Why are people who have one chronic pain condition like fibromyalgia or irritable bowel syndrome at a higher risk for other kinds of chronic pain? Why is chronic pain so often associated with depression, sleep disorders, and cognitive impairments? How should these overlapping conditions be studied and treated? Those were the questions that occupied twelve speakers and approximately 100 attendees at a symposium on advances in pain research, held April 14 at the National Institutes of Health in Bethesda, Maryland.
The one-day meeting is organized and sponsored yearly by the NIH Pain Consortium, a multi-institute initiative established in 1996 to coordinate pain research across the NIH. The Consortium was formed in recognition of the fact that no institute at the NIH is devoted solely to pain research. For its sixth annual research meeting, the Consortium chose the topic of comorbid pain conditions.
What follows is a synopsis of a few selected talks. If this piques your interest, you can view a videocast of the entire day's sessions. (To help you find a specific talk, consult the agenda on the symposium web site).
Central Concerns
The scientific program began with a talk from Robert Gereau of Washington University, St. Louis, Missouri, who reviewed the remarkable plasticity of the nervous system when it comes to pain, outlining what is understood about peripheral and central sensitization. Both can take place when nociceptive input from the periphery alters synaptic behavior of pain neurons, and both lead to amplification of pain signals. In the usual scenario, the neurons involved are peripheral nociceptors and dorsal horn neurons that receive the original input.
However, comorbid or widespread pain conditions do not conform to traditional schemes of peripheral or central sensitization. These conditions are associated with hypersensitization at sites distant from any peripheral nociceptive input, or at multiple sites. For example, Gereau and colleagues recently published that migraine patients are hypersensitive to heat and cold, and that the hypersensitivity is apparent in the pain-free periods between migraine episodes and on the migraineurs’ forearms and other body areas (Schwedt et al., 2011).
Using a mouse model, Gereau has pinpointed the signaling mechanisms whereby injury at a specific peripheral location (injection of formalin into the foot pad) can lead to synaptic changes in the central nervous system and a spreading of hypersensitivity to other sites. Specifically, he showed that GluR5 signaling in the central nucleus of the amygdala activates the extracellular signal-regulated kinase ERK and results in a form of central sensitization in the brain. This leads to the development of mechanical hypersensitivity not just in the injected foot, but in the uninjected, contralateral foot as well (Kolber et al., 2010). Gereau further showed that activation of the metabotropic glutamate receptor GluR5 in the right amygdala is sufficient to induce hypersensitivity in both paws, even in the absence of injury. These results identify a potential central driver of widespread pain, and a possible neural substrate that could underlie the comorbidity of pain conditions. The findings also support the idea that targets for treating widespread pain will be found in the brain.
Pain also alters brain activity outside of the “pain matrix,” said Dante Chialvo, Brentwood Biomedical Research Institute, Los Angeles, California. Functional magnetic resonance imaging (fMRI) reveals widespread changes in the activity or degree of connection between different cortical regions in response to chronic pain. The data started appearing three years ago (Baliki et al., 2008) suggesting that that there is a difference in the activity of the so-called default mode network (DFN) in brains of healthy subjects vs. those with chronic back pain. In the healthy brain, activation of some regions during a simple cognitive task is accompanied by a correlated deactivation in the DFN. In the brains of people with chronic pain, there is a marked deficit in deactivation. Changes in the connectivity of the cortical regions that make up the DFN are apparent even when the brain is ‘resting’—when there is no task at hand (Tagliazucchi et al., 2010). Chialvo has pinpointed one possible explanation for these changes by showing that chronic back pain patients have enhanced interaction between default mode network regions and parts of the pain matrix, including the insular cortex compared to pain-free subjects. New data from his lab in patients with fibromyalgia (not yet published) shows other changes in connectivity. These disruptions may be related to the attention disorders, depression, and cognitive deficits experienced by patients with chronic pain, Chialvo said.
A drawback of previous studies has been that they rely on comparisons between groups of patients. Chialvo talked about new techniques that allow brain dynamics during spontaneous pain to be analyzed in individual patients. Such approaches may have application for personalizing diagnosis and treatment.
Gayle Page and Michael Smith, both from Johns Hopkins University, Baltimore, Maryland, spoke about how sleep (or, to be more precise, lack of sleep) can make pain worse. Page showed how sleep deprivation exacerbated hypersensitivity in rat models of inflammatory pain and taxol-induced neuropathy. Smith is keeping actual human beings up at night and showing that sleep deprivation affects the ability of subjects to mobilize mechanisms of descending modulation (diffuse noxious inhibitor controls, or DNIC, ) or distraction-mediated relief of pain (Edwards et al., 2009, Campbell et al., 2010). Sleep disturbance is often seen as a result of pain, but Page’s and Smith’s work shows how it can also be a risk factor for chronic pain. The good news is that sleep disturbance is treatable, Smith said, making it a modifiable risk factor.
Peripheral Issues
During the first question and answer session, Michael Iadorola of the National Institute of Dental and Craniofacial Research voiced a more peripherally oriented view of pain. “If you block peripheral input effectively, all that central sensitization will normalize,” he said in response to Gereau’s work. “Get rid of the peripheral generator, and pain goes away.”
