IPRCC Meeting - 10/31/2016

Introduction:

The October 31, 2016 meeting of the Interagency Pain Research Coordinating Committee (IPRCC) was convened at 8:30 a.m. in Building 31, Porter Neuroscience Center, 6th Floor, C Wing, on the National Institutes of Health (NIH) campus.  In accordance with Public Law 92-463, the meeting was open to the public. Walter Koroshetz, MD, Director, National Institute of Neurological Disorders and Stroke (NINDS), presided as chair.

In attendance were the following members of the IPRCC:

Federal Members: Walter Koroshetz, MD; Chester Buckenmaier, MD (for Maj. Gen. Paul Cordts, MD); Charles G. Helmick, III, MD; Sharon Hertz, MD; Audrey Kusiak, PhD; Richard Ricciardi, PhD, CRNP; Martha J. Somerman, DDS, PhD; David Thomas, PhD (ad hoc for Nora Volkow, MD, PhD)

Scientific Members: Allan Basbaum, PhD, FRS; Rami Burstein, PhD; Ricardo Cruciani, MD; William Maixner, DDS, PhD; Judith Paice, PhD, RN, FAAN

Public Members: Penney Cowan; Christina Spellman, PhD; Cindy Steinberg; Catherine Underwood, MBA:  Michael Pasternak, PhD

Ex-Officio Members: Josephine P. Briggs, MD; Patricia A. Grady, RN, PhD, FAAN

Designated Federal Official: Linda L. Porter, PhD

Ad hoc IPRCC Members: Daniel B. Carr, MD; Jan Chambers; and Roger B. Fillingim, PhD

Welcome and Call to Order:

Walter Koroshetz, MD, Director, NINDS and Chair, IPRCC

After welcoming remarks, Dr. Koroshetz introduced three incoming members who are waiting for final approval to serve: Jan Chambers, Daniel B. Carr, and Roger B. Fillingim. Incoming members have initially joined as ad hoc, non-voting members, pending final approval. Dr. Koroshetz informed participants that the nomination slate for the new 2017 IPRCC members is now open. There currently are openings for three public and three scientific/clinical members. He encouraged participants to consider submitting a nomination packet for suitable individuals.

Dr. Koroshetz said that nominee Cathy Glaser has declined to serve in the IPRCC. He added that because of delays in slate approvals at the Secretary’s office, some slots have not yet been filled. As a result, some members' terms were extended to cover open slots. He thanked Allan Basbaum, Bill Maixner, and Penney Cowan for agreeing to remain on the Committee to accommodate the extended transition period.

He said the National Pain Strategy (NPS) was released in March and an implementation plan was approved by the Assistant Secretary for Health, Karen DeSalvo. Today's meeting will include updates on progress to date on the implementation plan and some early steps taken by federal agencies and external stakeholders to address some of the objectives of the National Pain Strategy. There also will be updates on the Federal Pain Research Strategy and presentations on pain relevant initiatives of the Patient Centered Outcomes Research Institute and the Precision Medicine Initiative.

Dr. Koroshetz highlighted three recent advances made by federally supported research projects:

1. A study by Osteen, et al.[1] (Nature, June 2016), investigated the use of selective spider toxins and their role in mechanical pain in mice. Local anesthetics can block pain through all Na_v channels, but it can be difficult to find ways to block individual channel subtypes, such as Na_v1.1. Toxin injection into the paw revealed that Na_v1.1-expressing fibers are modality-specific nociceptors. In other words, when activated they elicit pain behavior without inflammation as well as profound hypersensitivity to mechanical stimuli (but not thermal stimuli). This is an unexpected role for Na_v1.1 channels in regulating sensory nerve fibers that mediate mechanical pain. In addition, the toxin affected channels mediate increased mechanosensitivity in an animal model of irritable bowel syndrome.
2. Morphine is used to treat pain, but one of its potential effects – fatal respiratory depression – is thought to be mediated by μOR signaling through the β-arrestin pathway. In contrast, G-protein μOR signaling is thought to confer analgesia. Using a computer model, Manglik et al. [2] (Nature, August 2016), screened over 3 million compounds for potential analgesic effect. This yielded a small subset of compounds with the desired profiles and allowed the team to synthesize the strongest G protein and weakest beta-arrestin activator. PZM21’s novel chemical structure performed as they had hypothesized in mice, with promising analgesic efficacy and low side effect potential. This structure-based design enabled the researchers to speed up the development of a potential analgesic that demonstrates optimal signaling and therapeutic properties. 
3. Forebrain limbic circuits are thought to be important for the nervous system representation of pain. The medial shell of the nucleus accumbens (NAc) is a key node in this circuitry. Studies suggest that this convergence in the NAc is important in both acute and chronic pain states. Ren et al. [3] (Nature Neuroscience, February 2016), examined adaptations in NAc neurons in mouse and rat peripheral nerve injury models of neuropathic pain. They found that peripheral nerve injury creates a cell-specific increase in msNAc spiny projection neurons (iSPN) excitability that worsens tactile allodynia. This allodynia was reversed by inhibiting and exacerbated by exciting iSPNs, showing that they both participated in the central representation of pain and gated activity in ascending nociceptive pathways. Researchers also tested L-DOPA in pain reduction. The effects of L-DOPA in reducing the pain suggest a new therapeutic for neuropathic pain.

