Published September 15, 2020
Heather Bowersox, a 36-year-old medical biller and single mother of a teenage son, lives with multiple pain conditions: temporomandibular disorder (TMD), migraine, back pain, and irritable bowel syndrome (IBS). While those conditions might seem unrelated, Bowersox believes they share common threads. Researchers, too, are looking for those recurring characteristics to link seemingly unrelated conditions that keep showing up together.
Bowersox is far from alone. For many people, one condition leads to another, so that they live with what have come to be called chronic overlapping pain conditions (COPCs). The growing list of COPCs that tend to cluster together includes fibromyalgia (FM), TMD, interstitial cystitis (IC)/painful bladder syndrome, IBS, endometriosis, vulvodynia, chronic low back pain, chronic migraine, and tension-type headache. People with chronic pain – and these COPCs in particular – also often suffer from non-pain conditions like sleep and mood disorders, cognitive dysfunction, and fatigue.
Though the conditions that make up COPCs present different symptoms and affect different bodily areas, researchers are starting to dig into what these ailments have in common. Clues are coming from who is prone to develop COPCs; overwhelmingly they affect women. One thing has become clear: the factors contributing to the risk of COPCs are numerous and complex, with genes, childhood experience and current stress all playing a part. And many systems are involved, including the immune, endocrine (hormone), and central nervous systems. But when it comes to how to treat COPCs, the questions still far outnumber the answers.
“A wild goose chase”
As a teenager, Bowersox had trouble waking up in the morning and often felt like she was in a fog. But pain didn’t figure prominently in her childhood. In fact, she said she had, and still has, a high tolerance for pain. Then, in her 20s, she developed jaw pain, migraine headaches and other strange symptoms. “It was like everything kind of snowballed that year at once,” Bowersox said, though she says there was no particular event that triggered her symptoms.
In what she describes as a “wild goose chase” trying to make sense of her symptoms, Bowersox saw multiple doctors – her primary care physician, an ear, nose and throat specialist (ENT), a neurologist, a cardiologist, and several surgeons. Ten years ago, in 2010, she was finally diagnosed with POTS, or postural orthostatic tachycardia syndrome, a mysterious condition in which heart rate increases significantly upon standing. Her other diagnoses eventually followed. Doctors also found the root of her jaw pain: condylar hyperplasia, another mysterious condition in which the jaw bones don’t stop growing. She eventually underwent surgeries to replace both of her temporomandibular joints with prosthetics, which required sawing bone out of her skull and implanting the prosthetic joints with screws and bolts.
Between a knee surgery for a torn meniscus and four surgeries related to her jaw replacement, Bowersox had five surgeries in about five years. The early surgeries she described as “kind of a breeze,” but after her latest surgery in December of 2019, she said her postoperative pain went untreated. “It was the worst.” Now she suffers from debilitating jaw pain on one side. “I don’t know if it’s because the more surgeries you have the worse you do, or because my pain was not controlled. It seems like the more conditions you have, the worse it gets.”
Now, Bowersox said that when she has a flare-up of jaw pain, “I might lose five pounds in two weeks because I can’t chew on one side of my face. I have bad days where it hurts to talk. You don’t realize how much you use these joints to talk, to chew – sometimes you just can’t. If it’s a bad day, I just have to relax and wait for it to pass.”
While each of these overlapping conditions has its own signature – jaw pain for TMD; pelvic pain for IC or endometriosis; headache for migraine – they also seem to share some fundamental elements across conditions, in many people. In particular, the pain is often not predictable or stable; it may come and go, flare and remit, and move around the body. Overlapping conditions are often considered “idiopathic,” meaning that they have no discernible cause – no detectable injury or pathology in the tissue where pain is felt. In fact, COPCs are often diagnoses of exclusion, when doctors can’t find anything amiss such as cancer or injury. And, importantly, the conditions all share the key characteristic of increased pain sensitivity, which can be localized but is often widespread throughout the body.
A focus on commonalities
Even with these shared characteristics, each person with COPCs will look different from the next. Roger Fillingim, a clinical psychologist and pain researcher at the University of Florida in Gainesville, said he studies “what makes people so wildly different in how they experience pain, and what that might tell us about risks for developing chronic pain and multiple chronic conditions.”
He approaches the study of COPCs from a biopsychosocial perspective, which takes into account not just the biology of pain but also psychological and social factors that contribute to it, and considers the person as a whole, rather than as a collection of diagnoses (see related RELIEF feature here, and related RELIEF podcast with Fillingim here). Fillingim said all of those factors combine to form what he calls “a mosaic that creates the pain profile of any given individual.”
But as different as individuals are, researchers are hoping that the things people with COPCs have in common might shed light on how to treat them. For example, large studies of patients with COPCs have identified patient “clusters” with shared characteristics, even between people with different diagnoses. That suggests that studying what people have in common, rather than focusing on the anatomical location of their pain, could help researchers understand how to treat COPCs more holistically and effectively.
That will require a huge effort, and researchers have only recently taken up the task in earnest. Advocating for that research is the mission of the nonprofit organization Chronic Pain Research Alliance (CPRA), an initiative of the TMJ Association. Christin Veasley, CPRA director and co-founder, lives with multiple chronic pain conditions herself and was frustrated by the piecemeal efforts aimed at individual syndromes.
“We recognized that a substantial group of people had not only one condition but multiple pain conditions,” Veasley said. And while advocacy organizations and research efforts had been aimed at studying individual pain conditions in a siloed manner, “there was not an effort to look at education around or research behind the question of, ‘what is different about people who go on to develop any number of pain syndromes as well as non-pain comorbidities?’” (Co-morbidities are co-occurring conditions).
Veasley said the needed approach is to “step back to look at the collective, at what might be similar across multiple real-world conditions, rather than at an isolated condition. Let’s try to understand the underlying mechanisms behind chronic pain conditions as complex multi-system illnesses, and how they can manifest differently in different people.”
The aim is not just to learn more about the biology of these overlapping conditions, but how to best treat them, Veasley said. “We know the more pain sites a person has, as well as non-pain comorbidities, the less likely they are to benefit from treatments. They experience greater disability, and have decreased health outcomes and quality of life. So obviously that’s an important population to focus on.”
Getting to the root cause
Considering how much these overlapping conditions have in common, researchers have begun to hunt for their causal roots. “The fact that these conditions cluster together makes many of us think that they’re driven by overlapping mechanisms, if not identical mechanisms,” Fillingim said.
“The common denominator among these conditions seems to be the central nervous system,“ Veasley said, referring to the brain and spinal cord. “And from the evidence so far, immune, endocrine and neurologic mechanisms seem to be similar across these disorders.”
Clues to those mechanisms lie in what overlapping conditions have in common: their changing and mysterious nature, symptoms like fatigue, “brain fog,” and widespread pain. But, in particular, Fillingim said, the increased pain sensitivity that so often accompanies these conditions “is consistent with disrupted pain regulation due to changes in the central nervous system,” or CNS.
Researchers largely agree that whatever the origin of chronic pain, a key feature of these overlapping conditions is that the CNS undergoes changes in its structure and function. The result, Fillingim said, is called “central sensitization, which means that the CNS interprets incoming sensory information differently, whether that emanates from within the body or outside the body. And it’s not just a matter of being better at detecting things. It’s that, ‘I detect things and I evaluate them as bothersome and unpleasant.’”
While researchers agree that the CNS plays a critical role in chronic pain and overlapping conditions, that’s not to say that the brain alone is responsible. Although some symptoms affect a person’s entire body, as you would expect from a CNS influence, many still experience pain in specific areas, Fillingim said. That suggests some dysfunction in the body (often referred to as the periphery because it is outside of the CNS).
“Somebody with TMD pain knows that it hurts in their jaw,” said Fillingim, even when there’s no detectable sign of distress there. “I’ve wondered about this a long time: how do they know where to hurt if there’s no peripheral trigger?” That pain “trigger,” he said, “may be the same muscle activity that I have, but because I don’t have the vulnerability, my system doesn’t interpret it as pain, and someone else’s system may.”
Andrea Nicol is a physician-researcher at Kansas University in Kansas City who mainly sees patients with fibromyalgia and other COPCs. “We don’t have the ability to hold up a little magnifying glass to a part of the person’s body” and see what’s causing the pain. “We don’t know how much is peripherally maintained or centrally maintained. I think it’s very rare that you would have 100 percent of either; I think most pain states are mixed,” she said.
Nicol said her patients, and FM patients overall, tend to fall into two main groups: those who are more “centralized,” often with a life-long history of pain that has a high impact on their lives, and others who had a more definitive event that led to pain, sometimes with ongoing peripheral injury or dysfunction. (Despite this broad generalization, though, Nicol said, “everyone’s path from here to FM is different.”) The makeup of the mix of central and peripheral influences can be critical to choosing the best treatment, Nicol said. “I try to tease it out,” by gathering an extensive history dating back to childhood. “And if they are likely more ‘centralized,’ then maybe this person isn’t the best candidate for surgery,” which is intended to alleviate issues in the periphery.
On the other hand, she said, “if there is still peripheral input going on, [even if] they have FM, then you should still treat those peripheral issues. But if they truly have no pathologic findings that would lead to any need for peripheral interventions, then those are the people I focus on with medications, behavioral treatments, and exercise or physical therapy.”
Ultimately, understanding the shared causes behind COPCs could lead to better treatments for multiple conditions.