Gereau responded that peripheral drive and central sensitization “go hand in hand.” However, in many cases of chronic pain, it is difficult or impossible identify the peripheral driver, so he said researchers and clinicians “have to think beyond the site of injury.”
Later, Iadorola elaborated on peripheral targets in his talk on efforts to identify novel pain therapies aimed at the transient receptor potential cation channel V1 (TRPV1). TRPV1 is well known as a sodium and calcium permeable channel that is located in neurons that sense noxious heat, and can be activated by inflammatory mediators, acidic pH (a result of tissue damage) and the vanilloid toxin capsaicin. TRPV1 was identified and the gene cloned in 1997 (Caterina et al., 1997), setting off a race to develop channel antagonists as analgesic drugs. Two problems quickly arose that led to the termination or suspension of many programs: Channel antagonists caused an increase in core body temperature, and a loss of heat pain sensation throughout the body. The latter could prove to be dangerous. People taking one channel blocker reported that water at 49oC (120oF, or hot enough to scald) felt just right for a shower (Rowbotham et al., 2011). Such therapies might work in the controlled environment of a hospital, Iadorola said, but to be safe in the world, people need to be able to constantly survey their thermal environment.
To try to block chronic pain while maintaining the ability to perceive a cup of too- hot coffee or developing sunburn, Iadorola took the opposite approach, pursuing positive allosteric modulators rather than antagonists. He showed data on one compound, MRS1477, which causes an increase in calcium influx through activated channels. The mechanism of action of allosteric modulators is similar to capsaicin: by tipping the balance of ion flow when channels are activated, they introduce a toxic level of calcium into the cell. The responses are reversible—the nerve terminals regain sensitivity in few days. “It actually lesions nerve terminals, but they grow back,” Iadorola said. He reported he has just received an NIH Roadmap grant to support a high throughput screen for other allosteric modulators.
In the meantime, Iadorola is also studying resiniferatoxin (RTX), an ultra-potent capsaicin analog and channel agonist originally derived from Moroccan spurge plants. In rodent studies, systemic application of RTX selectively burns back TRPV1-containing nociceptors and leads to weeks-long but reversible hypoalgesia. Following studies on dogs with osteosarcoma (Brown et al., 2005), RTX has progressed into people, in an ongoing open label clinical trial of intrathecal administration for intractable pain due to advanced cancer.
Iadorola says he expects to see rapid and strong analgesia, a decrease in opioid use, a decrease in sedation, and an increase in appetite. Patients will lose thermal sensation in the lower parts of their bodies but should still have fully normal sensation in their upper bodies, including their hands and mouths.
Iadorola sees other possible applications of RTX in other cancers, in peripheral neuromas, after amputation, or for joint pain. The researchers have made an eye drop formulation that gives a long-lasting (3-4 day) analgesic effect in rats (Bates et al., 2010). “If you can point to the problem, it’s a potential target for RTX,” he concluded.
Outside Influences
A second session dealt with psychosocial factors that contribute to comorbid pain conditions. Anne Murphy, Georgia State University, Decatur, led off with her data from an animal model of neonatal pain. Her results are dramatic, indicating that a single injury to a newborn rat has lifelong consequences (Laprairie et al., 2009). In her model, an injection of carrageenan into the paw on postnatal day 1 results in transient swelling and pain that resolves in a few days. However, 60 to 90 days later, the animals display decreases in thermal pain sensitivity, which Murphy traced to persistent increased expression of the opioid peptides leu- and met-enkephalin and beta-endorphin in the periaqueductal grey area. Upon re-injury, the older animals experienced hyperalgesia, which Murphy attributed to increased spinal innervation subsequent to their earlier injury. The animals also showed altered expression of proteins in stress response pathways, and appeared hyporesponsive to acute stress. All of these responses were exacerbated in females, raising the question of whether neonatal pain is a predisposing factor for chronic pain in women.
Other speakers in the session included William Whitehead, University of North Carolina, Chapel Hill(Early Life Experiences: Effects on Chronic Visceral Pain Disorders), Emeran Mayer,University of California, Los Angeles (Sex Differences in Pain Responses and Susceptibility to Multiple Persistent Pain Conditions), and Jennifer Haythornthwaite, Johns Hopkins University, Baltimore, Maryland (Effects of Catastrophizing and Depressive Symptoms on Pain and Pain Management).
In a session on treatment strategies, Mark Jensen, University of Washington, Seattle presented data from his ongoing work looking at EEG changes in 19 subjects using nonpharmacological treatments (hypnosis, biofeedback, meditation, or transcranial direct current stimulation) for chronic pain due to multiple sclerosis, amputation or spinal cord injury. Although still preliminary, the results suggest that all of the treatments change brain activity, and that the changes are associated with changes in pain. There was no consistent pattern shared by pain conditions, or by treatments, however.
Talks by Charles Cleeland, University of TexasM.D. Anderson Cancer Center, Houston (Reducing Symptom Burden in Cancer Treatment), Eva Szigethy, University of Pittsburgh, Pennsylvania (Strategies and Hurdles in the Management of Abdominal Pain in Adolescents), and the previously discussed presentation by Iadorola rounded out the program.
If you were at the meeting, please add your comments. What did you find interesting? What made you think?
