One of the most stubborn and debilitating pain syndromes will come under intense and unprecedented scrutiny over the next seven years as researchers at the University of North Carolina at Chapel Hill fulfill a new $19 million cooperative agreement with the National Institute of Dental and Craniofacial Research. Collaborating in the effort will be scientists at the universities of Florida, Maryland and Buffalo-SUNY and Batelle Memorial Institute in Durham, N.C.
The federal support, a form of grant, is one of the largest in the university's history.
UNC leaders of the effort also will establish a new center on the Chapel Hill campus aimed at learning more about what causes temporomandibular joint disorder (TMJD) and eventually how treatments can be improved and pain either eliminated or eased. Each year, the illness incurs well over $1 billion in health-care costs in this country.
"Our initial purpose is to identify the biological, psychological and genetic risk factors that contribute to pain and dysfunction associated with TMJD," said Dr. William Maixner, professor and director of the new Center for Neurosensory Disorders at the UNC School of Dentistry. "This is an extremely common disorder that afflicts millions of people worldwide and ranks second only to headache in producing craniofacial pain and dysfunction in the U.S. population. One of our primary goals with this research and center is to identify new ways of improving therapies for TMJD and related conditions."
Maixner and Dr. David Savitz, professor and chair of epidemiology at the UNC School of Public Health, are co-program directors for the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study.
"Whereas health problems such as heart disease and cancer have been the focus of many epidemiologic studies and for which there are many experts, other common, under-studied health conditions such as TMJD have almost no history of this kind of research," Savitz said. "We were engaged to help ensure that the epidemiologic study design is the best that it can be and will be effective in advancing our understanding of the causes of this common but poorly understood disorder."
Complementing the various types of expertise represented by the interdisciplinary team of investigators will be a goal of the epidemiologists' involvement, Savitz said.
The research will involve investigative units directed by Drs. Roger Fillingim at the University of Florida; Richard Orbach at the University of Buffalo-SUNY; and Joel Greenspan and Ronald Dubner at the University of Maryland in Baltimore.
Other participating researchers and units are the biogenetics and statistical genetics core led by Drs. Bruce Weir at N.C. State University and Luda Diatchenko at UNC and the data management core directed by Dr. Charlie Knott of Battelle Memorial Institute. Senior scientists and staff at the National Institute on Alcohol Abuse and Alcoholism and National Institute of Dental and Craniofacial Research led by Drs. David Goldman, Mitchell Max and Inna Belfer will be involved, as will researchers at the University of Adelaide, South Australia, led by Dr. Gary Slade, formerly at UNC.
Some 3,200 men and women will be evaluated over five years in the project, which is the nation's first large multi-center prospective study on pain, Maixner said. Researchers expect that several hundred volunteers will develop TMJD during that time. Those patients will be further evaluated genetically, medically and psychologically to identify factors contributing to their pain and dysfunction.
Based on their individual characteristics, the subjects will be further classified into subgroups for which improved treatments can be developed and targeted. UNC scientists already are evaluating the possibility of using a class of drugs called beta blockers to help some TMJD sufferers.
"In a previous, smaller study, which was designed to determine the relationship between pain sensitivity and the risk of developing TMJD, we found that humans have a tremendous range in pain sensitivity," Maixner said.
"Some people are very resistant to pain, and it's almost like they have taken a clinical dose of morphine," he said. "We also found that people who are less sensitive to painful stimuli are protected from developing TMJD. These variations in pain sensitivity are stable over time, suggesting a genetic predisposition. If this is the case, one's sensitivity to pain and likelihood of developing a chronic pain condition is probably mediated by a complex interaction between genes and environmental exposures or events."
Already, the UNC team has identified a genetic variation that controls pain sensitivity in some way and contributes to the risk of developing TMJD. They recently showed that genetic variations in an enzyme known as COMT, which controls levels of epinephrine and other biological chemicals released in response to stress, explain significant variations in pain sensitivity and the risk of TMJD.
Diatchenko, associate professor in UNC's Center for Neurosensory Disorders, led those experiments.
"We identified three genetic variants of COMT that are highly prevalent in the human population," she said. "We also used molecular biological, cell culture and animal behavior experiments to show a relationship between variations in the gene that makes COMT, COMT enzyme activity and pain sensitivity. This was the first demonstration that a genetic variation influences both human pain perception and the risk for developing a chronic pain condition."
"By analyzing slight differences in the gene that produces the COMT enzyme, we can predict the risk of developing TMJD, which impacts more than 10 percent of the U.S. population," said Slade, the former UNC clinical epidemiologist.
The researchers believe those discoveries, along with new ones resulting from the more intense investigations to come, should apply to fibromyalgia syndrome, irritable bowel syndrome, chronic fatigue syndrome and several other chronic sensory disorders that are also characterized by enhanced pain sensitivity and are frequently seen in patients with TMJD.
"Currently, medications, muscle relaxation, physical therapy, biobehavioral intervention such as stress management techniques and orthotic devices for the mouth are used to treat TMJD," Maixner said. "They help some patients, but they clearly don't work with everybody. We firmly believe that this study will significantly improve our understanding of the risk determinants for this condition and related disorders. In so doing, we hope to make substantial and rapid progress in developing new diagnostic procedures and treatment strategies for our patients."
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