Fibromyalgia may be the most recognizable, and quintessential, of what were once called functional somatic syndromes. With its signature of widespread musculoskeletal pain, mental fog and fatigue, yet no detectable signs of any known illness, FM has confounded patients, doctors and researchers for decades. Only recently is FM even becoming accepted as “a real thing” by many physicians.
Fibromyalgia affects 10 million people in the US and an estimated 2 to 8 percent of people worldwide. But Ericka N. Merriwether, a physical therapist and pain researcher at New York University, said that the prevalence of fibromyalgia is probably much higher. “It’s horribly underdiganosed. It’s usually a diagnosis of exclusion, when health professionals can’t find anything else.”
During Nicol’s training in pain medicine, she said, “the ‘FM word’ was very much a feared diagnosis” for chronic pain clinicians. “The dogma was, ‘This patient is going to be more difficult, more challenging’ – those were always the words that were used.” Nicol carved out a niche treating primarily patients with FM and COPCs, but “I didn’t find fibromyalgia; it found me,” she said. As the only female in her pain group – fewer than one in five pain physicians are women – FM patients, who are overwhelmingly women, sought her out. “It was a natural fit,” she said.
“I have rarely seen FM as existing with minimal to no other pain conditions. Usually it presents later on or in parallel with other pain conditions,” Nicol further said. Fibromyalgia feels like a sort of apex among COPCs, perhaps the culmination of living with chronic pain. A 2018 review found that among people with pain conditions or endocrine, rheumatic or neurologic diseases, between 20 and 70 percent also had FM. “If I see a patient who lists IBS or anxiety or migraine or TMD [among their conditions], but I don’t see FM on there, that is a patient who, more often than not, will meet criteria for a fibromyalgia diagnosis,” said Nicol.
That doesn’t seem to be the case for Heather Bowersox, although she said her excruciating jaw pain, migraines and back pain can be exhausting. “Chronic pain gives you fatigue; that I never knew. I learned the hard way. When I come home from work sometimes, the pain – it knocks you down. I’m ready to eat dinner and call it a night. It’s crazy how much the pain wears your body down, because you’re constantly fighting the pain.” And yet she doesn’t suffer from the widespread pain characteristic of fibromyalgia. “So I don’t feel like I have FM. I don’t feel I’m at that point yet.”
But Nicol said that FM is far from a condition that you either have or don’t have. It’s almost as though FM encompasses all of the widespread, “centralized” symptoms, which can affect people to varying degrees. Some researchers have championed the term “FM-ness” to describe the degree to which the hallmark symptoms of FM affect a person.
“It’s this idea that we all exist on a spectrum,” Nicol said. “And that it’s the severity of symptom expression that mandates where you lie on this scale of FM-ness. And it’s a dynamic thing; FM is not just where you just put your finger on a number and that’s where you live forever.”
Risk factors provide clues
Clues to the causes of FM and other COPCs also lie in who gets them. Among the greatest risk factors for developing new chronic pain is having an existing chronic pain condition. In a review of published studies, researchers found that, among people with three of five common overlapping pain conditions, about a quarter also had jaw and face pain. In other words, people with existing pain conditions had over 26 times the chances of having jaw and face pain as someone without one. Other studies have found the odds are similar for other pain conditions. So, the more COPCs one has, the bigger that person’s risk for additional conditions.
Genetics certainly contribute to risk for COPCs, too; studies have identified hundreds of genes that contribute to pain in various ways, though scientists are just beginning to tease out how. Environmental factors play a critical role as well. Stress and trauma, particularly in early life, can have an outsized influence on risk for chronic pain.
But the most obvious risk for developing multiple chronic pain conditions is simply being female. Women are diagnosed with chronic pain conditions at far higher rates than men, and that’s especially true for COPCs. That may be partly because some conditions on the list, such as vulvodynia and endometriosis, affect only women.
Fillingim put it this way: “You don’t experience more pain because you’re a woman; you experience more pain if you’re a woman. And so the question is, ‘what is it about females in general that puts them at greater risk? What makes the pain experience different?’ We suspect that neuroimmune factors,” such as small signaling proteins called cytokines, “are part of the answer. Those factors are present in male and female rodents, but the way they influence pain is qualitatively different. And that’s critically important, because that suggests that at some point in the future, treatments for pain might be completely different for one sex versus the other” (see related RELIEF feature here).
Margaret “Peg” Heitkemper, a nurse and researcher at the University of Washington in Seattle, studies IBS, which is also more common in women. “Being female is definitely a risk” for COPCs, says Heitkemper. “Whether that’s due to childhood experiences, socialization, higher stress levels, or biology – we don’t know.”
