In Conversation: How to understand chronic pain

Chronic pain, a disease process that is so complex that we are only just beginning to understand its triggers, has recently been gaining recognition as a medical condition on its own. But how does living with chronic pain feel? And how do the body and brain deal with it?
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Aching, dull, gnawing, burning, sharp, shooting, piercing…
These are just some of the words people tend to use to describe their pain.
Now imagine you had to endure a bit of this every waking day until you don’t know what it’s like to go about your day without this baseline of pain slowly depleting your mental and physical energy in the background.
That is the reality for many people who deal with chronic pain.
Some days may be great, some days bad; the signs may not always be visible and it may be an inward battle hidden behind gritted teeth and forced smiles.
But how does chronic pain become, well, chronic?
In the latest installment of our In Conversation podcast dedicated to Pain Awareness Month, Medical News Today dives into the science behind chronic pain with Dr. Hilary Guite and Dr. Tony L. Yaksh, professor of anesthesiology and pharmacology at the University of California, San Diego, as Joel Nelson, longtime psoriatic disease and arthritis patient and advocate, shares his personal journey with pain.
Dr. Tony L. Yaksh
Joel Nelson

Primary and secondary chronic pain
Chronic pain may often be dismissed as purely a symptom of a larger problem or not taken as seriously because it is not life threatening. However, the burden of chronic pain is not only personal but also societal.
Studies show that people with chronic pain may have difficulty in going about their daily lives and doing activities, as well as have poorer overall health. People with chronic pain may also have to deal with job insecurity or unemployment.
Studies
It wasn’t until 2018 that the International Classification of Diseases (ICD) gave chronic pain its own code, in the preliminary version of the new ICD-11 coding system, paving way for its recognition and diagnosis.
until 2018
the International Classification of Diseases (ICD)
ICD-11 coding system
According to the World Health Organization (WHO), chronic pain is now classified into two categories: chronic primary pain and chronic secondary pain.
Primary pain, according to this classification, refers to pain that is not caused by or cannot be explained by another medical condition. Some examples may be fibromyalgia or chronic primary low back pain.
back pain
“Fibromyalgia [is] a condition that varies from person to person, but is a widespread pain condition affecting at least 4 to 5 regions of the body and lasts at least 3 months but usually longer. No other cause is found for the pain and it is, therefore, a type of primary chronic pain,” Dr. Guite explained.
Secondary pain, on the other hand, is secondary to or caused by an underlying medical condition. Arthritis, cancer, or ulcerative colitis-related pain would fall within this umbrella.
cancer
The very personal experience of chronic pain
“[M]y chronic pain started around 10 years old. And [since] then, chronic pain has kind of been an intermittent part of my life right through to the present day,” Joel Nelson told MNT‘s In Conversation.
Joel is now 38 years old, which means he’s been living with chronic pain for a good few decades.
“[M]y first experience with pain was [when] I got a pain in my hip; it was like a gravelly sort of burning feeling. And it just progressed; the more I used the joint, the [more it got] worse, it got to the point where I [was] sort of losing mobility,” he said.
That was the point he decided to reach out for help—as most people do.
Joel said one word to describe his chronic pain is “noise.”
“I always have described it as noise because on the days when that pain is intense, my ability to absorb other information, deal with multiple things at a time, it’s just gone,” he said.
“Living with my condition today, I think the most important takeaway about the experience is the fluidity of it. [U]ltimately, [my limits and mobility] can range from anything to where I can do more than walking, and I might be able to do a bit of running and cycling like I am currently, to next week I might be back on crutches. [A] lot of that is dictated by pain. So with arthritis, I get a lot of morning stiffness, but it’s the pain that limits my ability to do things.”— Joel Nelson
Likening it to “a series of chapters,” Joel said it’s not easy to anticipate what will happen next with his chronic pain.
Transitioning from acute to chronic pain
Behind acute pain becoming chronic, scientists have found that a gateway receptor called Toll-like receptor 4 (TLR4) may be a controlling factor.
