Catching Up With the 2017 North American Pain School Visiting Faculty: A Conversation With John Farrar

Editor’s note: The second North American Pain School (NAPS) took place June 25-29, 2017, in Montebello, Quebec, Canada. An educational initiative of the International Association for the Study of Pain (IASP) and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), and presented by the Quebec Pain Research Network (QPRN), NAPS brings together leading experts in pain research and management to provide 30 trainees with scientific education, professional development, and networking experiences. This year’s theme was “Where Does It Hurt and Why: Peripheral and Central Contributions to Pain Throughout the Body.” Six of the trainees were also selected to serve as PRF-NAPS Correspondents, who provided firsthand reporting from the event, including interviews with NAPS’ six visiting faculty members and summaries of scientific sessions, along with coverage on social media. This is the sixth installment of interviews from the Correspondents, whose work is featured on PRF and RELIEF, PRF’s sister site for the general public. See the other interviews here.

John Farrar, MD, PhD, is a neurologist and associate professor in the Department of Biostatistics and Epidemiology and senior scholar in the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania, Philadelphia, US. His main research interests are the design of clinical trials to explore new pain medications, brain function in people with pain, and new methods for understanding how people report pain in clinical trials. Farrar sat down with PRF-NAPS Correspondent Mark Bicket, an assistant professor at Johns Hopkins University, Baltimore, US, to discuss his path to pain research, his perspective on clinical work and on pain measurement in clinical trials, and his advice for junior investigators. Below is an edited transcript of their conversation.

What sparked your interest in the field of pain medicine?

When I was becoming involved in pain, there weren’t any pain fellowships. My primary training was in neurology where I found an interest in pain during my residency at Weill Cornell Hospital/Memorial Sloan Kettering Cancer Center working with Kathleen Foley in the Department of Neurology. The department ran the pain service, and we would rotate on it. I remember walking into the room of a patient whose cancer had metastasized to her bones. The patient was very uncomfortable, and while Kathy was talking to her, she began to inject morphine IV slowly over the course of her conversation with the patient. By the end of the conversation, the patient thanked her and said she felt so much better than she did before. That struck me in a really profound way—making people feel better who are suffering from a terminal disease.

My interest has been in the conduct of pain clinical trials, starting with the questions of how to measure pain and what patients mean when they report their pain. I’m also interested in how to design the most efficient trials to answer whether a treatment is adequate or not, and how to analyze data sets to explore interesting questions. More recently, I’ve become involved in some smaller studies looking at functional brain imaging, using fMRI and a third molar tooth extraction model.

How did your interest in research develop?

I was the kind of person, growing up, who loved to take things apart—sometimes to my parents’ chagrin when things didn’t always go back together exactly as they came apart—so I’ve had an interest in how things work for a very long time. Early in my career I was interested in the nervous system. I really enjoyed studying the brain and in college, I decided that I was most interested in the human nervous system, so I entered medical school with a clear intent to study neuroscience.
If was after finishing my pain medicine fellowship that the question of what patients mean when they say their pain score is a 5 out of 10, for example, or is severe, came up. How are we measuring pain and how can we actually use a subjective measure in clinical studies? Those questions prompted me to explore how pain ratings can be better understood.

What caught your attention early on regarding pain ratings?

What struck me during and after my training was that different people deal very differently with their pain. Some patients had very serious injuries and complained of significant pain, but they figured out how to deal with it and went on with their lives as best they could. Other patients had less serious injuries, and less severe pain, yet they were incapacitated by it. They couldn’t accept that they were unable to function completely normally, and it ruined their lives. That difference is a key issue in thinking about how to interpret pain. It’s not just what people mean when they say their pain is a 5 out of 10, or moderate to severe, but how it impacts their lives, and how you can have an impact on that problem by intervening in various aspects of their disease.

How does that perspective inform pain measurement?

As an example, consider the Brief Pain Inventory questionnaire, which asks about worst, least, and average pain. It originally used a Visual Analogue Scale (VAS) 10-centimeter line [corresponding to the amount of pain experienced], but ultimately moved to a Likert scale of 0 to 10 with defined end points. It was hard to know on that scale what a 5 or a 6 meant. Ultimately, the only way we would know was to look at measures of other factors that went along with the pain rating. It was a little bit troubling that this scale didn’t provide a single answer to the question of the significance of the pain.

I began thinking about what construct of the questionnaire was needed in order to appropriately obtain the information. One thing was clear: a 0 to 10 scale works very nicely in a clinical trial setting, where you’re really interested in whether an individual’s pain changes. In that setting, it doesn’t really matter what a 5 is or what a 7 is. If the person with a 5 and the person with a 7 each got better, then the treatment changed both individuals for the better.

What about using this scale in the clinic?

It can be a problem in clinical practice. We use the same 0 to 10 scale, and can check whether the treatment reduces patients’ pain or not. But, clinically, whether a treatment is good enough relates more to whether or not the treatment makes the pain more tolerable and allows people to function—to do things that are important them. There are different levels of function. One level includes activities of daily living that are a requirement for survival such as getting food, going to the bathroom, and washing one’s self. Another level of function is the ability to do things that are more for fun, such as going to the movies or for a walk, or even sitting in a chair long enough to enjoy nice weather. People tend to be able to continue to do the required functions even with significant pain, but will only do the elective functions if they are feeling better enough to make things enjoyable.

One of the outcomes of this thought process concerned our ability to determine what’s important to the patient using a 0-10 scale, or any scale. So we experimented by comparing changes in pain to other activities. By serendipity, I was involved in a study of transmucosal fentanyl, which is a drug that works very quickly. There were questions about how to conduct an ethical placebo-controlled trial to test efficacy. In the end, the compromise was that if the treatment didn’t work within 30 minutes, people could take something else for their pain.

What hit me was that the use of breakthrough medication is a great measure of whether treatments work or not. That’s what we use with patients clinically: is the treatment good enough? Does it work at all? Does it last a period of time? Patients basically vote with their feet, if you like. Either the treatment was good enough and patients don’t need anything else, or it wasn’t good enough and they need something else. And then you’re able to compare this outcome to the change in what was measured on a scale, and see what level of change correlates. We found that about a 30% change [in pain] correlated best with people not needing any additional rescue medications.

How has your viewpoint on pain scales in research and clinical settings changed over time?

There’s been a lot of discussion in the literature in the past about what measures we should use in clinical trials. The VAS has been described as potentially being a better measure, because it gives people lots of options with a 0-100 rating. When I started out you had to measure VAS with a ruler and that was a lot of extra work, though computers have now eliminated that. You also cannot easily use the VAS over the phone, so even if it was a little better this was a limitation.

There are a number of scales that use words, and while reasonable, any study involving multiple languages requires translation of those words, making them more difficult to use. In comparison, the 0 to 10 scale is generally applicable across languages and cultures. One argument was made that people who don’t like math might not like the 0 to 10 scale, but the counterargument is that people of different cultures always understand money. For example, they know that ten cents is more than a nickel; there’s almost no society in the world that doesn’t have some bartering system where two is greater than one. In clinic, I do ask patients what their pain number is on a 0 to 10 scale. Then I ask in words if they have mild, moderate, or severe pain. Although they are describing an intensity level, there is also some indication of meaning with regard to how the pain is affecting them.

We then need to explore how the pain affects the patient’s function and quality of life. One of my patients used what I called the basket scale; he was a weaver. I knew he was in good shape when he brought in a small sample of baskets, and if he came in without them then I knew things weren’t going as well. The point is that the scale should be adapted for the patient, and it has to mean something for that individual. We shouldn’t be egotistical enough to think that we know what is most important to the patient.

How consistent are reports of pain over time?

It is generally true that people learn how to report pain and they then report it in a way that makes consistent sense to them. To give you an example, I was taking care of a patient who had cancer-related pain, but never reported his pain as being higher than three, even when he was incapacitated. When I asked him about the reason, he explained it was because the end point was labeled as the worst pain imaginable. His father had been a survivor of the Holocaust, and he said he was sure that what his dad went through was so much worse than what he was going through. We tried to encourage him to use more of the scale to give us a better sense of where things were for him. Ultimately what we did was to adapt to him—so he was better when he was a two and worse when he was a three. However, in most instances, training people to use the full scale is doable, and potentially useful.

We also have patients who come in every time and report their pain as a 10. And you ask them, for example, to suppose they broke a bone—wouldn’t that hurt more? And they may answer yes. We interpret this as the patient’s way of describing their distress, if you like. And my interpretation of patients who always report a 9 or a 10 without any variation is that they are distressed about their pain.

What has been the focus of your work on pain education?

The amount of training that physicians and other healthcare providers receive about pain is vanishingly small, especially considering that pain is one of the primary reasons that people come to see a physician. Everybody reads Cope’s Early Diagnosis of the Acute Abdomen because you want to know what’s going on. But people ought to study more about what to do about the pain once you figure out what’s going on.

From an educational perspective, I lead one of eleven of the NIH [US National Institutes of Health] Pain Consortium’s Centers of Excellence in Pain Education and work with NIDA [US National Institute on Drug Abuse] to produce one or two educational modules a year. Along with the other ten centers, we will have a set of 40 or 50 modules that will be available for everybody to use. However, for any of the increasingly available online learning to be of use, more time and importance needs to be allocated to pain education in healthcare training.

What surprises have you encountered during the course of your career?

I haven’t had a straight-line path. I wanted to do a full medical residency before going into neurology, but ended up only doing two years. My wife was involved in international development work and we ended up at an up-country hospital in Sierra Leone instead of my doing a third year of medicine. I learned more medicine there than I would ever have learned in the US, about all kinds of things including Lassa fever, tuberculosis, and all types of parasites. I ended up getting malaria as well! I then came back and did my neurology residency and fellowship. My wife and I also went to India for three years, where I worked with the United States Agency for International Development [USAID].

When I came to the University of Pennsylvania with an interest in clinical research, the head of the epidemiology department looked at me and said, “John, you don’t know what you’re doing.” He is very nice and wasn’t being mean. He meant that I needed training to do rigorous research. I ended up doing a master of science in clinical epidemiology and eventually did a PhD in epidemiology as well.

At the time I was doing all of this, clinical research was not considered “real” research; it was just something that clinicians did on nights and weekends. The concept that there was a science behind all of it and could be done rigorously was not well accepted. And there wasn’t an obvious academic pathway for it either. I knew I wanted to study pain but I needed the basic science, the epidemiology and the biostatistics in order to do that. Ultimately that had a large part in shaping my life and giving me the tools necessary to look at how clinical trials are designed and how to make them better.

What type of training do you recommend to aspiring investigators?

Getting rigorous training in basic or clinical science is imperative. The next step is to learn the practical aspects of how to do research, which is equally important. In a basic science setting, that can take the form of a post-doc and working with people who understand how to do the best science. In a clinical setting, it really is about learning a new set of skills, and that’s epidemiology and biostatistics. Medical students only get a week or two of training on those topics, which is not enough exposure to understand the language necessary to convey the ideas to colleagues nor to grant-making agencies or other groups that are potential funding sources. It’s imperative that you work with people who know how to do that, and this applies to basic science as well as clinical science.

What key papers and insight would you share with early career researchers?

There are some really classic papers; the description of the descending pain modulatory system, while part of everybody’s learning these days, was truly instrumental in terms of thinking about pain. On the clinical side, a series of papers from the IMMPACT group led by Robert Dworkin and Dennis Turk has focused on developing a more consistent way of measuring pain and conducting studies of pain. The very first paper says that pain investigators need to measure pain, and the 0 to 10 scale is probably as good a measurement as any. Then they should look at quality of life, namely social functioning, affect, physical functioning and spiritual functioning. The idea is to use a consistent set of measures to allow comparison across clinical trials.

To increase the likelihood of a successful career in research, my advice to clinical investigators is to treat their research time the same way they treat their clinical time. You wouldn’t miss a scheduled day in clinic for most activities, because you take it pretty seriously, and you should look at your research time the same way. Otherwise, that time has a tendency to disappear. Research broadens your worldview. You meet interesting people, discuss interesting topics and contribute in a much broader way. Pain is an area of burgeoning information and knowledge. One aspect that I liked was that only a few people were involved in it when I started my career. Even now, with more people involved, almost every idea you come up with is potentially new or a change to our thinking. This presents a real opportunity for people to do something in the world that makes a difference.

Additional Reading:

Pain intensity rating training: results from an exploratory study of the ACTTION PROTECCT system©.
Smith SM, Amtmann D, Askew RL, Gewandter JS, Hunsinger M, Jensen MP, McDermott MP, Patel KV, Williams M, Bacci ED, Burke LB, Chambers CT, Cooper SA, Cowan P, Desjardins P, Etropolski M, Farrar JT, Gilron I, Huang I-Z, Katz M, et al.
Pain. 2016 May; 157(5):1056-64.

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations.
Gewandter JS, Dworkin RH, Turk DC, Farrar JT, Fillingim RB, Gilron I, Markman JD, Oaklander A L, Polydefkis MJ, Raja SN, Robinson JP, Woolf CJ, Ziegler D, Ashburn MA, Burke LB, Cowan P, George SZ, Goli V, Graff OX, Iyengar S, et al.
Pain. 2015 Jul; 156(7):1184-97.

Good 2008 PMID: 18655954

Farrar et al. 2006 PMID: 16632085

Core outcome domains for chronic pain clinical trials: IMMPACT recommendations.
Turk DC, Dworkin RH, Allen RR, Bellamy N, Brandenburg N, Carr DB, Cleeland C, Dionne R, Farrar JT, Galer BS, Hewitt DJ, Jadad AR, Katz NP, Kramer LD, Manning DC, McCormick CG, McDermott MP, McGrath P, Quessy S, Rappaport BA, et al.
Pain. 2003 Dec; 106(3):337-45.

Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale.
Farrar JT, Young JP, LaMoreaux L, Werth JL, Poole RM
Pain. 2001 Nov; 94(2):149-58.

Farrar et al., 1998 PMID: 9554444