A Workshop on Chronic Overlapping Pain Conditions

Meeting Summary

The National Institute of Dental and Craniofacial Research and the National Institute of Neurological Disorders and Stroke, together with the NIH Pain Consortium sponsored a workshop on Chronic Overlapping Pain Conditions. The workshop was held Monday and Tuesday, August 13 and 14, 2012 in the Natcher Conference Center, on the NIH Campus in Bethesda, Maryland. The workshop was co-chaired by Daniel Clauw from the University of Michigan and Elizabeth Unger from the Centers for Disease Control and Prevention. The goal of the workshop was to develop a coordinated research strategy addressing 1) underlying etiology; 2) trajectory of disease; 3) risk factors for onset, progression and reversal; and 4) approaches for developing outcome measures and diagnosis of chronic overlapping pain conditions. These overlapping chronic pain conditions include conditions such as fibromyalgia, irritable bowel syndrome and other functional gastrointestinal disorders, interstitial cystitis/bladder pain syndrome, temporomandibular joint disorder, chronic fatigue syndrome, vulvodynia, tension headache, myofascial pain syndrome, Gulf War illness, and multiple chemical sensitivity.

Chronic overlapping pain conditions represent a complex set of painful disorders that occur frequently in the population, lack a firm mechanistic understanding, and are in need of hypothesis-driven research efforts. This workshop brought together researchers with expertise in various pain conditions and other relevant expertise to discuss these conditions and to develop a forward-thinking research agenda. The workshop focused on our current understanding of chronic overlapping pain conditions, their etiology, risk factors, mechanisms of disease, outcome measures, and diagnosis. It was a two day meeting divided into three sessions with short presentations by panelists and extensive discussion periods. The first session provided an overview and epidemiology of chronic overlapping pain conditions. The second session focused on risk factors and mechanisms of disease. The third session centered on patient outcomes, leveraging of current data sets, and new scientific approaches incorporating systems biology. On the last day, four breakout groups met separately to discuss knowledge needed, research opportunities, and training  needs in four topic areas including patient classification, common and specific mechanisms of disease, risk factors for disease trajectory, and diagnostics and outcomes measures that will advance our understanding of these conditions. In the final session, all panelists then discussed the individual recommendations and summarized them in a final set of recommendations for the research community.

Recommendations from the Chronic Overlapping Pain Conditions Workshop

The research recommendations resulting from this workshop detailed below derived from discussions in the four topic area breakout groups. At the conclusion of the individual group presentations, a general summary session was held and six critical needs areas were underscored in the ensuing discussion.

They included:

• leveraging of existing resources and data repositories
• coordination of preclinical and clinical research
• conducting longitudinal studies
• studying central sensitization as a theme for discovery of common mechanisms of disease, diagnostics, and treatment
• developing a case definition of chronic overlapping conditions
• developing multidisciplinary research training programs in these disorders for researchers and health care providers, incorporating approaches to address health disparities in pain

In addition, there was discussion regarding the perceived need for specific peer review panels for pain grant applications containing appropriate scientific expertise. Discussions centered on applicants utilizing a common language and referencing generally agreed upon principles and practices in their applications that reviewers understand as acceptable standards in the pain field. Also, it was felt that members of the NIH Pain Consortium might be able to play a role in guiding any internal dialog regarding this issue.

Approaches to standardize patient classification:

• Need for validation of clinical measures and use of disease specific tools and measures, in light of a lack of diagnostic criteria for some of these conditions, measures must be practical for the patient population, and universally implemented
• Need for relevant animal models in order to translate research findings into patient classification and treatment groups
• Identification, validation, and collection of biomarkers
• Optimize use of existing national studies in order to identify predictors of disease and examine Gene x Environment interactions
• Need for studies of common and specific disease mechanisms for classification (engage both lumpers and splitters)
• New knowledge needed in basic disease mechanisms with use of new animal models for translational research
• Demonstration of the clinical applicability of tools developed for research purposes and a need for bi-directional flow of information, i.e. translational and reverse translational research
• Add chronic overlapping pain conditions to the case-based scenarios in the Centers of Excellence in Pain Education (CoEPEs) program

Common mechanisms of disease:

• Emphasize the importance of assuring the same understanding of terminology among basic and clinical scientists in order to advance translational and reverse translational research
• Bring together key basic and clinical researchers in order to advance translational research in this area, i.e. develop multidisciplinary translational research projects
• Leverage the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) program and the Multidisciplinary Approach to the Study of Pelvic Pain Research Network (MAPP) program analytical tools and resources, through addition of new research sites studying appropriate additional disorders and incorporation of small investigator teams into this leveraging process
• Use of Clinical and Translational Science Award sites (CTSAs) for translational issues and training infrastructure
• Investigate use and leveraging of the NIH Blueprint NITRC program, (Neuroimaging Informatics Tools and Resources Clearinghouse)
• Explore mechanisms of central sensitization and identification of the role of peripheral and central nervous system contributions over time to hypersensitivity
• Explore the role of the immune system, the role of the microbiota, and the interactions of the immune system and microbiota; the role of neuroendocrine systems including the HPA axis and the sympathetic/parasympathetic systems.

Risk factors for trajectory of disease:

• Define predictors for onset, progression, exacerbation, recurrence, remission, and treatment outcomes of disease through population studies
• Define a broad array of risk factors for discovery purposes and a narrower, deeper array for therapy development
• Identify early childhood exposures (but difficult to measure), measures of somatic awareness, dietary, hormonal, and gender risk factors; use a lifespan approach
• Build on existing funded studies, and also importantly, establish new studies including cohort studies, utilize clinical studies in order to identify people with disease and population studies to identify broader disease risks, consider developing family and twin studies, or a large birth cohort study
• Develop a minimum set of clinically relevant data for incorporation/use in health plans and electronic medical records so that data important for patient care is collected and becomes useful in longitudinal studies and thus helping to drive the research agenda
• Explore and emulate how the cancer and cardiovascular fields have developed research networks for data collection; partner with Veterans Administration and HMOs, (potential for availability of ~13 million medical records)

Development of research diagnostics and outcomes measures:

• Increase reliance on mechanistic approaches; while there is a large amount of data on individual disorders, the identification of common elements of disease among the overlapping conditions is missing
• Identify details of responder/non-responders with regard to therapeutic treatment in order to identify subpopulations
• Improve the definition of the natural history of disease, i.e. identifying when a disorder appears/disappears with or without onset of other shared diseases
• Develop a better understanding of shared mechanisms of disease, especially with regard to pain modulatory circuits and responses to treatment

General recommendations:

• Initiate pragmatic therapeutic trials designed to include emerging populations and cultural sensitivity
• Provide research training opportunities in both the NIH Extramural and Intramural research programs
• Develop health care provider training for these conditions to ensure rapid and accurate translation of clinical findings into practice
• Develop a central repository/data base for biomarkers/specimens
• Use public private partnerships and provide guidance to big pharma as to its contributions in this area
• Increase NIH Pain Consortium leadership in coordinating and developing a research agenda for chronic overlapping pain conditions

Proposed workshops:

• Meeting on developing new human clinical and preclinical animal trials for overlapping chronic pain conditions
• Meeting of MAPP and OPPERA users to summarize findings to date and propose collaborative efforts going forward
• Workshop to establish a common vocabulary for overlapping chronic pain

Support for this workshop was provided by the following Institutes and Offices: National Institute of Dental and Craniofacial Research, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health & Human Development, and Office of Research on Women’s Health.

---

Agenda

A Workshop on Chronic Overlapping Pain Conditions
August 13-14, 2012

Natcher Conference Center, Building 45
National Institutes of Health
Bethesda, Maryland

Day One
Monday, August 13, 2012

---

8:30 am                        Introductions and Welcome
                                    John Kusiak, Program Officer, NIDCR
                                    Story Landis, Director, NINDS
                                    Martha Somerman, Director, NIDCR
                                    NIH Pain Policy Advisor
                                    Workshop Co-chairs:  Dan Clauw, Univ. of Michigan and Beth Unger, CDC

Guidance to the Workshop Members

Session 1: Overview and Epidemiology of Chronic Overlapping Pain Conditions

9:00 -9:30 am                 Overview of the meeting and chronic overlapping pain conditions
                                       Dan Clauw, Univ. of Michigan

9:30 – 9:40 am              Discussion

9:40 – 10:00 am             Epidemiology of vulvodynia and overlapping conditions
                                      Barbara Reed, Univ. of Michigan

10:00 – 10:10 am           Discussion

10:10 – 10:30 am           Epidemiologic approaches to pain progression:  Lessons from migraine
                                      Richard Lipton, Albert Einstein College of Medicine

10:30 – 10:40 am           Discussion

10:40 – 11:00 am           Coffee Break

11:00 – 11:20 am           Overlapping pain conditions: Disparities and special populations
                                      Carmen Green, Univ. of Michigan

11:20 – 11:30 am            Discussion

11:30 – 11:50am             The presence of multiple functional somatic syndromes may be a marker for a
                                      common pathogenesis
                                      John Warren, Univ. of Maryland Medical School

11:50 – 12:00pm            Discussion

12:00 – 12:30pm            General Discussion

12:30 – 1:30 pm           Lunch (on your own)

Session 2: Risk Factors and Mechanisms of Disease

1:30 – 1:50 pm          Phenotypes/genotypes in common and specific to chronic overlapping pain conditions
                                 Bill Maixner, Univ. of North Carolina

1:50 – 2:00 pm          Discussion

2:00 – 2:20 pm           Understanding chronic overlapping pain conditions: Lessons learned from twin studies
                                 Niloofar Afari, Univ. of California San Diego

2:20 – 2:30 pm           Discussion

2:30 – 2:50 pm           Role of quantitative sensory testing in determining mechanisms of
                                  overlapping conditions
                                 Eli Eliav, Univ. of Medicine and Dentistry of New Jersey

2:50 – 3:00 pm          Discussion

3:00 – 3:20 pm          What has the CDC’s ME/CFS program taught us about overlapping conditions?
                                Beth Unger, CDC

3:20 – 3:30 pm          Discussion

3:30 – 4:00 pm          General Discussion

4:00 – 4:15 pm          Break

4:15 pm                    Patient/Advocate Forum:
                                 Terrie Cowley, The TMJ Association
                                 Kim McCleary, The CFIDS Association of America
                                 William Norton, International Foundation for Functional Gastrointestinal Disorders
                                 Christin Veasley, National Vulvodynia Association

4:45 pm                    Summary and Adjourn for the day

Day Two

Tuesday, August 14, 2012

---

Session 3: Current and Future Research Issues

8:30 – 8:50 am          Patient reported outcomes: Which are most critical? Are new ones needed?
                                 David Williams, Univ. of Michigan

8:50 – 9:00 am          Discussion

9:00 – 9:20 am          What can we learn from the study of other complex disorders using a systems biology
                                 approach (cardiovascular and autonomic nervous systems)?
                                 Daniel Beard, Medical College of Wisconsin

9:20 – 9:30 am           Discussion

9:30 – 9:50 am           Large scale pain neuroimaging using the PAIN.LONI repository
                                 Bruce Naliboff, Univ. of California Los Angeles

9:50 – 10:00 am         Discussion

10:00 – 10:30 am       General Discussion

10:30 – 10:45             Coffee Break

Session 4: Breakout Groups

10:45 am                   Guidance to the Breakout Groups
                                 Co-chairs:  Dan Clauw and Beth Unger

10:50 – 12:00 pm   Breakout Groups Meet

        Room  D:  Approaches to standardize patient classification

        Room  B: Common mechanisms of disease

        Room C1: Risk factors for trajectory of disease

        Room C2: Development of research diagnostics and outcomes measures

        Topics to be discussed by each group:

                Identify challenges/opportunities to advancing each area

                Identify new knowledge needed to go forward with each area

                How to develop a consensus approach

                What is feasible in 5 years/10 years?

                How to advance training and workforce growth in each area

12:00 – 1:00 pm          Lunch

1:00 -2:00 pm             Individual Reports from Breakout Groups

2:00 – 3:30 pm           Develop a consensus set of research recommendations addressing the 5 discussion topics

3:30 pm                      Wrap-up and Closing Comments
                                  John Kusiak, NIDCR
                                  Story Landis, NINDS
                                  Martha Somerman, NIDCR
                                  NIH Pain Policy Advisor

---

Panelists: