Thursday, February 23, 2012

TMJ Association Scientific Symposium: The Puzzle of Comorbid Chronic Pain | Pain Research Forum

At a recent scientific symposium sponsored by the Temporomandibular Joint Association (TMJA), researchers and patient advocates outlined an agenda for a dramatic change in how a sett of common and often co-occurring chronic pain conditions are classified and treated. Conferees laid out the latest science, and then went beyond that to envision a new, large-scale, longitudinal study of comorbid chronic pain conditions (CCPC). The design of the proposed study takes after two ongoing pain projects and signals an emerging acceptance among researchers that multidisciplinary, multicenter, comprehensive approaches are needed to solve the puzzle of chronic pain.

The TMJA is a nonprofit advocacy group with a mission to improve the lives of people affected by disorders of the jaw, which often involve severe and disabling facial pain. People with temporomandibular joint disorders (TMJDs) also suffer at higher rates from other pain conditions, including chronicfatigue syndrome, chronic headache/migraine, endometriosis, fibromyalgia, irritable bowel syndrome, interstitial cystitis, and vulvodynia. These conditions, which are sometimes also called functional pain syndromes, constitute CCPC.

The goal of the meeting, which took place 5-7 June 2011 in Bethesda, Maryland, was to identify gaps in knowledge and research into CCPC. Why are people with one functional pain condition at greater risk for others? Do the conditions have a common underlying cause, and/or shared risk factors? Are there common genetic factors at play? Are some CCPC the same disease, just called by different names?

To attack these questions, the organizers assembled a cross-section of the research world, gathering basic neurobiologists, imaging experts, clinical researchers, and even biomedical engineers for sessions aimed at defining new research directions. The participants faced chasms in the understanding of CCPC, starting with inconsistent case definitions, a lack of epidemiological data, and little understanding of biological markers or mechanisms. In response, the working groups laid out an ambitious wish list of studies that would redraw the boundaries of CCPC, transcending the current state of symptom- and organ-based definitions in favor of a classification grounded in an understanding of detailed phenotypes and biology.

A Problem of Definitions

The challenge for researchers is clear: Functional pain syndromes have, for the most part, unknown etiology and no apparent pathophysiology. The conditions often have no clear pain generator (e.g., no evidence of nerve damage or entrapment as in neuropathic pain, or obvious nociceptive input as in inflammatory pain). They do seem to be augmented by central nervous system processing (central sensitivity), and people with these conditions are more likely to be female, and to have a family history of chronic pain and a personal history of centrally mediated symptoms such as fatigue, insomnia, and sleep disturbances. Patients also tend to display catastrophizing, diffuse hyperalgesia, attenuated descending analgesia, and changes in functional neuroimaging measures.

Complications pile on when researchers try to look at the co-occurrence of several different pain conditions. Reviewing existing studies of CCPC, epidemiologist Gary Macfarlane, University of Aberdeen, U.K., found few high-quality studies looking at overlap of these conditions. A big problem is case definitions, and Macfarlane highlighted a striking commonality of symptoms across different conditions. Patients with fibromyalgia, for example, often meet the criteria for irritable bowel syndrome, chronic fatigue syndrome, or TMJD.

On top of that, the risk factors associated with each of these conditions are often the same, Macfarlane said, "so that it is not clear whether the diseases co-occur because of a shared pathophysiology or whether by virtue of shared risk factors, one person has simultaneous susceptibility to different diseases."

The CCPC Study

The lack of basic data on CCPC led the group to strongly recommend a large-scale, longitudinal, population-based study as the best way to gather the kind of data that would both yield mechanistic insights and inform clinical management. As described by discussion leader Emeran Mayer, University of California, Los Angeles, the ideal study would be a multicenter, international effort, and involve several thousand patients. Entry to the study would be based on current symptom criteria of the five to seven most common syndromes, but once in the study, all subjects would undergo a uniform and extensive characterization of symptoms and testing of sensory, psychological, and brain function.

In initial studies, investigators would look at easily achieved, high-throughput phenotypic measures: various types of "omics," brain imaging, and genotyping. After that, Mayer said, the old case definitions would go out the window. The investigators pool all the data and make an agnostic analysis, looking for new ways to classify diseases and patient groups.

Such a study should give definitive answers as to whether comorbid chronic pain is an entity distinguishable from neuropathic or inflammatory pain, and whether there are subgroups of patients that can be defined biologically. Based on the results of the first phase, the study could then progress to a second phase where researchers would carry out more specialized studies. In the end, the project would create a repository of data available to all researchers.

