Editor’s note: The 17th IASP World Congress on Pain took place September 12-16, 2018, in Boston, US. At the Congress, 12 early-career pain researchers took part in the PRF Correspondents program, a science communications training experience that provides participants with knowledge and skills needed to communicate science effectively to a wide range of pain researchers and to patients and the wider public. As part of this program, the Correspondents conducted interviews with plenary speakers.
Here, plenary speaker Jane Ballantyne, MD, sat down to chat with PRF Correspondent Nick Fallon, PhD, a research fellow at the University of Liverpool, UK. Ballantyne is a professor of anesthesiology and pain medicine at the University of Washington, Seattle, US. She received her medical degree from the Royal Free Hospital School of Medicine in London, UK. She trained in anesthesiology at the John Radcliffe Hospital in Oxford, UK, before moving to Massachusetts General Hospital (MGH) in Boston in 1990. She began her research career working with statisticians at the Harvard School of Public Health and Tufts Center for Evidence-based Medicine, developing an evidence base for the Agency for Healthcare Policy and Research (AHCPR, now AHRQ) pain guidelines. She became chief of the Division of Pain Medicine at MGH in 1999 and moved to the University of Washington in 2011 as a professor of education and research.
In this interview, Ballantyne discusses how pain treatment approaches have changed during the course of her career, particularly with regard to opioids. She also shares her thoughts on the opioid crisis in the US, the role of opioids in reward, and much more. Below is an edited transcript of the conversation.
How did you become interested in pain?
I had a strange passageway to pain. I was an anesthetist in Oxford, and my consultant asked why patients who we gave epidural diamorphine to scratched their noses; in those days in the UK we used diamorphine for epidurals. So I did a big research project looking at the reasons why opioids, particularly neuraxial opioids that are put into the cerebrospinal fluid and therefore access the brain, might cause itch. And it turned out—and I didn’t realize it at the time—that itch is very closely related to pain.
When I went to Boston to do a traveling fellowship, I was told I better hook up with the pain people because I had done all of this research on opiate-induced itch. That’s what started the whole thing, but this was pain research in the lab. I stayed in the US, and later I was persuaded to study clinical pain.
How has the treatment of pain changed since you began your training?
When I first trained in pain, in 1990, it was a time in the United States when people were very excited about opiates. There was this feeling that opiates should not have been stigmatized, that the risk of addiction was low, and that we should extend opiates to people with chronic pain because the existing treatments were inadequate. It had also been a time when, in the United States at least, doctors had to fight to use opiates even for the treatment of cancer pain, pain at the end of life, and postsurgical pain. This was because there were regulations in the United States that forbade doctors from giving opiates for the treatment of addiction.
It was an exciting time when we began treating people with opiates, and it was very successful for the first few years as the landscape changed. Whereas previously we had utilized non-opioid treatments, and multidisciplinary pain management was the most successful model, the use of opiates caused that approach to die off. Funders would no longer pay for multidisciplinary pain management, which is much more labor intensive and expensive, because they thought opiates were the answer, and in the first 10 years or so of my career, we thought opiates were indeed the answer.
But then we realized they weren’t the answer, for two reasons. One was that opiates weren’t actually providing very good pain relief, and the other was that they were producing a lot of problems, particularly addiction and leakage into the community—people who weren’t being treated with opiates were getting into trouble with prescription opiates because they were freely available from friends and others. There were huge amounts of opiates available, so it became a societal problem as well as a problem for patients. That really changed my career, because I was one of the first people to say that this was wrong and that we were not helping people. It also changed pain medicine a lot because we had such faith that opiates were the answer, and now we are having to rebuild along different lines.
Thinking of those different lines, are people looking back toward the multidisciplinary approach that was abandoned with the advent of opioids?
Very much so. We tend to lump chronic pain conditions together as one thing, as if all chronic pain is the same. The multidisciplinary model of the pain clinic is absolutely the best way to manage complex, refractory, difficult chronic pain. But there are many other pain conditions that don’t really need that model, like chronic low back pain, which is the most common pain condition throughout the world. In that case, we should instead encourage people to self-manage their pain, keep moving, live a healthy lifestyle, and avoid opiates.
Looking at your own research, what are you most excited about right now?
We have moved to a point where the initiatives in this country to control the opiate epidemic have largely reduced new starts of opiate treatment, which is a really good thing—that’s where we have been successful, and that will eventually be a positive thing for people with pain. But the epidemic in this country has produced millions of people who are still dependent on opiates and still take high doses in many cases, and it’s really difficult to know what to do with them; we don’t have the answers.
So my interest at the moment is to test the different ways that we can address the problems of those people. There’s a lack of consensus about whether they should be treated in the same manner as you would treat addiction. That is, do they need some sort of opioid maintenance? How useful is buprenorphine? Even if you don’t label the patient as having an addiction problem or an opiate use disorder, our experience is that buprenorphine is very helpful for those patients; it makes it much easier for them to come off of high doses. But there’s no consensus on that, and so there’s a really desperate need to try out treatments and programs, and test that they’re working.
Is there a specific phenotype of patient who might be at increased risk of addiction? Are there any biomarkers?
Yes, there are already some biomarkers, and I’m sure in the future that will be the direction that research takes. My clinical observation is that there are two types of pathways to addiction. One is for younger people who are risk takers. It has been known for a long time that risk-taking personalities are more likely to become addicted. People who have a sports injury or have wisdom tooth extraction and receive 30 days of opiates to treat the post-trauma pain or post-procedure pain will become addicted very quickly if they have that risk factor. And it’s totally independent of dependence; there is something different about those individuals that we will eventually be able to see or identify with a biomarker.
The other pathway to addiction is through dependence, and this tends to occur in older people who are taking opiates for a very long time. These are people who are probably vulnerable anyway because they’ve got chronic pain and often psychiatric comorbidities like depression and anxiety, or they may have a history of abuse or trauma. They are very likely to want to carry on taking opiates, and they are very likely to take increasing doses or go to their doctor often enough so that every time, they are forcing the issue of getting to high doses. Once they’ve been doing so for a long time, they’re at very high risk of becoming addicted. But it’s not even as simple as that, because sometimes they can be taking opiates exactly as prescribed, and you don’t see any addictive behaviors or any opiate use disorder behaviors, but when you try to take them off opiates, then the behaviors begin to emerge. So who knows? Were they addicted, did they have opiate use disorder, or did the behaviors develop because you took the opiates away?
My belief is that it’s akin to addiction. The way we diagnose addiction is through a combination of behaviors proscribed by the addiction criteria of the DSM [Diagnostic and Statistical Manual of Mental Disorders] and by taking of the drug. So if you take opiates and you display certain behaviors, you are addicted, or you have an opiate use disorder, but if you don’t see the behaviors you cannot make those diagnoses, but the dependence is still there. The other thing we have learned through all of this is that there is no way we can still say what we said in the 1990s, which was that dependence is only physical and easily reversed—it isn’t only physical, and it isn’t easily reversed.
What do you think of the media coverage of the opioid crisis in the US?
It’s very mixed. There are some journalists who are really smart and look into it. It’s a really difficult issue: It’s difficult ethically, it’s difficult in terms of blame—what blame do you put on the pharmaceutical industry, on doctors, on patients themselves?—and it’s difficult because we don’t have perfect solutions, so people move to extremes.
Now the epidemic is being blamed on prescription opiates, and there’s a huge movement toward reducing opiate prescribing, particularly for chronic pain. When that happens, the press becomes interested in how we are going back to the old days when people couldn’t get opiates to treat their pain and so are now suffering unnecessarily. It’s very polarized, and the press tends to exaggerate that polarization, and it’s not helpful.
But the truth is that there are unforeseen and unfortunate consequences of things like the Centers for Disease Control and Prevention [CDC] guidelines [for doctors in the US considering prescribing opioids]. People tend to be all or nothing; they say the CDC said not to prescribe high doses, and many practices say they’re just not going to prescribe at all because they don’t want their medical license under threat and because these patients are too much trouble anyway.
That means a lot of patients are abandoned because they can’t get opiates anymore since there are no doctors around to prescribe them. This is not bad, in my view, if they’ve never had opiates, but it is bad if they are already on opiates because it is unnecessary suffering—and it’s going to make things worse for them and for society, because they’re either going to keep desperately trying to get opiates through doctors or they’re going to get them elsewhere, and that’s not the right way to go. This is where maintenance therapy with buprenorphine can be very helpful. There are people who have been on opiates for years and are not going to do very well if they have their opiates taken away completely; it’s just not going to be helpful to anybody.
The press gets hold of the most vocal patients, the ones who are dependent on opiates and are very angry toward anybody who suggests they should not be on them. But I’ve never seen an angry patient who is not taking opiates. It’s people on opiates who are angry because they’re frightened, desperate, and need to stay on them. And I don’t blame them because it is very difficult to come off of opiates.
What about the role of opioids in reward?
We’re already learning a lot about this from neuroimaging research. We used to think there was a pain matrix—neural pathways specific to pain. Neuroimaging shows that they are not specific to pain at all, and that they interact and function together with reward pathways. The limbic areas of the brain calculate the salience and meaning of the input—whether it is reward or pain. That process can result in not perceiving anything despite pain generation or perceiving severe pain when there’s no pain generation. What neuroimaging has helped us to understand is that there is a difference between nociception, which is the stimulus that reaches the brain, and pain, which is what the patient feels and perceives.
You really can’t separate the pain-relieving and addictive effects of opiates, because they are going to produce both. The problem when you’ve become dependent is that the exogenous drug suppresses or overwhelms the endogenous opioid system, and so you no longer get those natural rewards or natural pain relief; you need the drug to produce those effects, and that’s the root of the problem for people who take opiates.
People have used opiates for the treatment of pain and known they are addictive for millennia. But before we got to the last century, in fact, when people began to understand top-down control of pain and before anybody knew there was an endogenous opioid system, you could only understand opiates as drugs. And there were different philosophies of pain; the Greek philosophy was different from Descartes’ philosophy, but they were limited by not knowing what we now know about what’s happening in the brain—that there is an endogenous opioid system, and that it’s not just there as a pathway for opiate drugs.
What else is going on in the pain field now that is grabbing your attention?
The science of pain itself is fascinating, and we haven’t really understood what pain is. We have this disconnect between nociception and what we feel as pain. In terms of acute pain, it is pretty straightforward and that’s the way it is supposed to be. But for chronic pain it’s really complex, and potentially it would be very therapeutic if you could work out how, or if, that translation of nociception into what you actually feel as pain can be changed. For example, when you’re injured, particularly in a fight or in war, you don’t feel anything, but how can that be? It means that there is a capability within the brain to actually not feel anything, and yet we don’t utilize that. The more traditional means of controlling pain, like meditation, did utilize that, and it was very effective.
Also, there is some work being done on hyperselective drugs, where people are proposing that we can produce opiates that only give analgesia and avoid respiratory depression in particular. I can see how that could be possible, but I can’t see how you could avoid reward. But this is all recent learning. If I were a young scientist, that’s what I would be interested in. You can’t avoid the endogenous opioid system and dopamine because they're so key to the pain system, so that’s bound to be part of it. But what is pain?