Published January 14, 2021
Editor’s note: Andrea Burden, PhD, is an assistant professor of pharmacoepidemiology at ETH Zürich. Her primary research line focuses on using pharmacoepidemiologic methods to advance assessment of medication safety and effectiveness for management of chronic diseases like rheumatoid arthritis, osteoporosis, diabetes, inflammatory bowel disease, chronic obstructive pulmonary disease, and gout.
For this interview, Burden spoke with Laura Sirucek, a PhD student at the University of Zurich, Switzerland, to explain what pharmacoepidemiology is, why it’s important in pain research, and to share her own experience as a person with rheumatoid arthritis, among other topics. Below is an edited transcript of their conversation.
Andrea, could you tell us what pharmacoepidemiology is and what kinds of questions you are trying to answer?
Pharmacoepidemiology is a very long word to describe something quite simple. At the core we just want to know if medications are working as they should and not causing unexpected problems. Medications are approved through a very lengthy process of clinical trials. These clinical trials are trying to determine whether or not a medication works and that there are no adverse events associated with taking the medication; an adverse drug event is an unintended harmful medical problem that is related to the use of a medication. However, these trials typically include a specific group of patients and take place under very controlled circumstances.
If there’s a favorable risk-benefit profile for the medication at the end of the clinical trial, it will generally be approved by one of the regulatory bodies, such as the US Food and Drug administration. But just because the medication was approved doesn’t mean that there is a complete absence of risk and we also don’t necessarily know how it works in a broader group of patients. Therefore, we need to continue to monitor medications after approval.
As pharmacoepidemiologists, we fill in this gap by studying the medication at a broader population level using healthcare data that could come from doctors, hospitals or pharmacies. We ensure that the medication still works as it should and doesn’t have any long-term adverse events. In addition, we also try to find patients for whom the medication may work best for, so we can get closer to a personalized medicine approach.
Why is the field of pharmacoepidemiology important when it comes to pain research?
There’s a lot to take into account in pain research. One of the main areas to look at is the safety of pain medications. We know that every medication is going to have some adverse effect in some patients, but we want to make sure the benefits outweigh that potential risk.
This is really important with pain medications. Naturally, we want to reduce the pain, but as we’ve seen with opioids, there can be adverse events associated with them and you definitely don’t want to be causing more problems for a patient while you’re trying to solve another one.
However, pain research is quite challenging when we want to look at whether the medications actually work since we don’t always have enough information to identify if and how patients benefit.
You have a very personal connection to one of the diseases you are studying, namely rheumatoid arthritis (RA). Could you share some personal insights about a life with RA?
Yes, a life with RA. I’m actually one of the fortunate people with RA. I was around 20 when I had the onset of my symptoms. It was a rapid, full-body onset; I went to bed one night completely fine and woke up the next morning in excruciating pain.
For a few weeks I was undiagnosed until I got very lucky: a nursing assistant at my doctor’s office recognized my symptoms even though my primary care doctor did not. She literally took me by the hand, walked me across the hall to the rheumatologist in the building and demanded that I be seen by him that day.
I was then put on prednisone and hydroxychloroquine, a disease-modifying antirheumatic drug, and within 12 hours I was symptom-free and doing very well. It’s been 17 years since that time and I’m still largely symptom-free. That is very unusual for an RA patient.
I think that’s one of the reasons why I’ve pushed myself into this field of research. I always wondered why I was a bit lucky – why did I turn out to have so few symptoms, while other patients either never get managed and are constantly living with pain or are going through multiple cycles with relapses. As a researcher, you want to reduce this suffering, find the medications that will work for the right patient and improve their quality of life.
So having RA – that really motivated you to do research in this area?
When I had the onset of RA, I was still doing my bachelor’s degree. I was quite naïve about RA at the time I was diagnosed so the rheumatologist encouraged me to learn more and provided me with some webpages. However, after seeing an image of a joint degrading over time, followed by a deformed hand, I thought, “Ooh, that’s bad,” and then closed the page and purposely blocked doing any research into RA for about 7 years.
But then I started my PhD and I was studying osteoporosis, which is a different disease of the bones. My mom was taking an anti-osteoporosis medication and I started to see this nice connection between the work I was doing and how it could potentially improve my mom’s life. Meanwhile, I would go to my rheumatologist and because I was generally doing quite well with my RA, most of my half-hour meetings with him would end up with a discussion of my research and PhD work in osteoporosis. As he was at an academic hospital, he was very involved with research and would constantly ask me when I would start doing research in RA instead of osteoporosis. With every visit he would give me more stories about why pharmacoepidemiologists need to go into rheumatology research, which pushed me to better understand my own disease and identify the gaps in medication safety and effectiveness in rheumatology.
When I then got the chance to do more independent research as a postdoc and now as an assistant professor, RA definitely became something that I’m very interested in. I also enjoy working with rheumatologists; they have a researcher mentality because there are so many unanswered questions in the field.
Your story really is an example of making the most of a difficult experience. You mentioned your mom’s treatment for osteoporosis. What are your experiences, good or bad, with pharmacological treatments?
I’ve never had a truly negative experience with pain medications; no major adverse events. With the RA it was prednisone that removed the pain. It’s almost a bit of a miracle drug, however, it has a lot of long-term negative effects. Prednisone is something that you try to take only for a few months and then get off of it. Since my pain was manageable this is exactly how it was for me.
However, I have seen negative consequences, particularly from opioid medications, that were not appropriately prescribed. I used to work at an opioid addiction clinic during my bachelor’s degree. I saw people coming in who were prescribed medications like oxycodone [an opioid medication sold under the brand OxyContin] for the pain but were not informed about the potential addictive qualities of it and the danger of dependence. You could really see how it impacted their lives; some of them had lost their spouses and jobs. It was all just very sad.
Speaking of opioids, the opioid crisis is well known in the US and Canada but I am not sure how aware of it people in Europe are. What is your experience with opioids in Europe and what should we learn from the crisis that we have seen in the US?
To answer your first question about the scale of the problem in Europe compared to North America – this is a great point. Whenever I, as a person from North America, try to bring up the topic of opioids, I get told quite frequently that this is just a North American problem and that research in this area is not needed here in Europe.
Yet, in the Netherlands and also in Germany, there’s a steady increase in the use of opioids such as oxycodone. And I consider it important, in research, to recognize that the moment we think that something can’t happen to us, that we’re doing something better than another field of research or another country, then we are likely running the risk of repeating their mistakes.
In the US, there was a huge failing in the legal handling of how certain opioids were advertised and pushed by sales representatives. Doctors were not uneducated or corrupt on the whole; they really had a belief that the medications could work. In Europe, the legal situation for the marketing of prescription medications is different, so this is a rather America-specific issue.
Still, one of the important things that we can learn from these events is to ensure data transparency from a very early stage in drug development. That way, one can have a look at clinical trial results of the drug and check whether there was any information in the sales presentation being hidden, such as addictive potential.
As a next step, we should have active surveillance for these medications to ensure that individuals are not running into addiction problems. This is important for all medications, but particularly for narcotics.
Overall, we also need to look at these issues in Europe. Just because we might not have high use of oxycodone, that does not mean we don’t potentially have an issue with other lower-dose opioids. Tramadol, as an example, is a synthetic opioid that is used heavily in Europe, while in North America it tends to be avoided because it’s a pharmacologically “messy” drug. It would be interesting to look at tramadol use, and its side effects, in Europe.
You mentioned before that in the addiction clinic, you had seen examples of inappropriate prescriptions of opioids and/or a lack of information about the potential risks. Are there cases in which opioid treatments make sense? And should we do something about how the risks and benefits of opioid treatments are communicated to patients?
Opioids absolutely have their purpose in pain management – just likely not in chronic pain management. We shouldn’t hand out a medication, with a known level of dependence, building up in the body for a condition that you are going to live with for many months or years. Over time, you will need more and more of this medication to get the same level of relief. For instance, one big mistake was to believe that opioids are well suited for chronic low back pain. Large quantities of opioids were handed out that would last for a month of use. That is an example of very inappropriate prescribing of opioids.
Can we find circumstances when opioids are ideal? I am not an expert in the area but they are likely ideal for palliative care or for cancer when they are being monitored by a physician. Can we give them to people living in the community? Yes, I think so, however, in my opinion, only for short-term use and acute pain, and patients should be given only enough medication for maybe a couple of weeks. In this way, patients have to return to their pharmacist or doctor, who can check in with them and make sure they’re not going through the medication too quickly and can assess when the medication should be stopped and can quickly identify dependency or abuse problems.
Should we work on the instructions from the doctors’ side? Yes, as well. We need to warn patients of the addictive potential. There might be some patients who would refrain from the drugs just because they know about the addictive properties and would ask for an alternative treatment. If patients still want to use opioids, they should be reminded that these drugs are meant for short-term use and the healthcare professional has to check on the patient regularly.
Lastly, more and more, changes to the guidelines on how to manage pain are being developed and it’s crucial that all doctors – primary care or pain specialists – regularly check in on those guidelines.
To sum everything up: from a researcher’s perspective, and from an individual patient’s perspective, do you have any advice for people seeking treatment for chronic pain?
From a researcher’s perspective, it is very difficult to expect individual patients to be aware of all the potential benefits and risks of their medications. They need to be able to trust their medical provider to a certain degree, whether that’s the pharmacist or their doctor. My message as a researcher is therefore more directed towards those healthcare providers. They have to make sure that they fully understand the medications.
One of the biggest difficulties in achieving this goal is that not all evidence is created equally. Studies can be subject to different types of confounding and bias, which can lead to faulty results. Medical providers should get training so they can critically appraise medical and epidemiological research. Then they can say which studies should be believed, which studies should impact how they prescribe medications and which studies they should put aside and not base their decisions on.
From the perspective of an individual who is seeking treatment for chronic pain, my advice is to ask questions to your healthcare provider – to ask for the current evidence on the best treatment plan for the type of pain that you have. As I said, you have to trust your medical provider, but you can do a quick check of reputable sources. Perhaps check if there have been any warnings from reputable governing bodies about a medication, such as the European Medicines Agency or the US FDA; agencies will release statements if there are concerns about a medication. You can also always look into something like the NICE [National Institute for Health and Care Excellence] guidance from the UK. NICE releases information for patients and looks into how to deal with different disorders. They usually present everything in an understandable way that is friendly for the general public.
The other thing is to trust your gut. The average patient tends to know when a pain treatment can be tapered off. Most patients realize that they have to be aware – that, yes, they try something to relieve their pain but they should not take a medication for the rest of their lives. So, if your gut tells you that you want to take less medication, trust that feeling and discuss it with your medical providers to hear their opinion as well.
Laura Sirucek is a PhD student at the University of Zurich, Switzerland.