The goal, said William Maixner, University of North Carolina, Chapel Hill, is to "create a whole new diagnostic criterion for these patients, a paradigm shift in how they would be evaluated and diagnosed, not by specialty or site, but by a broader case definition." In a few years, maybe we'll have CCPC1, CCPC2, and CCPC3, he suggested. "The goal is to totally break down the way we put patients into categories."

As Mayer put it, "The most important point is that we should admit that concepts we have about these disorders are based on flawed hypotheses. To understand CCPC, we have to enhance our observation, collect the data, and then reclassify patients based on approaches available today."

Pioneering Efforts

There are precedents for such a study, and representatives of two such projects were present at the meeting. Maixner is the lead investigator on the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study, an ongoing, multisite, longitudinal program involving 3,200 subjects at risk for TMJ disorders and 200 patients with chronic pain. With support from the National Institute of Dental and Craniofacial Research, National Institutes of Health, the subjects have been deeply phenotyped with quantitative measures of sensory function, autonomic function, and psychological factors.

The study is now in its sixth year, and three quarters of the subjects are still in the study, Maixner reported. So far, 258 enrollees have developed TMJD or other facial pain. That has allowed the investigators to analyze predictors of case status, which the data reveal include pressure pain threshold, mood/stress/coping measures, sleep disturbance, level of somatic awareness, and autonomic dysfunction. The initial findings are now under review as a series of articles that should appear in print in the next few months, Maixner said.

OPPERA has an active genetic research component, looking for common polymorphisms that underlie the risk factors for complex and persistent pain conditions. The researchers were originally funded to examine polymorphisms in 20 candidate genes, and have now looked at 350 additional genes involved in nociceptor transmission, inflammation, mood, and affect. Now, Maixner reports, they will completely sequence 500 target genes, and hope with future support to do genomewide studies. (For a look at some of the OPPERA data, view slides from a March 2011 symposium sponsored by the International Research Diagnostic Criteria-Temporomandibular Disorders Consortium of the International Association for Dental Research.)

A newer large-scale study is the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network, which was described by Mayer. The project brings together researchers studying interstitial cystitis, painful bladder syndrome, chronic prostatitis, and chronic pelvic pain syndrome in a multisite, interdisciplinary effort. Recognizing that traditional bladder- or prostate-specific research and translational efforts have been unsuccessful, in 2007 the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the U.S. National Institutes of Health (NIH) decided to take a whole-body approach and committed U.S. $37.5 million to fund the project at six main sites. After the funding was committed, Mayer said, the NIDDK told investigators that there would be no checks written until the group devised, together, a common project covering five key areas: epidemiology, phenotyping, biomarkers, organ crosstalk, and neuroimaging.

The NIDDK wanted one unified effort to recruit study subjects, and the group came up with the current scheme, which revolves around an extensive epidemiological study with standardized deep phenotyping of 360 chronic pelvic pain (CPP) patients, pulled from all the discovery sites. Subject characterization includes urologic symptoms as well as personality measures, comorbid symptoms, and pain pressure threshold measures, along with collection of blood, urine, and DNA. The data and biological samples would feed into work including biomarker discovery, imaging, and mechanistic studies. In addition to CPP patients, the study also incorporates healthy controls and so-called positive controls—patients with conditions that commonly occur along with CPP, namely, fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome.

The neuroimaging arm of MAPP, which Mayer leads, is enrolling 130 CPP patients, 80 healthy controls, and 80 positive controls at five sites, measuring grey and white matter and capturing resting-state functional magnetic resonance imaging (fMRI) images. The work will take advantage of the Laboratory of Neuro Imaging (LONI) at the University of California, Los Angeles, which has been a leader in other large multicenter imaging studies, including the Alzheimer's Disease Neuroimaging Initiative and the Parkinson's Progression Markers Initiative. Data that are collected at the study sites are transmitted to LONI, where the data enter the analysis pipeline and also become publicly available.

MAPP is now in its second year of five years of funding. Mayer said that an interim analysis of imaging data is planned for this summer. (For more information on MAPP, see the project website.)

Means of Support?

Because of these precedents, researchers interested in the constellation of CCPC need not start from scratch, but should be able to take elements from OPPERA and MAPP to design a new study in a relatively short time, said Maixner.

Is such a study possible, financially speaking? With funding for pain research scarce, talk turned toward how to support such an ambitious agenda. John Kusiak, director of the Molecular and Cellular Neuroscience Program at the National Institute of Dental and Craniofacial Research of the NIH, offered that this might actually be an opportune time to push for a new initiative. The NIH received a mandate in the health care legislation of 2010 to boost pain research, and leadership at the NIH is thinking about areas "that fit very nicely" with studies like that proposed, Kusiak said. It remains to be seen, however, whether and how the vision of an integrated approach to CCPC can become a reality.