Chronic Overlapping Pain Conditions and Stress: A Meeting Report From the CACPR 3rd Annual Symposium
Editor’s note: The following is a meeting report from the University of Maryland’s Center to Advance Chronic Pain Research (CACPR) 3rd Annual Symposium. The theme of this event, which took place on November 17, 2017, in Baltimore, US, was “Chronic Overlapping Pain Conditions and Stress.” This report is coauthored by Shana Burrowes, Samuel Krimmel, Janell Payano Sosa, and Jing Zhang, all from the University of Maryland, Baltimore, US.
The effect of stress on pain …
Kicking off the 3rd Annual Symposium of CACPR was Roger Fillingim, University of Florida, Gainesville, US, who addressed the reciprocal relationship between stress and pain. He emphasized that although “stress is a risk factor for chronic pain, pain is [also] a risk factor for adverse biological outcomes that in my view reflect the cumulative effects of a system under chronic stress.”
According to Fillingim, when “many people think of stress they think of the exposure, the things that are happening to them, as opposed to the response to that exposure.” Therefore, it is important to distinguish the stimulus (the stressor) from the response to that stimulus (stress). He also emphasized that there is both a biological response and a psychological response to a stressor. Clinical researchers try to measure both responses, though typically they have placed more attention on the latter.
However, Fillingim said the goal is not to get rid of all stress. Rather, as long as an individual is able to respond to and recover from stress, stress can be beneficial and promote growth. “It is when stress overwhelms our resources and our ability to recover that stress produces its deleterious effects,” he said.
Stress is associated with increased pain symptom severity, affects pain perception, and predicts future onset of pain conditions. For example, in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, which aims to understand who is at risk of developing temporomandibular disorder(TMD), healthy individuals were assessed every three months for three years. Fillingim noted that those with higher levels of stress had a greater risk of developing TMD months or years later. More interestingly, stress increased as individuals got closer to the onset of TMD. Fillingim presented recently published research showing that this association was only observed in individuals with a catechol-O-methyltransferase (COMT) haplotype that reduces their ability to metabolize catecholamines (Slade et al., 2015).
… but pain is a stressor, too
However, pain is also a stressor with detrimental effects on biological systems. As an example, Fillingim pointed to a previous study from his group examining the relationship between telomere length, which is a biological marker of cellular aging, and perceived stress and chronic pain (Sibille et al., 2012). In this cross-sectional study of 36 older adults, the researchers stratified a cohort of individuals with osteoarthritis, and healthy individuals with no pain, into high or low stress groups. They observed that those with high stress and high pain had the shortest telomeres, and those with low stress and low pain had longer telomeres. Furthermore, in a larger cohort of knee osteoarthritis, patients who were asked to report the frequency of their pain, pain intensity, time of pain, and total number of pain sites (the FITT chronic pain severity index), telomere length became shorter as the burden of pain increased (Sibille et al., 2017).
This was further supported by a study from another group reporting that individuals with severe fibromyalgia pain had shorter telomeres than individuals with fibromyalgia but lower levels of pain (Hassett et al., 2012). This study, which included 66 women with fibromyalgia and 22 healthy female controls, also found that those with shorter telomere length were also more sensitive to evoked pain and had less gray matter volume in brain regions associated with pain processing.
Another important factor, allostatic load, reflects cumulative wear and tear on multiple biological systems known to respond to stress (McEwen, 2008). In a 2016 study based on data from the Tromsø study, Fillingim and colleagues created an allostatic load-like index using available markers such as inflammation and body mass index, which they used along with FITT (Sibille et al., 2016). They observed a dose-response relationship where, as the burden of chronic pain increased, so did the allostatic load-like index.
One key similarity across many chronic overlapping pain conditions is that they are stress related, which should be considered when studying chronic pain. Further, studying the cumulative effects of both stress and pain can provide a better understanding of the risk of developing more than one pain condition.
Janell Payano Sosa is a PhD candidate in neuroscience at the University of Maryland, Baltimore, US.
IBS: a multifaceted disorder
Irritable bowel syndrome (IBS) is a chronic pain disorder characterized by a combination of symptoms such as abdominal pain, constipation, and diarrhea, or by an alternating pattern of these symptoms. However, gastrointestinal issues are but one layer of the multifaceted disease that is IBS. Margaret Heitkemper, University of Washington, Seattle, US, addressed how stress and quality-of-life factors such as sleep also play a role in IBS in her talk, “Irritable Bowel Syndrome: More Than a Gut Feeling.”
IBS affects approximately 10 to 15 percent of the US population and can begin in childhood or adulthood. Prevalence is higher in women compared to men (14 percent vs. 8 percent), and this pattern is seen globally (Lovell and Ford, 2012). IBS is associated with high morbidity, and the disorder accounts for 30 to 50 percent of gastroenterology visits.
The Rome IV criteria (which comprise stool descriptions) are used for the diagnosis of IBS, and Heitkemper noted that changes to the criteria make comparing results difficult across studies. Of note, individual patients define diarrhea differently, and so established guidelines are essential for classifying subtypes of the disease. Heitkemper and her group use a modified Bristol Stool Chart that includes five stool subtypes, which has been instrumental not only for studying classic symptoms of IBS but also additional clinical subtypes of the disease.
Furthermore, she pointed out that IBS, as a disorder of the gut-brain interaction, is one of a spectrum of disorders that are associated with much more than gastrointestinal distress. In addition, the lack of an objective biomarker makes IBS a disease that is commonly studied by assessing symptomology, so the identification of biomarkers both in and outside the gut are of great research interest in the IBS field.
The role of hormones in IBS
Like many chronic pain disorders, IBS is often comorbid with other conditions. Heitkemper first started studying IBS in women with dysmenorrhea. In a study looking at abdominal pain in women aged 18 to 45 years, she and her colleagues enrolled healthy controls, women with IBS alone, women with IBS and dysmenorrhea, and women with IBS and premenstrual syndrome (PMS; Altman et al., 2006). In all participants, including controls, there was increased abdominal pain right before menses. However, women with IBS reported pain across the entire menstrual cycle. As the number of conditions increased, so did the level of daily symptoms, such that women with IBS and dysmenorrhea, and those with IBS and PMS, reported more abdominal pain than controls or those with one disorder. The increase in abdominal pain directly before menses in all participants was attributed to decreasing levels of estrogen and progesterone. The role of hormones in IBS is an active area of research.
Gender differences in IBS also indicate a role for hormones. While research in IBS has shown that women seek healthcare more frequently than men do, these studies have been retrospective in nature, relying on patient recall. In a prospective study, Heitkemper and colleagues assessed the frequency of somatic, gastrointestinal, and psychological symptoms in 32 men, 66 postmenopausal women, and 89 menstruating women with IBS, using daily diaries completed over a period of 28 days (Cain et al., 2009). The study revealed significant differences in somatic symptoms among these groups. The difference between men and postmenopausal women was greater than that between men and menstruating women. Fatigue and stress were also higher in both groups of women compared to men, but there were no differences in anxiety or depression. The finding that sex differences in symptoms were most pronounced between men and postmenopausal women indicates that this population of women with IBS warrants further examination. Heitkemper also noted that the differences observed in the study between post- and perimenopausal women also require further research.
Sleep studies
The biopsychosocial model has framed much of Heitkemper’s work on IBS. As a way to capture the full experience of IBS patients, she and her colleagues have utilized daily diaries, kept over the course of 28 days, which capture information on 26 symptoms including psychological factors, medication use, and GI and somatic pain. These studies have shown that IBS patients not only have a high prevalence of psychiatric disorders but often report poor sleep as well. The diary reports show that women with IBS who report poor sleep have increased GI symptoms the following day, a pattern that is similar in animal models where increased visceral sensitivity occurs after sleep deprivation. However, Heitkemper explained that the relationship between sleep and GI distress is not always bidirectional; increased GI distress does not always predict poor sleep (Buchanan et al., 2014).
Prior to studies from Heitkemper’s group, sleep studies in IBS had been limited to observing patients for one night. However, her team ran a series of studies that kept patients in a sleep clinic for three nights and collected data on time to rapid eye movement (REM) latency, sleep efficiency, and stress. Compared to healthy controls, IBS patients reported poorer sleep. In addition, patients observed over three nights in the sleep lab had longer time to REM latency on the first night than controls, with significant differences between those with severe IBS and healthy controls. Differences were less pronounced on subsequent nights as all groups (controls, mild IBS, and severe IBS) rebounded on the second and third night (Heitkemper et al., 2012). These findings underscore the need to examine sleep in IBS over a period of time to capture a full sleep pattern, as sleep disruption on the first night and subsequent rebounding suggest that sleep patterns are influenced by both the novelty of the sleep lab and the presence of disease.
These studies also collected data on several stress biomarkers including cortisol, adrenocorticotropic hormone (ACTH), and norepinephrine. Here, Heitkemper reminded the audience of the importance of a standardized stool chart (such as the Bristol Stool Chart) to classify IBS patient subgroups. While there was no difference between the overall IBS patient group and controls, there were significant differences between the IBS with constipation group and controls, where the former demonstrated consistently higher levels of norepinephrine throughout the night (Burr et al., 2009). Recent follow-up work looking at the ratio of metabolites in the blood throughout the night found that reductions in early nighttime melatonin/tryptophan levels may be related to altered sleep quality in those IBS patients with diarrhea (Heitkemper et al., 2016).
Nonpharmacological treatment of IBS
Given the heterogeneous nature of IBS, there is a great need for therapy that addresses the disease in a holistic manner. The Comprehensive Self-Management (CSM) program, developed by a team at the University of Washington, is based on descriptive and mechanistic studies linking psychological distress, and poor sleep and eating behavior to GI distress. The researchers developed CSM as a nurse-delivered therapy and implemented it using a three-arm randomized controlled trial (Jarrett et al., 2009). One hundred eighty-six patients were randomized to receive nine CSM sessions in person, six of the nine sessions over the phone, or usual care. The CSM sessions covered different topics including diet, relaxation techniques, and sleep, with patients completing homework after each encounter. The investigators assessed patients at three, six, and 12 months. Both CSM patient groups showed improved GI symptom and quality-of-life scores compared to the usual care group. There was no difference between the telephone group and the in-person group, indicating that CSM can be delivered effectively using different modalities. And, to assess the sustainability of the intervention, patients were contacted one year after completing the CSM sessions, with the majority of participants still using strategies they had learned during the study (Zia et al., 2016).
Finally, by examining several biomarkers including stool calprotectin (a protein used to detect intestinal inflammation), genetics, cytokines, and heart rate variability (HRV), Heitkemper and her group have shown that HRV and the autonomic nervous system are predictors of success with CSM (Jarrett et al., 2016). In a two-arm randomized controlled trial comparing usual care to CSM, patients with higher vagal (parasympathetic) tone showed more benefit from CSM on abdominal pain compared to those with lower vagal tone. However, the relationship between heightened sympathetic tone and the efficacy of CSM in reducing abdominal pain remains unclear.
Shana Burrowes is a graduate student and epidemiologist at the University of Maryland, Baltimore, US.
Modeling chronic overlapping pain conditions in animals
A common observation in medicine is high co-occurrence, called comorbidity, of multiple distinct conditions. This phenomenon is also prevalent in chronic pain, as patients often suffer from chronic overlapping pain conditions (COPC). COPC manifests as a heterogeneous condition with combinations of symptoms from several different pain disorders, without an identifiable disease or illness that could explain the symptoms. Researchers currently believe that altered nervous, endocrine, and immune functions induced by one chronic pain disorder increase the probability of developing additional chronic pain conditions.
Standard animal models of chronic pain typically do not examine how chronic pain in one part of the body promotes development of chronic pain in other sites. This limits their utility in understanding illnesses like COPC. In a talk titled Can Chronic Overlapping Pain Conditions Be Modeled in Animals?,” Richard Traub, University of Maryland, Baltimore, US, discussed how his lab is addressing this limitation by studying the overlap of abdominal pain, a defining symptom of irritable bowel syndrome (IBS), and jaw pain, as experienced by patients with temporomandibular disorder (TMD). Clinically, these two illnesses show high comorbidity with approximately 30 to 60 percent of TMD patients displaying the symptoms of IBS.
In order to study the overlap of multiple pain conditions, Traub’s team induces facial pain in rats and then studies subsequent pain hypersensitivity in the viscera. Using this animal model, the group has found that stress increases visceral pain in animals with existing orofacial pain to a much greater extent than stress alone. There are sex differences, too, with females displaying greater pain behavior in this comorbidity model. While these findings are consistent with prior work, they offer unique insights since they are performed in models of comorbid pain.
Using their animal model to identify targets for treating comorbid pain, Traub and colleagues have studied whether descending pain-modulating projections from the brain to the spinal cord play a role in comorbid pain. They have found that inhibiting the action of serotonin, likely originating from rostral ventral medulla (RVM) projections to the spinal cord, reduces comorbid pain. In addition, results show increased expression of serotonin receptors in the spinal cord following craniofacial nerve injury in rats, suggesting that neural changes in the serotonergic descending pain modulatory system have occurred and likely promote maintenance of pain disorders. Drugs that target this system may prove useful for comorbid pain.
This research helps to advance understanding of an important category of chronic pain disorders that has been understudied. Such work will continue to identify targets for therapeutic interventions that may be tailored specifically for overlapping pain disorders.
Samuel Krimmel is a graduate student at the University of Maryland, Baltimore, US.
The brain, gut microbiome, and visceral pain
Visceral pain is a type of nociceptive pain coming from internal organs and is implicated in some types of abdominal disorders, such as irritable bowel syndrome. In a talk during the CACPR 3rd Annual Symposium, John Cryan, University College Cork, Ireland, explored the complex interaction among the brain, gut, and microbiome, and how that interaction modulates visceral pain. Specifically, adverse early-life events negatively affect the gut microbiome, which can lead to long-term effects on visceral pain. Cryan proposed that pathways in the microbiome-gut-brain axis enable two-way communication between the gastrointestinal tract and brain. One of the major pathways is the vagus nerve, which can be targeted to treat visceral hyperalgesia. (For a more extensive discussion of these themes, see PRF related meeting report on Cryan’s talk delivered at the 2016 IASP World Congress on Pain, as well as an IASP webinar presented by Cryan).
Jing Zhang is a clinical research assistant at the University of Maryland, Baltimore, US.
Panel discussion …
The symposium ended with a panel discussion led by four scientists in the field of chronic pain research, including Simon Ackerman, a preclinical research scientist with a focus in migraine and cluster headache at the University of Maryland, Baltimore, US; David Shurtleff, who focuses on nonpharmacological therapies for chronic pain at the National Center for Complementary and Integrative Health (NCCIH), Bethesda, US; Jennifer Haythornthwaite, who studies chronic pain with a focus on stress at Johns Hopkins University School of Medicine, Baltimore, US; and Rita Valentino, who has spent decades studying the impact of stress on the norepinephrine system and is now at the National Institute on Drug Abuse (NIDA), Bethesda, US. The panelists focused on how the research covered throughout the symposium could be used to launch translational studies and new therapies to manage chronic pain.
In keeping with the theme for the symposium, all panelists agreed that chronic pain conditions involve more than just the pain. Ackerman explained that migraine patients, in addition to experiencing debilitating headaches, commonly have gastrointestinal disorders, anxiety, stress, and sleep disorders. Meanwhile, Shurtleff noted that pain is a complex emotional state that also includes a cognitive component, which drives the need for holistic therapeutic strategies such as cognitive behavioral therapy (CBT) and mindfulness-based stress reduction (MBSR). These are approaches that allow patients to be involved in their treatment.
Haythornthwaite told the audience that no two patients are alike and that these individual differences make treatment a constant challenge. For instance, she provided the hypothetical but common example of two osteoarthritis patients in the clinic. One is incredibly disabled but with little to no evidence of osteoarthritis according to a knee x-ray. The other patient spends his days playing golf but has evidence of severe osteoarthritis on x-ray. The processes that lead to such individual differences are often not captured in research, as studies are usually cross-sectional, capturing only a snapshot of time, or start only after years of exposure have already occurred. She challenged basic scientists to find a way to incorporate individual differences in animal models, and for both preclinical and clinical researchers alike to recognize the importance of life exposures such as childhood trauma, stress, and nutrition on chronic pain.
Valentino added that her research on cognitive and emotional responses to stress have identified sex differences in this regard. To explore these differences, basic science research continues to examine subpopulations of animals (i.e., those with different genetic characteristics) to assess coping strategies to deal with stress and identify molecular and genetic markers that may be related to those strategies. These studies are important in assessing and understanding the individual differences to which Haythornthwaite drew attention, which will be critical for translation of basic science into new treatments.
… and audience questions
What are some high-value therapeutic targets and interventions that would be useful across all chronic pain conditions?
Shurtleff said that stress and, in particular, unpredictable stress, should be the target of therapies that address chronic pain. He explained that the strength of treatments such as MBSR is that they enable patients to take control and think about how their behaviors such as diet and sleep affect their health. Ackerman agreed, noting that migraine patients often report stress as a trigger for their migraines and, in particular, disruptions to routines such as changes in meal times.
Regarding treatment of chronic pain, Haythornthwaite said a change is in order. Using diabetes as a comparison, she said that chronic pain treatment today is comparable to care of diabetes 25 years ago. In the past, diabetics and their physicians met routinely, tried several medications, and monitored blood sugar over time—the focus was much more on pathophysiology. But today, diabetes care takes a patient-centered approach where the physician acts as a consultant and the patient is expected to keep a proper diet, exercise, and pursue other self-management techniques. Haythornthwaite said that the pain field, too, needs to find a way to communicate this need for patient-centered treatment in a patient population that is difficult to treat. Patients themselves need to be convinced of this approach, as do their family members. She stressed that with a condition like chronic pain, where symptoms such as depression predict treatment failure, treating the patient as a whole person is crucial.
What types of molecular biomarkers would enhance pain research?
With regard to biomarkers, particularly those in the microbiome, Shurtleff, pointing to Cryan’s research, noted that while there is evidence that some of the microbes in the gut produce the inhibitory neurotransmitter GABA, it would be interesting to know if there are additional neurotransmitters coming from the gut that modulate pain in the brain. Also, the role of probiotics and their influence on the microbiome and brain mechanisms of pain is an area that requires further research. The development of a system that can model and assess neurochemical processes would provide insight. Cryan and Shurtleff agreed that predicting the substances that the microbiome produces is difficult, and knowing the exact mechanisms by which they act requires additional work. —Shana Burrowes
Image credit: paulrommer/123RF Stock Photo.
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