Hormones almost certainly play a role, but how is not understood. “Our pediatric colleagues don’t necessarily see these sex differences in children; it’s when you go through that pubertal change” that female sex becomes a factor,” said Heitkemper. “So what is it that happens? I’ve been asking that question for 30 years, and it frustrates me that I still don’t know the answer.”
And while the immune system is a major influence too, researchers are just beginning to investigate how. Merriwether, the physical therapist and pain researcher, is researching the mechanisms behind chronic widespread musculoskeletal pain in people with obesity or who identify as fat or full-figured. Preliminary work suggests that changes in the immune system are related to pain, fatigue and other symptoms of FM. In those with widespread pain, she said, “we saw that their immune cells were functioning differently in their appearance and the type of proteins they produced,” compared to cells from people without pain. Merriwether and her collaborators are hoping to build on these findings to better understand what contributes to pain in FM and other chronic widespread musculoskeletal pain conditions, including using animal models.
Stress: early and ongoing
Researchers roundly agree that stress increases risk for developing COPCs, and for experiencing a pain “flare.”
“There are two different time frames of stress,” Fillingim said. “There’s early-life stress like adverse childhood experiences. And then there’s what’s happening now – recent life stress. Stress is a major driver of our health writ large, and it has a variety of biologic effects. It causes systemic inflammation, release of hormones like cortisol, it disrupts sleep and causes its own biological signaling cascades,” which can lead to disease.
“Studies that have documented life stresses very early in childhood and evaluated people as adults have found that those early life experiences do indeed increase risk for developing chronic pain later in life,” Fillingim continued. “The exact reasons for that, we don’t really know.” But researchers believe that traumatic events can make the brain more vulnerable to chronic pain. “There can be changes in brain structure and function that are more or less lifelong, and that alters how the brain processes emotional experiences. How we respond today under stress is partly determined by what happened to us early in life,” according to Fillingim.
During the extensive history she takes for each patient, Nicol said, “the topic of stress and trauma is one of the earliest associations I would notice.” That hunch was confirmed by a 2016 study Nicol did looking at over 3,000 people with chronic pain. She found that those with a history of abuse fared worse than those without it; they had greater pain severity and interference in their lives, more physical disability, more anxiety and depression, and higher scores on the scale of “FM-ness.”
“Ongoing stress can be a major driver” too, Fillingim said. “Imagine this cycle where stress is limiting our ability to manage pain, which takes its toll on our biological systems. That then renders us further unable to manage pain, and we get into this spiral where pain is aggravating stress, and stress is aggravating pain.”
Animal studies confirm the importance of real-time stress. Richard Traub studies the role of stress and hormones in chronic visceral pain at the University of Maryland in Baltimore. Traub and his colleagues in the dental school developed an animal model of COPCs. Stress alone can increase visceral hypersensitivity or pain, Traub said. “If you stress the animal,” which they did with what’s called a 3-day forced-swim paradigm, “the female animals develop a visceral hypersensitivity that lasts a couple of weeks – but there’s no injury, no gut inflammation.”
But, strikingly, when the rats had a pre-existing pain condition, their gut hypersensitivity lasted much longer. The researchers injected rats in the jaw muscle with a substance that causes painful inflammation and then subjected them to the forced swim. “If you stress the animal while they have the inflammation and orofacial sensitivity, they develop this prolonged visceral hypersensitivity that goes on for months,” Traub said. He is now working to understand the mechanisms that underlie this.
While stress is a contributing factor to COPCs, and to many other diseases, it’s certainly not the only cause. Veasley, the patient advocate, said that “stress from a patient perspective is kind of a hot-button trigger word, because so many people have been told to just relax and you wouldn’t have these conditions, that you’re being hypervigilant.” She said it’s clear that stress is “not good for your body, it’s not good for your physical and emotional health. On the other hand, being told that you just need to deal with your stress is not necessarily the answer to the problem.”
The importance of stress could explain some of why women are at greater risk for COPCs, because women are also at greater risk for early-life trauma, especially sexual abuse, and for higher stress levels as adults.
But genetics also have a part to play. In a huge study of twins published in 2009, researchers aimed to tease apart the genetic and environmental influences on four conditions, including widespread pain and IBS. They analyzed data from over 30,000 twins in Sweden, where health data is customarily collected over many years.
They found that the conditions all shared two main risk factors, with the relative influence of each factor ranging from 20 to 74 percent, depending on the condition. The first factor, which also influenced risk for anxiety and depression, was more heavily influenced by genetics, and was associated with the emotional aspects of chronic pain – the suffering, so to speak. The second factor was more closely linked with environment and had to do with the actual bodily sensation of pain. Each condition was also influenced by factors unique to it.
As researchers continue to work out the various risks, influences and mechanisms behind COPCs, these seem to grow only more complex. But patients, doctors, and researchers all agree that taking a holistic approach to COPCs will be the key to a better understanding – and better treatments.
Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD