This is the seventh in a series of Forum interviews with PRF’s eight new science advisors for 2014-2015.
Eija Kalso, MD, DMedSci, is professor of pain medicine at the University of Helsinki, Finland. She is the immediate past president of the International Association for the Study of Pain (IASP). She is trained in anesthesiology and also received special competence in pain management. Her main research interests include opioid pharmacology, spinal mechanisms of nociception, cancer pain, clinical trial design, evidence-based medicine, persistent postsurgical pain, and the genetics of pain. She currently coordinates the European Union Seventh Framework Programme (FP7) project, GLORIA, which focuses on the role of glia in pain and in opioid tolerance and hyperalgesia, and includes two different lines of drug development. Kalso spoke with Neil Andrews, PRF executive editor, to discuss the projects she is working on now, challenges and opportunities in the pain field, and the importance of considering both mind and body when treating pain. Below is an edited transcript of their conversation.
What are your current research interests?
We are working to understand why acute pain becomes persistent in some individuals. In 1996, I was invited to give a plenary talk at the IASP meeting in Vancouver on this topic, and I worked through the literature all summer. It was a very young field at that time, but since then it has become one of the most important areas in pain research. It’s so fascinating because there are both animal and clinical models that allow us to study mechanisms of chronic pain, risk factors, and how to prevent pain.
One way we are studying the pain chronification process is by examining patients before surgery for breast cancer and assessing their pain sensitivity using experimental pain tests. Then, we give them standardized anesthesia and postoperative pain management, and follow them for five and a half years to learn about factors that may contribute to persistent pain. We are currently investigating pain sensitivity as a phenotype, as well as genetic aspects—we are now working on a genomewide association study. We are also studying psychological factors.
We also have another project that is quite interesting. We have used a quality-of-life measure with 15 dimensions, called 15D, to follow the efficacy of our multidisciplinary pain management programs. The good news is that, on average, our patients benefit significantly in terms of quality of life. The intriguing finding is that for people who do extremely well, their quality of life is still significantly improved even three years after management at the pain clinic, but for individuals who do very poorly and don’t respond to therapy, quality of life continues to deteriorate after they have left the pain clinic. We are now conducting a multicenter study in Finnish pain clinics and are collecting as much information as possible, including biomarkers, to understand why some patients benefit whereas others don't.
Can you tell me about your interest in glia?
I coordinate GLORIA [Glial Opioid Receptor Interface in Analgesia], a multicenter project supported by the European Union that focuses on the role of microglia and astrocytes in different types of pain and in opioid-induced hyperalgesia [see here for more information about GLORIA]. We have animal models of neuropathic pain, opioid-induced hyperalgesia, osteoarthritis pain, and rheumatoid arthritis pain, and we will also develop an animal model of fibromyalgia; we are also studying these pain conditions in people. We are trying to develop new analgesics that will block activation of microglia by the immune receptor Toll-like receptor 4, and we have some new compounds under investigation. We are also interested in glial-derived neurotrophic factors as drug targets for treating neuropathic pain and other conditions where glial activation is involved.
You also work in cancer pain research. What are some of the key research questions in this area?
One of the most important things we have learned is that cancer pain consists of many different components, and therefore most patients need multimodal pharmacological management. Usually opioids are very effective, but there are differences between the different opioids in terms of pharmacokinetics, and there may also be interesting differences in how they function. But we also know that nonsteroidal anti-inflammatory drugs are effective in cancer pain, particularly in cancer-associated bone pain, because the COX-2 enzyme is important for the survival of cancer cells and because inflammation is often present, particularly surrounding bone metastases. These drugs should be very effective for pain and also reduce the growth of cancer and/or metastases. But, surprisingly, while there are many studies on the efficacy of opioids in cancer pain, there are hardly any on the effectiveness of non-steroidals, so this is an area into which we should put more effort.
One new challenge in cancer pain management is that high doses of opioids are not the solution in all patients, many of whom do not achieve good analgesia. One reason for this may be the anxiety, fear, and other psychological factors characteristic of cancer patients. We need much more research in this area, and we should also give greater attention to the psychosocial support of cancer patients in the clinic.
Another possibility why opioids can be ineffective is that they cause hyperalgesia, and the pain becomes opioid-insensitive. In this respect, ketamine, which is an NMDA receptor antagonist, is a very exciting tool, and understanding the pharmacology of ketamine is another research interest in my group, both in the clinic and in the lab.
Finally, several decades ago, opioids were used only in the terminal phase of cancer, but now the situation is very different because many cancer patients who have been on opioids are either cured or are in remission. We need more research in cancer survivors to understand their pain problems and the place of opioids in their treatment. Because many cancer patients who have been on opioids now survive, we have become aware that they may have become dependent on these drugs, and so we also need to find new tools to manage their pain.
There is a lot of effort among pain researchers to examine the placebo effect—another area in which you have been active. Could you share your thoughts about these investigations?
Research in this area has had a great impact on how I think about the power of the mind in relieving pain. One of the most important studies in which I was involved used positron emission tomography to show that exogenous opioids like remifentanil and the placebo effect activate partly overlapping systems in the central nervous system. This finding spurred a lot of research on the mechanisms of placebo analgesia, and is an area that continues to expand each year. This field of research has had a significant impact on understanding how important the patient-physician relationship is. That relationship can either enhance or decrease the efficacy of the therapeutic intervention being tried. But if the interaction doesn't work—for instance, if the patient feels insecure, or if there is conflicting information where one physician says the intervention works and another says it doesn’t—then there may be a nocebo effect, which can eliminate a large part of the efficacy of therapy. So it's not just the drug itself that is important, but also what the patient thinks about whether the drug is going to work or not.
Looking at the pain field more generally, are there any obstacles that are hindering research?
One of the major challenges is the huge bureaucracy facing clinical trials. This has made it impossible for clinician researchers to initiate studies. Clinical trials also require increased levels of funding. As an example of these problems, the most effective drug we have in Europe for neuropathic pain is amitriptyline; it is a very old drug. It is also a very cheap drug, but there are very few clinical studies of amitriptyline, and existing studies are rather small because no pharmaceutical company is interested in studying it. Clinician researchers just don't have enough resources to study an old drug using the current criteria that are required for clinical trials. Overall, funding for research is getting more difficult in most of the Western world, which is a big problem.
What is the path forward?
In numerous countries in Europe, many patients are treated at university hospitals. But it's very hard to do clinical research unless you have a sufficient research budget. So I think that, particularly in university hospitals, all patients should be research subjects. In Finland, we have a National Health Service, and the amount of money that patients pay is minimal. We should consider patients as partners in healthcare-related research. Patients who receive treatment for very little money should participate in research by providing biomaterials, such as blood samples, or tissue that has been removed during surgery. This will benefit not only their own treatment, but also future generations of patients. If there are any studies of new interventions, patients should be encouraged to participate, particularly because many of those interventions are in no way dangerous to them. Of course, if there is a risk to the patient, then he or she should have the option of not participating.
What are some promising developments in pain research?
There are many new targets that look quite promising. Transient receptor potential A1 (TRPA1) is particularly intriguing, because a drug that targets it could be the first disease-modifying analgesic we have for neuropathic pain.
Another exciting area is the use of modern technology in pain management. One fantastic example is a virtual reality program called Snow World, which has been developed at the University of Washington. We have been trying to bring this program to our hospital, where we would use it in the unit for burn patients, but it is not commercially available. Snow World is a game where a burn patient can throw snowballs at penguins. While concentrating on doing that, the patient doesn't notice that the nurses are attending to daily wound care, which can be very painful. So instead of giving lots of analgesics that may make the patient drowsy, particularly after the wound is taken care of, the patient can be engaged with this virtual reality program and not notice the pain.
This is an example of the power of the patient’s mind, which we still underestimate, particularly when it has a positive impact. We know a lot about the obstacles the patient’s mind may create in the rehabilitation process, but patients also have positive resources that can greatly benefit them.
Do you have any advice for young researchers?
Pain is the most fascinating field of research because feeling pain is at the core of humanity, and because the main goal of medicine is to relieve suffering. Pain is such an integral part of being a human being, and can be studied in many different ways. You can take just one part that you are really interested in, but what may happen next is that you will also become interested in surrounding fields. That will certainly expand your understanding of the patient as a whole human being, including the mind and the body, which are inseparable. What I have really enjoyed in my own work is that I’ve done research in very standardized circumstances, such as in the pharmacology research lab where I do basic research, but I’ve also tried to understand patients as whole human beings and how the mind affects the body and the body feeds back to the mind; an example is my research on placebo mechanisms.
Also, a person needs to cross borders in order to be a good pain researcher. For instance, an anesthesiologist with an interest in pharmacology should learn more about psychology, neurology, and other areas. And it is important to cross borders not only within the clinic but also from the clinic to the lab, and from the lab to the clinic, to really understand the multifaceted phenomenon of pain.
Is there anything else you would like to add?
Multidisciplinary pain clinics have been shown to be the best model when treating chronic pain, and there are many other disciplines that are now adopting many of the models that pain clinics have developed. This is something our field should be very proud of—that, in fact, we have been at the forefront of understanding the patient as a whole human being.
Thank you so much for speaking with PRF.
It has been a pleasure speaking with you.
See PRF related content on the right.
Lilius TO, Jokinen V, Neuvonen MS, Niemi M, Kalso EA, Rauhala PV
Br J Pharmacol. 2014 Oct 9. Epub ahead of print.
Meretoja TJ, Leidenius MHK, Tasmuth T, Sipilä R, Kalso E
JAMA. 2014 Jan 1; 311(1):90-2.
Kaunisto MA, Jokela R, Tallgren M, Kambur O, Tikkanen E, Tasmuth T, Sipilä R, Palotie A, Estlander A-M, Leidenius M, Ripatti S, Kalso EA
Anesthesiology. 2013 Dec; 119(6):1410-21.
Kambur O, Kaunisto MA, Tikkanen E, Leal SM, Ripatti S, Kalso EA
Anesthesiology. 2013 Dec; 119(6):1422-33.
Borsook D, Kalso E
Eur J Pain. 2013 Sep; 17(8):1109-25.
Moore A, Derry S, Eccleston C, Kalso E.
BMJ. 2013 May 3;346:f2690.
Sipilä R, Estlander AM, Tasmuth T, Kataja M, Kalso E.
Br J Cancer. 2012 Oct 23;107(9):1459-66.
Petrovic P, Kalso E, Petersson KM, Ingvar M.
Science. 2002 Mar 1;295(5560):1737-40.
Other Forum Interviews with PRF’s 2014-2015 Science Advisors: