This is the eighth in a series of Forum interviews with PRF’s eight new science advisors for 2014-2015.
Claudia Sommer, MD, is a professor of neurology at the University of Würzburg, Germany. She received training in psychiatry, neuropathology, experimental anesthesia, and neurology. At the University of Würzburg, she serves as a consultant in neurology, organizes an outpatient clinic for patients with pain, and leads the Peripheral Nerve Laboratory. With her research group, she investigates the role of cytokines in the pathophysiology of pain, the improvement and standardization of diagnostics in neuropathies, and the pathophysiology of antibody-mediated diseases. She is active in the development of national and international guidelines on treatment of peripheral neuropathies, on nerve and skin biopsies, and on treatment of fibromyalgia and neuropathic and facial pain. Sommer spoke recently with Neil Andrews, PRF executive editor, to discuss what led her from the field of psychiatry to pain research, the evolving understanding of fibromyalgia that she is helping to push forward, and the challenge of understanding the role of cytokines in pain. Below is an edited transcript of their conversation.
What was your path to pain research?
I started my career in psychiatry, and learned some things about pain in that field. For example, I was surprised to see people with spinal cord stimulators on the psychiatric wards who had lots of problems; this early experience may be something that biased me against very invasive measures for pain treatment. I then worked in neuropathology, because I wanted to see things—to see what somatic disease actually looked like—rather than only listen to the problems that patients had. My research area was the peripheral nerve, and since peripheral neuropathies are often very painful, I was already on my way to pain research.
I then did training as a neurologist, where I continued to study peripheral neuropathies. When I completed my training, I met Bob Myers at one of the Peripheral Nerve Society meetings. He was at the University of California, San Diego, and invited me to come there as a postdoc to help establish the Bennett [chronic constriction injury of the rat sciatic nerve] model of neuropathic pain in his lab and work with it. I found this work very interesting, and so my interest in pain research grew further. After spending two years in San Diego, I went back to Germany and obtained staff positions, first as a neurologist at the University of Aachen, and then as a professor of neurology at Würzburg University Hospital. From then on I knew that my fields of interest were pain and peripheral neuropathies, and I’ve been pursuing them ever since.
What was it specifically about pain that interested you?
As a scientist, on one side, pain is a phenomenon where we can learn a lot about biological mechanisms in the peripheral and central nervous system; I’ve always been fascinated by the nervous system—that’s why I became a neurologist in the first place. On another side, patients who come to pain specialists have real problems and need help. Trying to bring these two sides together—science and clinical work—has always interested me, and pain is a very good area to do this.
What are some of the projects you are working on now?
At present and over the last few years, we have been very interested in fibromyalgia, which is a very difficult pain syndrome. There are many people who don’t believe that fibromyalgia exists at all; there are others who call it a somatoform psychological disturbance; and there are yet others who consider it a central pain syndrome. Our lab is a peripheral nerve lab, and so we have looked at the periphery in fibromyalgia patients and found some pathology and loss of function there; other groups have found this as well (see PRF related news story). In the beginning, this was more or less a chance finding that we didn’t really expect. But since our initial findings, research in this area has really taken up speed. We have seen many patients, and are continuing to study them even more thoroughly.
The big question now is why fibromyalgia patients have abnormalities in the peripheral nervous system—what exactly is happening there? This is a very exciting field because, as I mentioned, fibromyalgia is a disorder that isn’t even accepted as a disease by many people. Even those who do believe that it exists say it’s very enigmatic and that we don’t know why fibromyalgia patients are in pain, and so finding that there is actually pathology in the periphery is very exciting. One problem, though, is that fibromyalgia is very difficult to model. There are some models for aspects of fibromyalgia, but not for the disorder as a whole, and so we are working on that aspect, too.
You mention the skepticism about fibromyalgia as a real disease with scientific underpinnings. Is your research helping to change how people view this condition?
There is still a lot of resistance, though I know we have convinced some people. Sometimes after I give talks, colleagues come up to me and say that until they heard my talk, nobody had been able to convince them that fibromyalgia is a real disease. But I still get many calls from patients who tell me that they have suffered from pain for several years and that their doctor could never explain it. In fact, just earlier today, before this interview, a woman told me that a few days ago she stumbled across the term ”fibromyalgia,” read about it on the Internet, and after reading about all the symptoms, realized it was exactly what she had. But when she told her doctor about it, the doctor laughed and said the disease doesn’t exist and that it was all in her head.
So there is still skepticism, and it’s going to be a long way before we can convince everyone, but the more we work toward finding physiological abnormalities in fibromyalgia patients, the more we will be able to sway our colleagues.
What other projects are going on in your lab?
Another area of great interest to our lab is the role of microRNAs in pain (see PRF related webinar). We are part of a consortium, funded by the European Union and including partners from many different European countries, which is looking at microRNA patterns in different pain diseases. We are looking primarily at neuropathic pain conditions such as diabetic neuropathy and complex regional pain syndrome. What we are trying to determine is whether there are differences in microRNA patterns between patients who suffer a nerve injury and go on to develop neuropathic pain and those who don’t, and whether those differences could serve as prognostic factors to help guide treatment decisions very early in the course of disease.
We are very much at the beginning in this area of research, and at the moment we are phenotyping large cohorts of patients and collecting material from them so that we have a really good patient database. Then the microRNAs will be analyzed, and we hope we will find patterns emerging there.
You also have a long-standing interest in the role of cytokines in neuropathic pain. Are you continuing work in that area?
Yes. We started off looking at the contribution of cytokines to pain by using animal models. We asked whether there were higher cytokine levels in tissue from animals exhibiting pain behaviors compared to normal animals, and whether we could induce pain by administering certain cytokines or treat pain by blocking them. This is an area that was explored by many labs, and it became accepted that pro-inflammatory cytokines induce pain, and anti-inflammatory cytokines reduce pain, working in the periphery and perhaps in the central nervous system as well.
Our next step was to take the research into the clinic, but this wasn’t easy because while we thought that patients with more pain should have higher cytokine levels, this was not always the case. We have published a few negative studies on this question, but we also did find some correlations. Of course, in humans there are many more factors that need to be considered, since the clinical situation is different from the standardized environment characteristic of the animal models.
We found that patients with fibromyalgia have lower levels of interleukin-4 (IL-4), which is an anti-inflammatory and analgesic cytokine. We have taken this finding back to an IL-4 knockout mouse, which also has a pain phenotype, and are exploring the pain protective effect of IL-4 in the animals. In neurophysiological experiments, we have made recordings from spinal cord dorsal horn neurons from the knockouts and are now looking at how those neurons react to pain stimuli. The groundwork has been laid for studying the cytokine contribution to pain, and now one has to go deeper into some of the specific mechanisms at play.
Can you say a bit more about why an understanding of the cytokine contribution to pain has been elusive?
At first it seemed quite simple: it was thought that if TNF [tumor necrosis factor] levels were elevated, then levels of prostaglandins and bradykinin would also increase—these compounds all exist in one cascade—leading to pain. But the more work that was done in this area, the more complicated things became. For example, if you inject a cytokine in the periphery, it may induce pain, but if you inject the same cytokine in a specific brain area, it might block pain. Furthermore, if you block one cytokine, nothing may happen because others may take its place, since cytokines are pleiotropic and redundant.
It’s a very difficult system to fully comprehend, and even if you can establish some rules for how cytokines function in the setting of pain, the rules may not apply to all disorders. For instance, in some painful diseases, like rheumatoid arthritis, it is quite clear that TNF has an important role, as does IL-1 and probably IL-6; if you administer drugs to block these cytokines, you can reduce pain and even ameliorate the disease. But in other disorders, such as low back pain, the data have been going back and forth with positive results and negative results, and it is like this for many pain disorders. So although in laboratories we know very well what the cytokines do, in clinical pain diseases we still need some time to gain a good understanding of the role that cytokines play.
Tell me about your work on autoantibodies and pain.
One of the diseases that we have looked at in detail is a very painful condition called stiff person syndrome. These patients have stiff muscles that hinder movement, and they experience muscle spasms that are extremely painful. Why stiff person syndrome is painful is a question for people looking specifically at muscle pain, but we have looked at general mechanisms that may underlie this disorder. We have found that stiff person syndrome has features in common with some pain disorders. For example, there is a lack of inhibition in the spinal cord because of deficient GABAergic or glycinergic signaling, which is also a mechanism in central pain disorders. In stiff person syndrome, the effects are mostly observed in the motor system, and problems with the sensory system are probably secondary, although we don’t really know that with certainty.
What we did was treat these patients using plasma exchange. The patients allowed us to use their autoantibodies, which we obtained from plasma exchange material, for experiments where we could look in vivo and in vitro to study what the antibodies do. This was a great tool for answering some interesting questions, such as how the autoantibodies influence synaptic transmission. Although this wasn’t pain research per se, we learned a lot from this autoantibody-associated disease for our pain studies.
We are also studying the pathophysiology of peripheral neuropathy, which is often associated with autoantibodies. We are looking at autoantibodies directed against nodes of Ranvier, which are structures in the peripheral nerve that are needed for saltatory conduction along the axon.
Looking beyond your own work, what research is catching your eye?
What has been and is really exciting is work on ion channels, especially research on voltage-gated sodium channels, which has been an eye-opener. There were diseases characterized by too much pain or insensitivity to pain that nobody could explain, but then it was discovered that one mutation in one ion channel could be responsible for these diseases. Work on TRP channels has also been very interesting. But the larger context is genetics in general, since there is more to pain genetics than voltage-gated sodium channels and TRP channels, although these have been quite prominent in the literature. Many genetic factors have been described that influence pain sensitivity, and that is very important from a conceptual point of view—it’s not that a person is weak and cannot endure pain, but rather that the person has a genetic susceptibility such that pain is perceived more strongly. Just learning that has helped us a lot.
Are there any obstacles hindering pain research?
Of course, there isn’t enough grant money. In the field of neurology, it is easier to convince people that research is needed for diseases like stroke, Parkinson’s disease, and Alzheimer’s disease, since these are diseases that everybody knows by name, whereas pain is still difficult to grasp. That’s certainly an obstacle.
Another challenge, especially for research on treatments, is that pain is very difficult to assess; we have no objective measures. If there is a new treatment for stroke, for instance, you can measure how far a person can run after the treatment, or their muscle strength; there are many things that can be measured better than pain. This is something that hinders clinical trials and the development of more effective treatments.
Do you have any advice for young researchers?
First, I recommend that researchers read through all the literature, look at the groups who have done really good work, see what you find exciting, and then try to join one of those groups. By working in a really good laboratory, you will learn what you need to become a good researcher, regardless of whether or not you stay in pain research later on. Second, you should focus on what really interests you, as it is very likely you will become good at research in the area that most captures your attention.
Can you talk about the challenges of working in the lab and the clinic?
I must admit that this involves sacrifice, because, all the time, you think about how you are not doing one or the other enough justice. There are few clinician-researchers who can compete with the best basic researchers, because we just can’t put in enough time and energy to it. And, of course, there are pain clinicians who are much better than I am because they devote all their time to patients. People like me need to team up with others who are excellent basic scientists, and also with clinicians who see other kinds of patients that I would not see. In the end, teamwork is one of the very important things that we need in the pain field.
Thank you for speaking with PRF.
Thank you—this was fun!
See PRF related content on the right.
Uçeyler N, Riediger N, Kafke W, Sommer C
J Neurol. 2015 Jan; 262(1):203-12.
Uçeyler N, Valet M, Kafke W, Tölle TR, Sommer C
PLoS One. 2014; 9(8):e105269.
Uçeyler N, Sommer C
Pain. 2013 Nov;154(11):2569.
Uçeyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, Casanova-Molla J, Reiners K, Sommer C
Brain. 2013 Jun; 136(Pt 6):1857-67.
Pain. 2011 Dec; 152(12):2675-6. Epub 2011 Jul 30.
Üçeyler N, Topuzoğlu T, Schiesser P, Hahnenkamp S, Sommer C.
PLoS One. 2011; 6(12):e28205.
Uçeyler N, Kafke W, Riediger N, He L, Necula G, Toyka KV, Sommer C
Neurology. 2010 Jun 1; 74(22):1806-13.
Uçeyler N, Eberle T, Rolke R, Birklein F, Sommer C
Pain. 2007 Nov; 132(1-2):195-205. Epub 2007 Sep 24.
Other Forum Interviews with PRF’s 2014-2015 Science Advisors: