Alexander clarified that the survey looked specifically at whether payers had policies that blocked patients from receiving high-risk treatment regimens (e.g., slow-release, long-term opioid prescriptions) until they had first failed to respond adequately to lower-risk treatment options, including nonpharmaceutical approaches such as physical therapy. Almost invariably, the coverage plans included in the survey gave patients less expensive, low-barrier access to opioid treatments.

Pain Research Portfolio Analysis Update

Dr. Leah Pogorzala, Policy Analyst, Office of Pain Policy and Planning

Dr. Pogorzala reported that the Office of Pain Policy and Planning maintains a unique public-facing database on federal pain research supported by NIH, CDC, VA, AHRQ, FDA, and DoD. Each grant is coded using classifiers that are specific to pain research, which makes the database a very useful resource for the pain research and policy community. The database, which was integral in formulating the FPRS, currently includes 2012 to 2016 data; data from 2017 is being coded and should be publicly available by the end of 2018.

In addition, the Office of Pain Policy and Planning’s research portfolio analysis, which helps to identify critical gaps in clinical and basic research, is being updated. Grants in the portfolio are coded along three tiers: (1) Research Type (Basic, Translational, or Clinical), (2) Research Themes (e.g., Pain Mechanisms, Disparities, Risk Factors and Causes), and (3) Pain Type (e.g., musculoskeletalàneck pain, craniofacialàheadache). The most common type of grant in the 2016 portfolio, grouped by tier two codes, focused on Pain Mechanisms (34 percent), followed by Disparities (13 percent). Grants that focused on low back pain represented 6 percent of the total 2016 portfolio.

Additional HEAL Concepts Under Consideration

Pain Effectiveness Research

Dr. Jane Atkinson, Director, Trial Innovation Network, NCATS

Dr. Atkinson stated that the Pain-Effectiveness Research Network (Pain-ERN) has been proposed and is currently under review, in response to the FPRS priority to “develop a pain research network.” In part because it is difficult to recruit and retain patients for clinical trials, there is a need for further research on the effectiveness of pain treatments in broad populations. Pain-ERN would aim to (1) conduct clinical trials and studies designed to establish effective interventions or programs to manage, reduce, or prevent acute and chronic pain, (2) leverage the existing Clinical and Translational Science Awards Trial Innovation Network to implement meritorious clinical trials and studies of interest at multiple NIH Institutes, Centers, and Offices, and (3) support studies that provide evidence to inform practice-based guidelines. Pain-ERN would support both the planning and the implementation of clinical trials, which will aim to utilize standardized outcome measures and scales to quantify pain and pain modifiers to enable future meta-analyses. In addition, data would be collected and stored centrally for future data-sharing.

Pragmatic Trials

Dr. David Shurtleff, Acting Director, NCCIH

Dr. Shurtleff explained that, in response to the FPRS priority to identify “the most effective approaches to deliver evidence-based effective acute or chronic pain management programs,” Pragmatic and Implementation Studies for the Management of Pain (PRISM) has been proposed and is currently under review. PRISM would capitalize on the PMC Collaboratory by embedding studies in health care systems, with the aim to improve adherence to evidence-based guidelines for pain management within those systems and to better integrate evidence-based approaches into health care delivery. PRISM trials would help to inform health care policy makers, especially at CMS, about coverage decisions. PRISM would also leverage the PMC³ to assist project trials, improve rigor, and ensure that project milestones are achieved. In addition, although PRISM is not yet officially approved, two Notices of Intent to Publish a Funding Opportunity have been released.

Pain and BRAIN

Dr. Nick Langhals, Program Director, Bioengineering, NINDS

Dr. Langhals reported that the BRAIN Initiative aims to image brain circuitry in action to understand better how brain activity relates to physical and mental events, how the brain can be monitored and manipulated for improved function, and how disordered brain circuits cause neurological, mental, and substance use disorders. Thus far, the BRAIN Initiative has focused on seven high-priority research areas, including discovering the diversity of brain cell types, creating brain maps at multiple scales, and creating human brain research networks.

The BRAIN Initiative has recently proposed to translate novel discoveries about the brain into effective stimulation devices for pain treatment under the HEAL Initiative. This proposal would entail leveraging ongoing mapping and target discovery activities as well as expanding existing public–private partnership efforts to engage the medical device industry to explore repurposing devices for new indications. The initiative would include several new activities, including (1) optimizing next-generation diagnostic and therapeutic devices to prepare for large animal or clinical studies, (2) developing translational programs to support regulatory approval of new diagnostics and therapeutics, and (3) conducting small clinical trials of technologies that are ready for human application. Most of these activities would occur in conjunction with the SPARC Initiative. These activities will aim to develop innovative nonaddictive therapies to improve patient outcomes and decrease or eliminate the need to prescribe opioids. These efforts align with several of the FPRS priorities.

Pain and SPARC

Dr. Gene Civillico, Program Manager, Office of Strategic Coordination

Dr. Civillico described the work of SPARC to create and share anatomical and functional maps of the peripheral innervation of major organs (especially the heart, lungs, stomach, intestines, and bladder). SPARC investigators seek to understand better the neural control of organ function and to lay the scientific groundwork for the next generation of neuromodulation devices that act peripherally. These efforts are comprised of four initiatives that focus on (1) developing high-resolution anatomical maps of peripheral neural networks, (2) creating new probe and sensor technologies to conduct such mapping, (3) building partnerships to drive studies in humans, and (4) producing integrative online data hubs to synthesize and share neural map data.

SPARC recently proposed a new initiative to perform “anatomical and functional mapping of pain-related visceral organ neural circuitry.” Although already studied by some SPARC investigators, pain circuits have not yet been a specific focus of SPARC. The strategic goals of this initiative—which would support up to 10 projects in anatomical tracing and functional probing of neural pathways processing afferent information from internal organs—would be to expand SPARC research outputs of neural pathways that mediate visceral pain and to generate future targets for study of device-based pain interventions. These efforts align with the FPRS priority to better understand the “heterogeneity of the circuitry involved in pain sensation and modulation.”

Adjourn

In closing, several participants expressed optimism at the tremendous progress that has been made in pain research in recent years, and at the influx of attention and resources that this field has recently received to pursue diverse research avenues to help address the opioid crisis. Still, it remains a challenge to build the capacity within the pain research field to make maximal use of these resources. In the coming years, it will be crucial to train talented young investigators who will continue to carry the field forward and build upon the existing knowledge of pain.

Mr. Carter shared optimism regarding future possibilities for pain management but highlighted the urgent needs of pain patients across the United States who are currently experiencing pain crises yet are being denied the opioid treatments they need to cope with their suffering, in part because of the misapplication of the CDC guideline.

No public comments were submitted. The meeting was adjourned.

We certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.

Linda Porter, PhD
Designated Federal Official
Interagency Pain Research Coordinating Committee
Director, Office of Pain Policy, National Institute of Neurological Disorders and Stroke
 
Walter Koroshetz, PhD
Chair Interagency Pain Research Coordinating Committee
Director, National Institute of Neurological Disorders and Stroke
 
These minutes have been formally approved by the committee.