"Pain not just a symptom"
10 June 2022
Pain is often seen as a symptom, but it can be a disease in itself which requires treatment. One example is fibromyalgia, which mainly affects women. Professor Eva Kosek has extensive experience in pain research and has now returned to Uppsala, where 40 years ago she studied medicine.
We meet at Uppsala University Hospital’s pain clinic. Here, Eva Kosek works clinically with patients one day a week. The rest of the time, she leads two research groups, one at Uppsala University and one at Karolinska Institutet.
Upon being appointed professor at Uppsala University in autumn 2020, she retained her previous professorship, at Karolinska Institutet.
“Pain is a somewhat neglected area in Sweden, especially clinically, but also perhaps in clinical research. That's one explanation for this shared professorship. I find that the clinical base in Stockholm is very weak, but the clinic in Uppsala is one of the best in Sweden."
She now hopes to increase collaboration between Karolinska Institutet, which has outstanding preclinical pain research, and Uppsala University, which has good clinical pain research.
Second most common cause of sick leave
Today, pain is the second most common cause of sick leave in Sweden, after mental illness. Pain is often considered a symptom that disappears once its underlying cause is treated, for example, by knee surgery or treatment for rheumatism. But it’s not always that simple.
“If you have a long-term pain condition where pain is initially a symptom, it can still be that after the nervous system has been bombarded by pain signals for a long time, the function of the nervous system changes and starts to amplify the pain signals, becoming like a loudspeaker where you turn up the volume. In some cases, it seems to be irreversible," says Eva Kosek.
For example, about 30% of patients with back pain or arthritic knee-pain who undergo surgery are not pain-free afterwards. This also applies to patients with rheumatism. For 20-30%, the troublesome pain persists despite successful treatment of the inflammation.
Studies of fibromyalgia
This type of pain is called nociplastic pain. One example is fibromyalgia, a whole-body pain that mainly affects women. With experiments where pain stimulation was administered to subjects who rated their own pain, researchers have developed response curves. They also use magnetic-resonance imaging to study the brain’s pain response.
“On the one hand, we have seen that people with fibromyalgia are much more sensitive to all types of pain stimuli. On the other hand, we can see that, during pain stimulation, they do not activate their pain-modulation system in the normal way. We have been able to pinpoint the location in the brain of this dysfunction as well as how it is affected by, for example, expectations."
Interaction between the immune and nervous systems
Researchers are also studying how the immune system and the nervous system interact, by looking for different biomarkers in blood and cerebrospinal fluid. For example, people with pain have been found to have increased levels of cytokines, proinflammatory substances, in their cerebrospinal fluid.
You might think that these substances increase pain, but it may also be a defence mechanism, says Eva Kosek.
“In patients with osteoarthritis of the knee, we have observed a negative correlation between the levels of some of these cytokines and how much pain the patient experiences. This contradicts our expectations quite definitively, so now we are investigating this further. It is quite exciting, since it could potentially lead to other treatments.“
The researchers also use PET scanners and have observed, in fibromyalgia patients, an activation of the brain's immunocompetent cells. These cells trigger the immune system, suggesting that something is happening in the interaction between the immune system and the nervous system.
Antibodies in fibromyalgia
Another line of research, which has received much international attention, is antibodies in people with fibromyalgia. In collaboration with Camilla Svensson, professor at the Department of Physiology and Pharmacology at KI, they have drawn blood from patients with fibromyalgia, extracted antibodies and injected them into mice.
The researchers have found that the antibodies bind to a specific type of cell, known as satellite glial cells, which are activated. These satellite glial cells surround the cell bodies of the nerve cells and probably release substances that affect the nerve cells and amplify pain signalling.
The findings have attracted considerable international interest. Not least, UK newspaper The Guardian named the study one of 2021's ten most important scientific discoveries. Eva Kosek sees big opportunities ahead.
“Should we succeed in this, we could have diagnostic methods for some severer forms of fibromyalgia. Then you could select patients with lots of these antibodies and offer currently available immunomodulatory therapy. Ultimately, entirely new biologicals could be developed specifically for fibromyalgia.“
When Eva Kosek started researching fibromyalgia, back in 1996, she was asked: "How can you research something that doesn't exist?" A lack of belief on the part of GPs remains a serious problem, especially for fibromyalgia patients, but also for other sufferers from long-term pain.
“This is partly due to the misconception that all pain is symptomatic. Considering pain as a disease in itself makes it easier to comprehend. You don't need to see anything on the x-ray, there may be something wrong with pain regulation.“
Eva Kosek works extensively to spread information about pain as a disease. She led the working group of the International Association for the Study of Pain that introduced the term ‘nociplastic pain’. And she is looking forward to the new global diagnostic codes in the International Classification of Diseases (ICD 11), which will soon be in use.
“Pain has finally been given its own chapter, using the term ‘primary pain’ for pain as a disease. This is a direct reflection of our own research and that of others," says Eva Kosek.
Clinical Pain Research
The pain research at the Department of Surgical Sciences, Uppsala University consists of several projects with the aim to determine the causes of chronic pain, why certain individuals develop chronic pain while others, with similar injuries/diseases do not, and how the treatment of the various types of chronic pain can be optimized. '
The main research questions are: How does the nervous- and the immune-system interact in different types of chronic pain? Why does a certain type of nerve injury lead to the development of chronic neuropathic pain in certain individuals but not in others? What are the associations between sleep and pain? Why does opioid tolerance, dependence and addiction develop and how can it be prevented? How does invasive neurostimulation work and when to use it?
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