By: Patricia A. Grady, PhD, RN
Story Landis, PhD
Lawrence Tabak, DDS, PhD

For millions of Americans, one of the most frustrating aspects of living with chronic pain like fibromyalgia is its uncertain etiology. Most enjoyed good health in the past, which allowed them to raise children, pursue careers, and lead active lives.

Now they battle muscle pain and constant fatigue, and they don’t know why. Uncertainties about the causes of fibromyalgia leave them unsure how to manage the disorder and its related conditions. But, most importantly, it leaves them unclear about how to regain control of their lives. Story Landis, PhD, Lawrence Tabak, DDS, PhD.

Defining Pathways

The first involves basic research studies to broadly define the pathways of pain. By “pathways,” we mean the routes that sensory signals travel from the peripheral nervous system to the central nervous system for rapid processing and routing to the appropriate centers of the brain. That is where we perceive and react to pain. Currently, for a variety of technical reasons, most of the body’s sensory pathways remain uncharted. So, just as it would be impossible to navigate through the boroughs of New York knowing the names of only a dozen major streets, researchers today must stick to a few known pathways when studying pain—or risk getting lost.

But many of the needed technological tools now exist or are under development to uncover more complete pathways of pain, and the NIH is moving forward to find them more systematically. This work will, in essence, provide a more detailed map of the main sensory thoroughfares and side streets with their unique twists, turns, feedback loops, and centers for processing sensory information.

On a parallel track, scientists are working hard to better define the characteristics of chronic pain. Years of study have revealed that chronic pain is not all in our heads; it can be a disease unto itself that involves changes in brain structure, alterations in pain pathways, and aberrant production and processing of sensory signals.

Work is underway to learn more about the barrage of biochemical signals released from the peripheral nervous system upon injury, and how they affect the signal-receiving protein receptors and their mediators in the central nervous system. How do these myriad inputs that travel to the brain—if repeated frequently or vigorously—alter the learned behavior (plasticity) of the central nervous system? Does the central nervous system amplify or erroneously repeat these signals to produce chronic pain?

Many scientists are now studying the factors that influence brain plasticity. By that, we mean the ability to remove old connections and make new ones in regions of the brain that are not related to pain. Insights gained from this research should be transferred rapidly to our understanding of pain perception and how it can change in the brain.

Taken together, the outcome of this basic research is particularly important for people with fibromyalgia. Previous studies suggest that fibromyalgia is linked to a process called central sensitization, a pathological rewiring and over-amplification of pain signals in the central nervous system that appear to contribute to a lower threshold for pain. Researchers lack a complete picture of central sensitization.

Thus, they also have yet to identify a uniquely defining tissue pathology or biochemical marker associated with central sensitization and its presumed link to fibromyalgia. In medicine, such a marker is classically required for a condition to be defined as a disease. Assuming unique pathological markers are identified, the debate about whether fibromyalgia is a disease will cease once and for all. A new scientific debate will emerge about how best to target and ultimately treat the pathology, a true sign of progress.

Investigating Genetics

The second line of study involves the genetics of pain. Why do some people have a lower pain threshold than others? The scientific evidence now strongly suggests that part of the answer is written into our genes. People differ in their inherited ability to process various sensory signals. It would be extremely helpful to know which genes are involved.

Researchers also want to know which environmental factors influence these genes and thus further modify our ability to withstand pain. This line of research will feed into the larger issue of whether one’s inherited ability to process sensory signals might predispose one, when severely stressed or exposed to certain environmental factors, to develop chronic pain conditions such as fibromyalgia.

Let us offer an example. At the National Institute of Dental and Craniofacial Research

(NIDCR), scientists have turned to the temporomandibular joint (TMJ) disorders to look for genetic clues into the threshold of pain. “TMJ disorders,” also called TMD, is an umbrella term for more than 20 distinct conditions that affect the area in and around the TMJ. (These two large, ball-and-socket joints connect the jaw to the skull on both sides of the head and, although often taken for granted, the TMJ and its surrounding muscles are fundamental to our ability to speak, chew, and clench our teeth.)

As many readers also know, these conditions frequently affect people with fibromyalgia. The NIDCR is now supporting a unique clinical study that will track 3,200 healthy volunteers from three to five years to see how many develop a TMJ disorder. Participants are providing DNA samples, and the scientists are now searching for possible alterations in genes known to modulate the processing of sensory signals. Although this may sound extremely technical in nature, the study’s results likely will provide very practical new leads.

In an earlier pilot study, for example, the scientists looked for a series of shared variations, or typos, written into a gene known to encode an enzyme that inactivates certain types of nerve-signaling compounds. These genetic variations are collectively called a haplotype. The scientists determined that participants who had what they soon determined to be the low-sensitivity-to-pain haplotype were as much as 2.3 times less likely to develop a TMJ disorder. As the scientists noted, the finding makes biological sense. Those with the low-sensitivity haplotype had much higher levels of the enzymatic activity compared to the other haplotypes, and their previous animal studies show that inhibition of the enzyme produces a profound increase in pain sensitivity.

Meanwhile, scientists at the National Institute of Nursing Research (NINR) are using new genetic tools to better assess an individual’s response to pain and treatments for pain. These researchers are analyzing genetic variations among different patients to understand why individuals respond differently to analgesic treatments for chronic pain conditions, including fibromyalgia. Understanding these genetic variations could allow for the development of a diagnostic tool known as a biomarker that uses a gene chip for the rapid assessment of an individual’s genetic makeup. Using a gene chip in studies of pain will allow scientists to better characterize molecular-genetic mechanisms of pain and analgesia, suggest new targets for analgesic drugs, and test the efficacy and adverse reactions of newly developed or currently used drugs.

Understanding Comorbidities

The third line of study builds on the recognition that many people suffer from more than one chronic pain condition at a time. For instance, people with a TMJ condition also often battle coexisting chronic illnesses that contribute to and often mimic some of the symptoms of their jaw disorder. These other painful conditions, called comorbidities, include fibromyalgia, chronic fatigue syndrome, multiple chemical sensitivity, irritable bowel syndrome, migraine headache, atypical facial pain, and visceral pain.

Further complicating the research, scientists know little about the underlying biological and sociological mechanisms that link the symptoms of these associated conditions with a TMJ disorder. Once these mechanisms are delineated, scientists will have a clearer view of the pathology of these conditions, an understanding that is essential in learning to design targeted and more effective treatments for people with a TMJ disorder or, of course, fibromyalgia.

Another way to tap into these mechanisms of pain is through the emerging field of systems biology. Systems biology studies a cell, a tissue, or an organism as an integrated unit and information-processing system. It is the difference between an in-depth analysis of an individual tooth wheel extracted from a Swiss watch, and the simultaneous evaluation of all 130 components of the watch. By studying the cell as a whole, scientists can gain a more comprehensive and realistic picture of how it works or breaks down under stress or disease. This line of research will go far in explaining the mechanisms underlying chronic pain, including those for fibromyalgia.

The NIH Pain Consortium has a long and productive history, but never have the research opportunities looked more promising in the field. As the underlying biology of pain is more clearly defined now and in the years ahead, new leads will emerge with broad applicability to the estimated 34 million adults in America who suffer from some form of chronic pain, including those with fibromyalgia.

At the National Institutes of Health, research is ongoing to explore the pathology and causes of chronic pain conditions. There are three areas of study in particular that will be helpful in drilling down to find the causes of fibromyalgia. As co-chairs of the NIH Pain Consortium, a group of NIH institutes that work together to enhance pain research and promote collaboration, we would like to briefly lay them out for you.

Dr. Patricia A. Grady was appointed Director of the National Institute of Nursing Research (NINR) in April 1995. She received a master’s degree from the University of Maryland’s School of Nursing and a doctorate in physiology from its School of Medicine.

Dr. Story Landis has been Director of the National Institute of Neurological Disorders and Stroke (NINDS) since September 2003. She received her undergraduate degree in biology from Wellesley College and her master’s degree and PhD from Harvard University.

Dr. Lawrence Tabak was appointed Director of the National Institute of Dental and Craniofacial Research (NIDCR) in September 2000. He earned his DDS from Columbia University and a PhD from the State College of New York at Buffalo.