 

Approval of the Minutes of the December 3rd, 2015 IPRCC Meeting

Linda Porter, PhD, Director, NINDS Office of Pain Policy

The IPRCC considered and approved the December 3rd, 2015 IPRCC meeting minutes with one minor correction.

 

THE NATIONAL PAIN STRATEGY

Implementation of the National Pain Strategy

Thomas Novotny, MD, MPH, Deputy Assistant Secretary, HHS

Dr. Novotny, Deputy Assistant Secretary for Health explained that the National Pain Strategy is the government’s first broad-ranging effort to improve how pain is perceived, assessed, and treated: a significant step toward the ideal state of pain care.  It was approved and released by the Office of the Assistant Secretary in March 2016. The coordination of implementation of the plan will be led by the Office of the Assistant Secretary for Health with assistance from the Office of Pain Policy at NIH.

The organizational and operational and structure for the NPS’ implementation is established.  It is based on the Behavioral Health Coordinating Council, an effective structure for broad and large-scale initiatives.   A principal Coordinating Council will include leads of agencies who missions support the NPS.  The council will  provide a forum for implementation work group (IWG) updates, provide policy direction and evaluate and set current and future priorities for implementation efforts. The Council also will direct the resources needed to implement the strategy and promote coordination across federal agencies and departments. They will meet twice each year.

An Implementation Steering Committee (ISC) with representatives from various agencies and departments (AHRQ, ASFR, ASPE, CDC, CMS, DoD, FDA, NIH, OASH, ODPHP, OS, SAMSHA) held its first meeting on September 2016. The Steering Committee will oversee, guide, and monitor the process, efforts, and progress of the IWGs and report to the Council. It will hold biannual outreach meetings to facilitate stakeholder engagement/collaboration and to ensure dissemination of information on NPS progress.

Implementation Work Groups will address assigned deliverables of the NPS and coordinate the monitoring and evaluation of the deliverables. Dr. Novotny informed the group that members are being sought for the IWGs.

To date, the ISC has developed an inventory of ongoing and planned efforts that address certain deliverables of the National Pain Strategy and related efforts that can be leveraged to support implementation of the objectives. The inventory will be posted on the IPRCC website when this process is completed.  Another means to provide update on progress will be through biannual meetings with key external stakeholders to report on and receive feedback on implementation of the NPS deliverables and to identify and facilitate collaborative opportunities. 

The steering committee is in the process of selecting staff leads with relevant expertise to lead the activities of the work groups, as well as all the federal members to populate the work groups. These selections are based on the recommendations of key federal stakeholders listed in the NPS report.  The steering committee also is collecting a list of external stakeholders, non-voting members, who will provide guidance, support, and resources as appropriate to implementation. The committee will call on for advice, external stakeholders who share an interest in promoting and implementing the objectives of the NPS.

Proposed Timeline Milestones

• Short Term
  • Convene Council
  • IWGs develop plan for short term deliverables
  • Implementation and completion of for short term deliverables
  • Evaluate short-term deliverables
• Medium Term
  • Develop plan for medium-term deliverables
  • Implementation and completion of for medium-term deliverables
  • Evaluate medium-term deliverables
• Long Term
  • Develop plan for long-term deliverables
  • Implementation and completion of long-term deliverables
  • Evaluate long-term deliverables

Discussion Points

• Ms. Steinberg asked if members of the pain community could be included in the work groups. Dr. Novotny said the work group voting members must be federal staff, but external stakeholder input is important.
• Alicia Richmond-Scott, OASH, explained the federal work groups will reach out to stakeholders, who will not serve as formal members, but who will be engaged and asked for input. There will be biannual stakeholder meetings with updates on NPS and open discussion and feedback. Notice of the meeting will be through social media, the website and other resources.
• Dr. Maixner asked whether resources available for the opioid epidemic might be directedto improved pain management in a manner that is balanced. Dr. Novotny acknowledged the imbalance and recognized the need for resources to support the NPS.Dr. Helmick asked about the best way to keep up on HHS efforts surrounding opioids Dr. Novotny replied that the Surgeon General, who is doing an opioid tour, has been briefed on the importance and objectives of the National Pain Strategy and will provide information on the NPS while on tour.
• Dr. Carr asked if there was a central location where all federal efforts will be catalogued that could help inform and guide some of the state’s efforts so that states don't "reinvent the wheel." Dr. Novotny replied that some of the information will be posted on the IPRCC website. He said it might also be a good idea to involve the Surgeon General  Regional Directors to initiate a data call to collect information on what is being done at the State level.
• Ms. Underwood asked if the key stakeholders listed in the NPS are those that would be part of the implementation work groups.Dr. Porter said that the NPS key stakeholder list is being used to guide the composition of the work groups.

 

Progress on NPS deliverables

Linda Porter, PhD, Director, NINDS Office of Pain Policy

Dr. Porter's presentation focused on progress and steps taken to address the National Pain Strategy objectives. A recent study by Von Korff, et. al [4] (Journal of Pain, October 2016), validated an assessment tool developed by the NPS population research work group.  The tool was designed to assess high-impact chronic pain, pain that interferes with a person’s activities and affects their function.  The study used electronic health records and a mail-in survey to collect data.  The study indicated that the assessment tool would be appropriated for large scale studies.  It’s use generated data showing that 14 percent of the individuals surveyed had high-impact chronic pain. Compared with persons with lower-impact pain, they were more frequent users of health care services for pain, had higher costs of health care, and lower quality of life. They were typically treated in primary care.

Dr. Porter explained that a new developmental objective on chronic pain has been added to Healthy People 2020: Decrease the prevalence of adults having high-impact chronic pain. She said that pain-related questions were added to the 2016-2017 National Health Interview Survey. These questions are based on the Von Korff pilot study and intended to help gain more population level data on high-impact chronic pain. Efforts also are underway to include additional chronic pain objectives in Healthy People 2030.

The Centers of Excellence in Pain Education, an NIH Pain Consortium supported initiative, are developing case-based pain care teaching modules that cover a variety of pain conditions. These educational resources will be posted for free public access through the NIH Pain Consortium website as they become available. An example is the case study titled "Edna" which features an adult with apparent chronic low back pain. It has been evaluated for effectiveness as a teaching tool among medical students. A case studies on burning mouth syndrome and phantom limb pain are also under development.

Dr. Porter informed participants of the recent release of the  HHS Opioid Research Portfolio Brief – Translating Science into Action. The document summarizes the portfolio of research on pain,  safer opioids, opioid alternatives, and opioid use disorder, funded or conducted by HHS. It also includes specific research objectives put forward by the Office of the Secretary for Health. She also informed participants that a page in the IPRCC website has been dedicated to the NPS implementation. This page includes information on the structure discussed today to implement the NPS and provides updates on NPS deliverables. 

Discussion Points

• Dr. Basbaum asked who is the target audience for the case-based patient presentations. Dr. Thomas said the target audience is medical, dental, pharmacy, and nursing students, but that they are useful to a broader range of health care providers.
• Ms. Steinberg asked if data were in from the pain questions added to the National Health Interview surveys that could be analyzed. Dr. Helmick, CDC, said that data are usually available 6 months after the end of the calendar year. As a result, 2016 data will be available by June 2017. He added that the analysis of prevalence estimates of high impact chronic pain will be straight forward. There are many other pain related factors in the NHIS that can be co-analyzed to explore pain at the population level though they add complexity to the queries and their integration will take more time.
• Ms. Steinberg asked how to get a CDC Vital Signs report done on the survey data obtained. Dr. Helmick said this might happen in the future once more data are obtained.  Vital signs that include both pain and opioids may be of greater interest to the CDC.  
• Ms. Chambers asked if dropping pain as the "fifth vital sign" would change the collection of pain-relevant data needed for population level information, especially with respect to electronic health records. Dr. Helmick said the surveys currently being used are not considering pain as a fifth vital sign, but rather ask more generally about pain. It is unclear therefore, that dropping pan as a fifth vital sign would affect this data set.

Treatment Coverage for Acute and Chronic Low Back Pain: A Pilot Study

Christopher Jones, PharmD, MPH, Director, Division of Science Policy, Office of the Assistant Secretary for Planning and Evaluation

Dr. Jones presented the results of a recent pilot study to determine public and private insurer’s treatment coverage for low back pain. He explained that little is known about current coverage parameters for many types of pain treatments. Having such information can help to frame and target policy interventions among public and private payers that are necessary to promote the use of non-opioid alternatives to treat acute and chronic pain.

Coverage was examined across three large systems Medi-Cal, Anthem, and CVS Caremark (large state Medicaid plan, a large private insurer, and a large pharmacy benefit manager, respectively). A list of 64 medications were examined, including opioids, NSAIDs, antidepressants, and anticonvulsants. In addition, coverage offered by these plans for non-pharmacological treatments, such as physical therapy, cognitive behavioral therapy, yoga, injections, and chiropractic care were examined.

Results showed variability across plans in treatments covered and parameters of those treatments. For example,  Medi-Cal and CVS Caremark covered only 30 percent of the opioids in the list, while Anthem covered nearly 85 percent. For non-opioid medications, 43 percent were covered by Medi-Cal, 80 percent by Anthem, and 67 percent by CVS Caremark. Medi-Cal did not require prior authorization for opioids while CVS Caremark required prior authorization for 50 percent of the opioids on their list.

Variations also were seen across non-pharmacological interventions in the three systems. Some evidence based treatments for low back pain were not covered by all plans.   Dr. Jones explained that certain policies for non-pharmacological therapies, such as determinations of medical necessity, could be barriers to using these treatments.

Limitations of the study included its small sample size and lack of generalizability to other plans and other pain conditions. This pilot study will help develop methodology that can be scaled in future national-scale research, helping to drive policy for low pain care coverage.

Discussion Points

• Dr. Briggs asked if CBT was a paid option. Dr. Jones said it was not covered in two of the plans examined.
• Dr. Koroshetz asked if either Anthem or Medi-Cal had a database where one could obtain information on utilization (e.g. frequency of prescription). Dr. Jones said this information would be based on how things were billed and claimed. Dr. Jones suggested a potential collaboration among insurers to examine this on a plan-by-plan basis. CMS data could also be analyzed.
• Dr. Maixner said that reaching out directly to patients or enrollees may reveal barriers they face with respect to reimbursement and copayments. He also asked if future studies would go beyond lower back pain. Dr. Jones agreed it would be a good idea to understand if this could be applicable more broadly. He also agreed it would be informative to speak with patients, but there are federal limitations on how many people researchers can talk to.
• Dr. Basbaum asked if the results would be different if a different state Medicaid program was chosen. Dr. Jones said the results likely would be different. He said that a national level sampling strategy may provide a better overview.
• Dr. Burstein asked how plans make decisions to determine what is covered. Dr. Jones said they would like to do additional key informant interviews in a follow-up study to determine the evidence thresholds as well as impacts of rebates and chargebacks.
• Ms. Steinberg asked if the data would be published. Dr. Jones said that the data haven't yet been published, but that it likely will be done in 2017.
• Dr. Cruciani asked if medications were broken down into formulary tiers 1, 2, and 3. Dr. Jones said that Medi-Cal does not have tiers (however, CVS does have tiers). He explained that the majority of opioids are in tier 1 but researchers could not distinguish specific differences between some tiers.This would be something that could be examined further in future efforts.

 

AHRQ Systematic Review on Non-Pharmacological Pain Management

Richard Ricciardi, PhD, CRNP, Director, Division of Practice Improvement, AHRQ

Dr. Ricciardi provided a brief overview of AHRQ and its systematic review process of the evidence base related to public health issues. He discussed the systematic review for non-pharmacological treatments for  pain that is currently underway. He explained that AHRQ's mission is to produce evidence to make health care safer, higher quality, more accessible, equitable, and affordable, and to work within HHS and with other partners to make sure that the evidence is understood and used.

The systematic review of evidence for non-pharmacological pain management is being done in conjunction with CDC and ASPE. The study addresses the benefits and harms of noninvasive, non-pharmacological therapies in adults with chronic pain which was defined as pain lasting greater than 12 weeks or past normal tissue healing time. The review included review of studies on five chronic pain conditions: low back pain, neck pain, osteoarthritis, fibromyalgia, and tension type headache.

The evidence base for interventions examined in the review include psychological therapies, multidisciplinary rehabilitation, exercise, physical modalities, manual therapy, massage, mindfulness meditation, yoga, tai chi, Qigong, and acupuncture as compared against sham treatments, usual care, no treatment, exercise, and opioid analgesics.

Dr. Ricciardi informed the group that the study's key questions will be posted online for comment on December 2016. A draft of the report will be posted by September 2017 and the final draft on December 2017. He also informed participants that a technical brief will be soon published on Medication-Assisted Treatment Models of Care for Opioid Use Disorder.

Discussion Points

• Dr. Maixner asked why TMJ was missing in the study. He added that it’s one of the most prevalent musculoskeletal conditions and is often not covered and asked about the possibility of adding it to the study. Dr. Ricciardi said that it might be challenging to change the targeted conditions at this time, as agreements already made with the CDC and ASPE and the process is underway.
• Dr. Carr noted that a 2014 AHRQ review of opioid efficacy introduced a threshold for inclusion that stated studies of one year or less would be of "inadequate duration." He said that the clear majority of drug therapies are usually no longer than 100 days. He asked if this threshold would continue to be used. Dr. Ricciardi suggested emailing the program lead directly for specifics regarding the inclusion and exclusion criteria of studies for review

 

The American Pain Society’s Funding Announcement for the NPS Objectives

Catherine Underwood, MBA, CEO, American Pain Society

Ms. Underwood discussed the collaboration between the American Pain Society and Pfizer's Independent Grants for Learning and Change to Improve Chronic Pain Care. Ms. Underwood informed participants that while Pfizer provides funds for the grants, it does not have influence over any aspect of the initiative and only asks for reports about the results and impact of the initiative, which may be shared publicly.

In September 2015, the APS appointed a panel to author the Request for proposals (RFP) and serve as the grant review group for the applications submitted in response. A letter of agreement was signed between APS and Pfizer in December 2015. In 2016, proposals were sought through the RFP that translate scientific knowledge into clinically useful approaches that improve the care of individuals with chronic pain, and achieve that goal while addressing one or more objectives of the National Pain Strategy.

The RFP opened in March.  Nearly 100 letters of intent were received and reviewed by panel members. APS then invited 15 applicants to submit full proposals, which are currently under review. Funding recommendations will be made on November 9. The goal is to have signed letters of agreement before the end of the year. In terms of funding requests, proposals ranged from $250,000 to $750,000 each.

Next steps include convening a meeting for successful grantees to coordinate efforts. The outcomes will be presented at the 2018 or 2019 APS Annual Scientific Meeting. The findings will also be published in a peer-reviewed journal, such as The Journal of Pain.

Discussion Points

• A participant asked about the type of research proposed. Ms. Underwood said some are on population-based research, while others are more technical in terms of studies of effectiveness outcomes. They are “all over the map.”

THE FEDERAL PAIN RESEARCH STRATEGY

Processes and Progress of the FPRS Work Groups

Allan Basbaum, PhD, University of California, San Francisco

Dr. Bausbaum's presentation focused on the organizational structure for the Federal Pain Research Strategy, an effort to develop a long-term strategy to enhance the federal pain research portfolio. The IPRCC established a Steering Committee (SC) to charge, inform, advise, and monitor five thematic work groups and to integrate and prioritize their research recommendations. The NINDS Office of Pain Policy provides the needed resources, logistics, and technical support for the work groups to review the current portfolio, determine the research gaps and recommend research opportunities to advance the science. The work groups then will inform the Steering Committee which will, in turn, inform the IPRCC of their prioritized research recommendations.

Five work groups were created based on the continuum of pain and charged with their tasks:

• 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 in Pain and Pain Care

The co-chairs made recommendations for membership in their groups which were then reviewed and approved by the SC. The work groups have met and developed their priorities. Recommendations then will be submitted to the IPRCC.

 

Disparities Work Group Priorities

Roger Fillingim, PhD, University of Florida

Cheryl Stucky, PhD, Medical College of Wisconsin

Dr. Fillingim explained that five subgroups were created to address primary disparity issues in specific populations:

Aging/Older Adults, Race/Ethnicity, Sex/Gender, Pediatrics, and, Socioeconomic Status.

These five subgroups held individual meetings and then reported to the entire work group. Based on these discussions, the work group developed nine priorities. These priorities are cross-cutting through the entire disparities domain. The priorities are to:

• Better define the epidemiology of pain – prevalence, incidence, impact, risk factors – in different populations.
• Conduct research to determine optimal methods to assess and treat pain in different population groups.
• Investigate biological, psychological, and social mechanisms underlying the development and persistence of pain in different population groups across the lifespan.
• Identify specific developmental periods and life stages that confer differential risk for and/or protection against specific pain conditions and determine mechanisms underlying these developmental/lifespan influences.
• Characterize within-group variability in the experience of pain in different population groups.
• Evaluate the impact and long-term consequences of pharmacological and psychosocial interventions across the lifespan, specifically on the developing nervous systems.
• Analyze the influence of the sensory and affective dimensions of pain on the pain experience and their functional outcomes in different population groups.
• Elucidate sex-specific pain mechanisms and their implications for optimal treatment through preclinical and clinical research.
• Increase the understanding of the relationship between socioeconomic status (SES) and pain and the underlying biopsychosocial mechanisms.

Discussion Points

• Dr. Fillingim said that SES could influence pain is by impacting access to care, availability to care, and insurance coverage. Even when coverage is equal, access to care may not be equal.
• Dr. Basbaum said the co-chairs of the groups will be discussing any overlaps in terms of the priorities suggested by all the work groups.
• Dr. Koroshetz noted that in the past, groups propose their top three priorities, as this tends to be helpful to funders.
• Dr. Basbaum said that the groups will decide how to address cross-cutting issues. For example, should "Sex Differences" be one of the priorities or simply be added to the preamble of the document as a cross-cutting theme?
• Dr.Volkow suggested presenting the priorities in a matrix format. That way cross-cutting priorities can be preserved.

 

Prevention Work Group Priorities

Robert Gatchel, PhD, University of Texas Arlington

Dr. Gatchel explained that the work group used the definition of chronic pain developed by the NIH Chronic Low Back Pain Task Force, which is "a pain problem that has persisted at least 3 months and has resulted in pain on at least half the days in the past 6 months." The work group's approach is to define conditions with a high prevalence of acute and chronic pain and delineate research gaps.

The work group created five subgroups: Primary Prevention or (prevention of onset of pain); Secondary Prevention (preventing recurrent pain)  and Tertiary Prevention (reducing the severity, impact, and disability caused by chronic pain); and Cross-Cutting Mediators/Moderators. Each of these subgroups made specific recommendations.

• Primary Prevention
  • Public health education to modify attitudes and expectations regarding various aspects of pain
  • Primary prevention in the different environments where injuries and related pain may occur
  • Preventive efforts to reduce severity and impact of anticipated situations when pain cannot be completely eliminated
  • Better self-management techniques are needed
  • Primary prevention of common pain syndromes
  • Predicting who is at risk for addiction/medication overuse
• Preventing Recurrent Pain
  • Early interventions for post-trauma and surgery to facilitate recovery and reduce negative impact
  • Avoiding ER visits to manage pain
  • Specialized clinical areas
  • Transition from acute to chronic pain
• Reducing the Severity, Impact, and Disability Caused by Chronic Pain
  • Define tertiary prevention, including the goal of improving function and decreasing disability
  • Identifying risk factors, including validity/utility of specific risk-assessment items and instruments
  • Effectiveness of early interventions for tertiary prevention
  • Optimal therapies for tertiary prevention
• Cross-Cutting Mediators/Moderators
  • Predisposing/Protective Variables (Moderators)
  • Precipitating Factors (Etiological)
  • Perpetuating/Protective/Alleviating Variables (Mediators)

Discussion Points

• Dr. Cruciani asked if the figure presented of “80 percent of patients getting better” also applied to the elderly population. Dr. Gatchel said that among the aging population, low back pain is the most prevalent type of disability. Unfortunately, there have been no studies looking specifically at an elderly population.
• Dr. Carr said that there was an effort convened by the American Pain Society and the American Academy of Pain Medicine to update a taxonomy for acute pain. This could be helpful for the work groups. He also noted that when thinking about mediators one should also consider the biological phenotyping of the inflammatory response in the subject. Dr. Gatchel agreed and added that one should also consider immunosuppression, as this can impact the healing process.
• Dr. Maixner said that one should consider a more significant role for environmental exposures. He stated that the pain field currently has little in the way of validating instruments to collect information related to exposures (injury, stressors, etc.) that could help determine the transitional states of pain in susceptible individuals. One should consider developing these instruments.

 

Acute Pain Work Group Priorities

Christine Miaskowski, RN, PhD, FAAN, University of California, San Francisco

Dr. Miaskowski explained that the group identified research gaps in acute pain mechanisms, measurement, and management. It also conducted an online survey of anesthesiologists and nurses to assess gaps in measurement and management of acute pain. The work group also held subgroup meetings which then reported to the work group as a whole. Based on these discussions they developed following priorities to address research gaps:

• Acute Pain Mechanisms
  • What are the molecular mechanisms of heterogeneity in acute pain?
  • What are the cellular mechanisms of heterogeneity in acute pain?
• Acute Pain Measurement
  • Identify preclinical acute pain models that best represent naturally occurring pains conditions.
  • Identify optimal acute pain assessment parameters and biopsychosocial predictors of acute pain so as to optimize individualized pain management.

• Acute Pain Management
  • Identify strategies to provide optimal individualized acute pain management.
  • Develop strategies to deliver evidenced-based acute pain management with/across various health care systems.

Discussion Points

• Dr. Miaskowski asked for the group's thoughts on biomarkers for profiling patients related to acute pain. Dr. Basbaum replied that during previous discussions a member of the Steering Committee was disappointed that a GWAS study was not being proposed for either acute or chronic pain. He added that this is a plausible way to find a biomarker.
• Dr. Carr said that in CRPS the are some instances that suggest an aberrant neuro-immune interaction. One should consider adding immune or other biomarkers while continuing to pay attention to neuro-markers.
• Dr. Maixner said that the term "biomarker" can be a catch all term for many dimensions that we think are etiological pathways for pain conditions. A better way to think about this is to consider molecular profiles while also considering biopsychosocial measures to stratify the population into subgroups. This could help point to new targets and potentially help identify more precision or tailored treatments to a patient substrata in a given condition. Also, the use of phenotypes to produce strata could help inform the molecular profile of those strata.
• Dr. Buckenmaier also suggested looking at gut biomes in addition to biomarkers.

 

Transition Work Group Priorities

Ted Price, PhD, University of Texas at Dallas

Dr. Price explained that transition from acute or no pain can arise from different mechanisms, all resulting in a comparable chronic pain state. However, it is not clear whether the transition process is reversible. The work group members developed three main themes: Plasticity and Resolution, Lifespan, and Risk Protection and Resilience. Listed below are the research priorities discussed under each theme.

• Plasticity and Resolution

(Basic Research with Long-Term Impact)

• Develop tools for human molecular neuroscience.
• Use samples from well phenotyped patients to test preclinically defined mechanisms that may be applicable to humans.
• Optimize use of stem cells: e.g., sensory neurons in a dish – examples from channelopathy genotypes.
• Use clinically meaningful endpoints in animal models to enhance translation of preclinical findings.
• Develop and/or utilize new technologies to assess brain-wide connectivity changes in animal models that can parallel human imaging work but add molecular insight to develop novel, non-opioid analgesics.

• Lifespan

(Basic and Clinical Research)

• Determine how early life experience can influence long-lasting pain. Are acute pain mechanisms different at birth than later in life?
• Identify protective mechanisms and critical periods that underlie resilience and risk.
• Study hormonal/neuroendocrine levels across the lifespan and determine how these influence transition.
• Create large datasets across the lifespan to identify people who transition to chronic pain and distinguish them from people who do not.
• Study mechanisms of transition and differences in analgesic efficacy in the elderly.
• Risk Protection and Resilience

(Basic and Clinical Research with Relatively Shorter-Term Impact)

• Determine the susceptibility for transition to chronic pain. Identify protective factors (including psychosocial factors) in clinical populations and integrate with other risk factors.
• Develop mechanistic clinical trials to target risk and/or resilience and turn this into more than just a correlation.
• Determine whether some acute pain management strategies promote transition.

Discussion Points

• Ms. Steinberg asked if considering a "tipping point" in pain would be appropriate. For example, multiple pain assaults over time that can tip the individual into chronic pain. Dr. Price said this was one of the hypotheses discussed surrounding the first theme.
• Dr. Carr suggested caution in applying the term "opioid induced hyperalgesia" to a hyperalgesia which follows the infusion of a high-potency opioid, because when the high-potency opioid is removed one is measuring a subject that is withdrawing rather than a subject that meets the criteria for hyperalgesia.
• Ms. Chambers explained that the thinking behind the development of that priority was not about aggressively treating pain (or withholding treatment) which would cause the body to perform differently.
• Dr. Maixner asked if there have been any discussions about the need for outbred strains (wild rat/mice studies) where one could obtain a population-based assessment and where one could look at heterogeneity within a strain (but across a species). Dr. Price said he would take this point back to the group for further thought.
• Dr. Briggs said that in her Center’s portfolio they have studies of experimental laboratory pain in humans. She wondered if this would be the right model for acute pain as it is experienced in clinical settings, as well as transitional studies.
• Dr. Price said it might be important to have a biomarker of the target one is going after, rather than a biomarker of pain, since there could be pro-resolution mechanisms that can act independently of the mechanisms that created the pain in the first place.
• Dr. Hertz said that perhaps the answer from a pharmacological perspective is not as simple as a single entity agent but perhaps a finely tuned combination of targets that will maximize the many different systems involved as targets without having to activate any one of them. In other words, be more of a modulatory product so that it's tolerable as well as effective.

 

Chronic Pain Work Group Priorities

Seddon Savage, MD, Geisel School of Medicine Dartmouth College

Dr. Savage said the chronic pain group started out by creating a grid representing important areas in the field of chronic pain. They then identified members that either had research or clinical expertise in those defined areas. Each group member was asked to do some preliminary work prior to the work group meeting. They were asked to sketch out clinical needs and gaps in their area, identify key research findings and clinical observations in the past two decades, identify current areas of robust research, and think about new and emerging questions.

This information was used to develop emerging themes and research priorities. The priorities were then matched with a specific work group leader so they could be defined in-depth. The following priorities emerged from the discussions:

• • Determine the mechanisms that sustain, modulate, and/or resolve chronic pain.
  • Determine the relationship among common chronic pain co-morbidities, such as BMI, fatigue along with sleep, emotional, psychological, and cognitive.
  • Distinguish mechanisms of and most effective treatments for childhood chronic pain.
• • Fill gaps in our knowledge base about how to safely and effectively treat – and ideally cure – chronic pain.
  • Determine the benefits, risks, and costs of chronic pain treatments to inform regulatory approval, reimbursement, and clinical decisions.
  • Identify precision medicine approaches that improve chronic pain treatment and reduce risks.
  • Determine the optimal parameters of self-management strategies for chronic pain.
• Research Approaches
  • Provide a comprehensive evaluation of the chronic pain experience: identify domains, outcome measures, and biomarkers (as well as their utility) in both animal and human studies.
  • Develop large national data sets and/or prospective registries of chronic pain populations across the lifespan to inform pain research and clinical care.

Discussion and Questions

• Dr. Carr suggested making an explicit reference to socioeconomic status or social determinants of health. It might be helpful to reproduce the WHO diagram of social determinants of disease.
• Dr. Somerman said there are various overlaps in the priorities proposed by the work groups. She suggested that perhaps one or two people could sit in other work groups to make sure we are synergizing instead of duplicating efforts.
• Dr. Porter said they have begun co-chair to co-chair conversations to address overlaps. All the co-chairs will soon get together to look at the big picture and work out redundancies.
• Dr. Koroshetz said he was surprised to learn that the 14 percent of the people who had disabling chronic pain also had significant comorbidities. He urged that one should not forget that this group is suffering from chronic pain even though they may have other comorbidities.
• Dr. Basbaum said that isn’t a major pain foundation that funds pain research in a comparable manner. The only resource are therefore government agencies and, to a smaller extent, pharmaceutical companies.
• Dr. Cruciani asked about the increasing suicidality of chronic pain patients and how this could be prioritized to determine the correlation between suicidality and how chronic pain is treated.
• Dr. Savage said this would be a good idea. Perhaps one should add opioid associated distress.
• Dr. Burstein noted that animal models cannot predict which drugs will work in the clinic, because we cannot create the complexity of pain in an animal model. Perhaps the group should look into how to define an appropriate model for pain research.
• Dr. Carr said that hundreds of testimonies were gathered in the IOM process and one of the key themes was “stigma.” He suggested contextualizing this topic. It could help build bridges to patients and patient advocates since they have to live with stigma.

 

Next Steps for FPRS

Linda Porter, PhD, Director, NINDS Office of Pain Policy

Dr. Porter summarized the next steps for the Federal Pain Research Strategy:

• Co-chairs of all work groups will resolve overlap.
• The groups will present their priorities in a consistent manner through a template approved by the steering committee.
• The groups will prioritize recommendations across all work groups.
• The groups will determine cross-cutting topics that could be discussed in the preamble.
• They will decide whether some of the lower priorities should be included as an appendix.
• The SC and IPRCC will review the final document prior to releasing it to the agencies for funding considerations.

 

Patient Centered Outcomes Research Institute and Pain Research

Penny Mohr, MA, Senior Program Officer, PCORI

Ms. Mohr presented an overview of the Patient-Centered Outcomes Research Institute (PCORI) and some of the pain research projects it is currently undertaking. PCORI is a nonprofit, nongovernmental organization created as part of the Affordable Care Act. It is funded through a trust-fund totaling approximately $650 million.

PCORI was funded to study comparative clinical effectiveness of two or more strategies that have limited efficacy information or are in widespread use. The aim is for research to impact the development of guidelines and health policy with the ultimate goal to improve patient centered outcomes. PCORI research topics are chosen through a broad stakeholder process.

As of October 2016, PCORI has a portfolio of 45 projects totaling $135.8 million for the study of non-cancer pain management or opioid use. PCORI funds projects through three major funding streams:

• Broad Funding
  • Investigator initiated
  • Funding for up to $2-5 million over 3-5 years
  • Covers five broad national priorities
• Pragmatic Clinical Studies Funding
  • Funding for up to $10 million over 3-5 years
  • Covers approx. 25 PCORI high-priority topics
  • A topic can be chosen or proposed
• Targeted Funding
  • Funding for up to $22 million
  • Covers one topic which may have multiple research questions
  • Topic is chosen by PCORI

PCORI isn’t a governmental agency, but works closely with government agencies. Its goal is to fund research projects that complement – rather than duplicate – ongoing and planned federal pain research.

 

The All of Us Research Program: The Future of Medicine Begins with You

Joni Rutter, PhD, Director of Programs and Strategic Implementation, NIH

Dr. Rutter provided an overview of the All of Us Research Program which was unveiled on October 13, 2016. “All of Us” will engage one million or more volunteers living in the US to contribute their health data over many years. Accumulated data will provide opportunities for researchers to access one of the world's largest biomedical databases to accelerate breakthroughs, improve health outcomes, and fuel the development of new treatments for disease.

All of Us is not a study on any one disease. It is a data resource to inform many research studies on a wide variety of health conditions. The program reflects the country's rich diversity to produce meaningful health outcomes for historically underrepresented communities Diversity will be approached from four broad perspectives; people, geography, health Status, and data types.

The program will include a data repository, biobank (with 35 million samples by the end of the program), participant technologies center (participant portal, smartphone access), and enrollment centers (regional medical centers, community health centers, and VA medical centers).

A total of $70 million is invested and the program currently is preparing for launch. Six modules have been reviewed for participants to provide information: sleep, overall health, personal habits, socio-demographics, and health care access and utilization. Other modules are under development, including modules about pain and substance abuse.

Discussion Points

• A participant asked about the age range for recruiting patients. Dr. Rutter said that in the first phase of the launch they are recruiting patients 18 and older.
• Dr. Burstein asked how a participant’s personal health information is protected. All individuals who submit clinical data have to be HIPAA compliant. Dr. Rutter replied that the data in the database are under a FedRAMP and a FISMA level of security. In addition, every entity is covered by a Certificate of Confidentiality.
• Dr. Briggs explained that a data enclave creates the ability to track the misuse of data. If data are misused or hacked, there are enforcement mechanisms to find out how it happened.
• Dr. Rutter said that data are held on a "raw data lake" which includes PHI. All those data are then transitioned into a curated de-identified data set that is available to researchers.

Adjourn

Following no public comments, 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.

 

___________________________________________________________________________________

Endnotes

[1] Osteen JD, et al. Selective Spider Toxins Reveal a Role for the Nav1.1 Channel in Mechanical Pain. Nature. 2016 June 6;534(7608):494-9.

[2] Manglik A, et al. Structure-Based Discovery of Opioid Analgesics with Reduced Side Effects. Nature. 2016 August 17;537(7619):185-190. 

[3] Ren W, et al. The Indirect Pathway of the Nucleus Accumbens Shell Amplifies Neuropathic Pain. Nature Neuroscience. 2016 February;19(2):220-2.

[4] Von Korff, et al. United States National Pain Strategy for Population Research: Concepts, Definitions, and Pilot Data. Journal of Pain. 2016 October;17(10): 1068–80.