Chronic pain is “a hidden epidemic,” according to guest speaker William Maixner, DDS, PhD, of the University of North Carolina-Chapel Hill, as he opened the inaugural symposium of the University of Maryland, Baltimore (UMB) Center to Advance Chronic Pain Research (CACPR) on Dec. 14.
The meeting in the University of Maryland BioPark showcased talks by two leading chronic pain researchers: Jeffrey Mogil, PhD, professor and Canada Research Chair in Genetics of Pain and E.P. Taylor Chair in Pain Studies at McGill University in Montreal, Quebec; and Maixner, the Mary Lily Flagler Bingham Distinguished Professor and director of the Regional Center for Neurosensory Disorders at the School of Dentistry of the University of North Carolina-Chapel Hill. Claire Fraser, PhD, professor at the University of Maryland School of Medicine and director of its Institute for Genome Sciences, spoke on her research on the human microbiome.
The CACPR is co-directed by distinguished pain scientists Susan Dorsey, PhD, RN, FAAN, associate professor and chair of the Department of Pain and Translational Symptom Science at the University of Maryland School of Nursing, and Joel Greenspan, PhD, professor and chair of the Department of Neural and Pain Sciences at the University of Maryland School of Dentistry.
CACPR was founded as a Universitywide organized research center to unite the robust research projects UMB scientists are conducting to examine chronic pain, across the University’s schools. Chronic pain affects at least 100 million American adults and costs as much as $560 billion to $635 billion annually in lost productivity and costs in America, according to the Institute of Medicine’s landmark 2011 report “Relieving Pain in America.”
At the symposium, Maixner discussed his research into temporomandibular joint disorders (TMD) as an example of chronic pain. The key to the future of chronic pain diagnosis and treatment, he said, is to enable clinicians to tailor treatments specifically to their patients’ needs.
“Personalized pain medicine is the holy grail,” he said. “We find it is a very difficult task, but we are moving in that direction.”
Chronic pain is an extremely dynamic condition that varies in each patient, and scientists should expect that diagnostic and therapeutic tools will have to vary as well, Maixner explained.
“The kaleidoscope of signs and symptoms change as a consequence of gene and environmental interaction,” he said.
Patients’ genes interact with environmental factors such as their life history, past trauma, and exposure to chemicals in a relationship that makes chronic pain patients unique from each other.
Maixner discussed his research, conducted with colleagues at UMB, that is identifying innovative ways to identify chronic pain patients and sort them into predictive groups by degree of severity. One of his important findings is that a patient’s sensitivity to pressure pain seems to correlate with the onset of TMD in many patients. He and his colleagues also have identified a number of genes that could help determine what type of illness a patient has and what treatments might work best.
Finding new genetic or environmental measures that could help identify patients early and predict the onset and severity of their condition paves the way for treatments uniquely designed for each type of patient, he noted. “I think we’re really on the verge,” he said.
Mogil spoke about the sex-based difference in pain and pain research. He discussed the fundamental question of the sexes in pain treatment and research – which gender is more sensitive to pain? Research has found that women report more pain than men, but there might be other reasons for that – maybe women are more aware of their own bodies, or develop pain conditions at higher rates. “This debate is misguided,” Mogil said.
The true issue in studying pain and the genders is the extreme prevalence of male animals and humans in pain research, Mogil explained. Seventy-nine percent of basic science studies in pain use male rodents, according to a 2005 paper Mogil and colleagues published in the journal Pain.
“I think this is a scandal,” Mogil said. “It is an ethical problem of very high degree.”
Scientists still persist in using male mice, even since the 2005 study, Mogil said. Most researchers explain “they are afraid if they switch over to female rodents their research will be bedeviled by … fluctuating gonadal hormone levels,” Mogil explained.
In fact, Mogil’s Pain study found that there is more hormonal fluctuation in male mice than in female. The explanation is that male mice have hormonal changes as they fight for dominance in the laboratory cages.
“What everyone is afraid of is empirically false,” he said. The failure to switch to both genders of mice “is a matter of pure inertia, and that, of course, is what’s unethical,” Mogil explained.
The implications of using only one gender of animal model in pain research are alarming, he said. Research that Mogil and colleagues published in 2004 found that a drug combining morphine and dextromethorphan in pain control – a drug that had shown promise in male-only studies – was completely ineffective in female mice.
Another of Mogil’s studies found that both humans and mice are more sensitive to pain in the laboratory setting if their experimenter is male. This sex-based difference seems to be a response to the chemical signals that indicate the presence of testosterone in both humans and mice. Further study has found that human women, but not men, are stressed by the compound, 3-methyl-2-hexenoic acid, that indicate testosterone in sweat.
These differences between the genders indicate that many other significant difference may exist, still undiscovered, Mogil said. This potential highlights the need for research on both genders, not just one. “One of these days we will be able to find drugs that work in one sex and not the other,” he said.
Fraser explained the basics of the study of the human microbiome, the microbes that live on and in the human body, interacting with the human genome to produce results that science doesn’t entirely understand. About 90 percent of the cells that human beings carry are microbial cells – just 10 percent are human. Ninety-nine percent of those microbial cells exist in the gastrointestinal tract, the area that Fraser studies.
Fraser was part of the 2006 meetings at the National Institutes of Health (NIH) that established the Human Microbiome Project, a multimillion-dollar, five-year NIH initiative that began in 2008 and involved many researchers from the Institute for Genome Sciences. The project formed the foundation for the current understanding of the complicated, intricate relationship between human genes and the microbes in our bodies.
“We and our microbial partners represent a co-evolved ecosystem that exists for the benefit of both of us,” she said. Microbes perform critical roles such as aiding in digestion, fueling metabolism, producing vitamins, maintaining the immune system, defending against pathogens, and influencing behavior. Fraser and her colleagues have been examining probiotics and their potential to make changes in the gut microbiome, and what those changes would mean for overall health. The field of research has potential in many areas of medicine, including chronic pain, she said.
“This field is still very much in its infancy,” Fraser explained. The days of examining only the host genome – that of the human body – are over. Now science must consider environmental factors and the microbiome as well. “It is important to take a more holistic view of human health,” she said.