Toll-like receptor 4
“We know that under a tissue [or nerve] injury of various sorts that we can activate signaling that normally is associated with what we call innate immunity. And one of the mediators of that is something called the toll-like receptor and it turns out that while those are normally there to recognize the presence of foreign bugs, for example, E. coli, those bugs have in their cell membrane, something called lipopolysaccharide, or LPS. We don’t have that normally in our system, but it comes from bacteria,” said Dr. Yaksh.
E. coli
“You’re born with it, you don’t have to develop it. It’s there all the time. What we’ve come to find out over the last years [t]hat there are many products that your body releases that will [a]ctivate those very same toll-like receptors,” he added.
Toll-like receptors may prime the central immune system for heightened states of pain. In response to harmful stimuli, stressors, or tissue injury, especially in the microbiome or the gastrointestinal tract, the body starts to release products from inflammatory cells.
“When this happens, these products that are released from our own body can [a]ctivate these toll-like receptors, and there’s [one] we call TLR4 [which] is present on inflammatory cells, and it’s also present on sensory neurons,” he explained.
Dr. Yaksh said that activating TLR4 itself doesn’t cause as much pain, but that it sets the nervous system up to become more reactive.
Coupled with this priming, if there are other stressors present at the time—such as a bad diet or psychological distress, pointed out Dr. Guite— this can set off a whole cascade that can fuel this transition to chronic pain.
“[The activation of TLR4] sets up a whole series, a cascade in which there will be an increased expression of a large number of receptors and channels that are able to drive an enhanced response of the system. When this happens, you get this enhanced response downstream to the initial tissue injury. It’s not so much that [it] causes the pain condition, it just sets the system up to be more reactive.”— Dr. Tony Yaksh
He said Joel’s situation fits within the notion that a person can transition from one type of pain to another.
“[T]hat can be exacerbated by the stresses that are ‘psychological’ which can exacerbate a pain state to one that may, in fact, have an underlying physiological component that we may not really understand,” he added.
In Joel’s case, for example, Dr. Yaksh suggested it was likely that the stress (and joy) of becoming a father and all the other aspects played a role in what exacerbated Joel’s condition, and made it harder to keep the pain under control. He stressed that this did not make the pain any less real.
stress
“I think that probably there was this very strong, emotive component that’s associated what Joel’s situation was, […] that the pain condition and the events that were associated with the psoriatic diagnosis and other aspects, perhaps, in fact, did establish the transition from one state to another— [what] we call a transition or an acute to chronic, or the chronification of the pain state,” he elaborated.
Is it all in the brain?
Theories so far suggest pain happens at the intersection of where the body meets the brain.
“[Y]our comment about pain [being] in the brain is absolutely the correct way to think about it; the output function of anything comes from the higher centers,” said Dr. Yaksh.
It all boils down to how the brain registers pain when there is tissue damage.
boils
Pain is a crucial function for our survival; it is essentially a warning system that alerts our bodies that there is damage or illness to deal with. After an illness or injury, the nerves surrounding the area start sending signals up to the brain through the spinal cord, which encourages us to get help and stop further damage.
After the body sustains an injury, the damage to the body’s organs and tissues triggers an acute inflammatory response that involves immune cells, blood vessels, and other mediators. However, sometimes, even after this initial injury phase passes and the body heals, the nervous system may stay in this state of distress or reactivity.
When this happens, the body may become hypersensitive to pain. If this increased sensitivity is to heat or touch around the injured area, this is called “peripheral sensitization.”
peripheral sensitization
“[I]f I were to jam my finger, or if I were to develop, in Joel’s case, an event that leads to a local autoinflammation of the joint, then, in fact, that inflammation leads to the release of factors, which now sensitize the innervation of that joint,” Dr. Yaksh elaborated.
inflammation
Dr. Yaksh said this is something all people experience, regardless of whether it is chronic pain. He explained that after an injury, however, an innocuous activity such as wiggling one’s finger can “[become] extraordinarily noxious.”
He described this as a sensitization generated by peripheral injury and inflammation, where this information is then relayed to the brain through the spinal cord.
“The brain is now seeing what is otherwise an innocuous event, generating a signal that looks as if, as we would say, hell has frozen over, bad news is coming up the pipe.”— Dr. Tony Yaksh
How stress can amplify pain
However, sometimes this prolonged response to the initial injury may cause the lingering pain to be widespread, rather than localized to the injured area. This is called “central sensitization.”
central sensitization
“[I]t’s interesting in [Joel’s case], that you clearly have a peripheral issue, whether it’s the inflammation of a joint, inflammation of the skin, or changes in peripheral nerve function. And so not only do you get changes in joint morphology and things of that sort, but you actually get changes that lead to changes in the way that the information that goes into the spinal cord, and then to higher centers,” Dr. Yaksh explained, “and you’ve activated specific populations of sensory fibers that are normally activated only by severe injury.”
“[I]t’s possible for that spinal cord, which is now, in a sense, organizing the input-output function from the periphery to the brain can become reorganized very much like if I were to take a radio and turn the volume up—the signal to the radio hasn’t changed, but the volume gets louder. So, think of the spinal cord as a volume regulator.”— Dr. Tony Yaksh
“And it says, bad news has happened. But we now know actually, that some of that input that comes up the same pathway [g]oes to areas of the brain that has nothing to do with where that pain [comes] from—only that it is intense,” he said.
These outputs that travel up the spinal cord inform the brain of where and how intense the pain is. One area these are processed in is the limbic system, or “the old smell brain,” said Dr. Yaksh.
the limbic system
“These are areas of the brain that are, in fact, associated in humans with the input associated with emotionality,” he added.
This stress can also modulate how pain is perceived by the body; it can cause muscles to tense or spasm, as well as lead to a rise in the levels of the hormone cortisol. This may cause inflammation and pain over time.
This can, in turn, can lead to sleeping problems, irritability, fatigue, and depression over time, creating a vicious cycle that adds to an already stressed nervous system, worsening the pain.
sleeping problems, irritability, fatigue, and depression
Mindfulness and the neuroscience of pain
Although treatments for acute pain often involve taking various medications such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or opioids, treatment and management strategies for chronic pain are quite limited.
NSAIDs
“[W]e started out this conversation by saying pain is in the brain. And your perceptions of what the world is about impact you very directly, and in a way that is actually experimentally definable, changes the way your brain reacts. So when I say pain is in the brain, I am not saying it’s, it’s any less real in any way, shape, or form. It’s a real thing,” said Dr. Yaksh.
“We now teach medical students that, you know, just because you don’t see the primary diagnosis as being a swollen joint doesn’t mean the patient doesn’t have something,” he pointed out.
Dr. Yaksh said mindfulness is often used in therapy to treat or manage fibromyalgia. He said that this doesn’t mean there is no physiological component of fibromyalgia and indeed, recent research has shown that it is very likely to be an autoimmune condition — “just as real as the presence of antibodies that define the presence of an arthritic joint,” he said.
treat or manage fibromyalgia
very likely to be an autoimmune condition
“Mindfulness, in a way, can help the individual respond to the nature of the afferent traffic that’s coming up the spinal cord; it’s not something you could become mindful enough to say have surgery done. But it might [t]ake the edge off of some of the things that are, in fact, driving this exaggerated response. Fibromyalgia is a perfect example.”— Dr. Tony Yaksh
“[Mindfulness] doesn’t make the pain state any less real [but it] demonstrates that changing the way you think about your pain condition [can] help you deal with that pain condition,” he said.
Joel added that, from the perspective of someone with chronic pain, it is a journey to see how the brain and the body work together to maintain pain:
“….[I]t is a really delicate conversation when you talk about pain and it residing in the brain and, as somebody who’s gone full circle through that journey of being horrified when that was first suggested to going through pain management, and then understanding it so that I could process it better. It changed everything for me.“
What the future holds for treating chronic pain currently remains unclear. However, hope is that drugs might be developed to impact receptors such as TLR4 in a way that might not result in the pain going from acute to chronic, and that our understanding of how psychological processes interact with the neuro-immune interface increases over time.
psychological processes interact with the neuro-immune