At the International Association for the Study of Pain (IASP) 2021 Virtual World Congress on Pain, to take place June 9-11 and June 16-18, IASP will present awards to honor the achievements of up-and-coming as well as more established investigators (these awards were originally to be presented at the 2020 World Congress on Pain in Amsterdam, which was canceled due to the COVID-19 pandemic). In advance of the meeting, PRF spoke with each of the winners. In this interview, we chat with Srinivasa Raja, MD, winner of the John J. Bonica Distinguished Lecture Award. Read more about the award here.
Raja is professor of anesthesiology and neurology, and director of pain research at Johns Hopkins University, Baltimore, US. His clinical and research interests focus on understanding and managing chronic neuropathic pain states and identifying novel peripheral targets for alleviating chronic neuropathic pain. He also served as chair of the IASP Definition of Pain Task Force, which recently published its output (see here).
Here, Raja chats with Lincoln Tracy, a research fellow at Monash University, Melbourne, Australia, to discuss his path to anesthesiology, his work on identifying novel targets for neuropathic pain, and his experiences with John Bonica. Below is an edited transcript of their conversation.
What first got you interested in medicine?
In India, where I grew up, you have to make a decision very early on in terms of your career path. I was reasonably good at math and science, so I was caught between engineering and medicine. Both my grandfather and great-grandfather were physicians. Although I didn't get to meet either of them, I heard a lot of stories about them and how they were respected in the community. But in my dad's generation and my generation, including my cousins and siblings, nobody was going into medicine. I was accepted into both engineering and medical school, but I thought I should keep up the family tradition and pursue medicine. It wasn't a very well-planned decision, but I don’t have any regrets about it – it has been an immensely satisfying career in many ways.
What drew you to pursue training in anesthesiology?
After graduating from medical school, I was enamored of surgery. In fact, for the first two years, I trained in surgery – a year-and-a-half in India, and then I started as a surgical intern when I immigrated to the US. As I was working in the operating room, I noticed that I was becoming increasingly attracted to what's happening on the other side of the "ether screen," particularly monitoring the dynamic changes in physiology to maintain homeostasis. Shortly after, I started chatting with anesthesiologists, trying to get a feel for the field, and it became more and more attractive. Another aspect was that at the end of anesthesia, when the patient wakes up, there was a degree of instant satisfaction as I could see in their face that everything went well.
What was the arc of your research?
I started working with James [Jim] Campbell and Richard [Dick] Meyer, who introduced me to the pain research field almost four decades ago. We were asking simple mechanistic questions that arose from our clinical experience. For example, one of the first questions came from when I was doing postoperative rounds on patients after surgery, especially after major abdominal surgeries. It was very clear that their pain was not limited to the incision site; it was much more widespread. Patients found it painful to cough, which limited their ability to take deep breaths and often led to postoperative fever and respiratory dysfunction. I started asking myself, What was responsible for this diffuse secondary hyperalgesia after a tissue injury?
At that time, Jim and Dick had done a series of studies reporting that peripheral sensitization could explain what was happening at the site of tissue injury. But this couldn’t explain what was happening outside the injury site – the mechanisms of secondary hyperalgesia. Eventually we began noticing clinical similarities in the neuropathic pain patients we were seeing in the clinic, particularly with respect to allodynia and secondary hyperalgesia. We wondered if there were common central mechanisms that may underlie those two symptoms. So we started studying the mechanisms of allodynia and hyperalgesia in patients with neuropathic pain.
Subsequently, as I started working in the clinic and treating more patients with postherpetic neuralgia, post-amputation pain, and complex regional pain syndrome, we noticed there was very little evidence about what drugs were effective. In the '70s and '80s, tricyclic antidepressants were the only drugs available. We started looking at comparisons of tricyclics and opioids, and then with other drugs later on, to build evidence-based randomized clinical trials to guide therapies for neuropathic pain. It became clear that many of these therapies were limited by their central nervous system [CNS] adverse effects. So I returned to the bench to explore targets that would be efficacious, but with minimal CNS adverse effects. That's what led me to focus more on peripheral targets.
Can you say more about why targeting peripheral activity is a good approach for developing safer therapies for patients with neuropathic pain?
It makes sense mechanistically, in terms of both preclinical and clinical data. There's very little debate about what initiates neuropathic pain after nerve injury or in diseases of the peripheral nervous system. The controversy has been over what is responsible for maintaining neuropathic pain states – whether it is dependent on the periphery or if the CNS becomes an autonomous pain generator site. Preclinical data show that spontaneous and ectopic activity from peripheral afferents and the dorsal root ganglion play an important role. But until earlier this decade, the evidence was less clear from a clinical perspective.
The clinical studies have clearly shown that blocking peripheral nerves or the dorsal root ganglion with local anesthetics in peripheral neuropathic pain states reverses ongoing pain. Marshall Devor's group looked at phantom limb pain in amputees, while other groups have looked at diabetic neuropathic pain and pain after injuries to peripheral nerves. Multiple peripheral neuropathic pain states provide good clinical evidence that blocking afferent signals toward the CNS with local anesthetics can reverse the pain state, transiently. And this led us to look at the periphery. So we think that with peripheral targets we can potentially block the pain generator without blocking normal sensations. Targeting the periphery can also minimize the adverse CNS side effects such as sedation, dizziness, and dependence. It also has the ability to potentially reverse the central sensitization.
Tell me more about the sites that have been identified within the peripheral nervous system as potential targets for novel therapeutic strategies in neuropathic pain.
If you just talk about sites, there are numerous possibilities that may vary depending upon the nature of the injury or the disease. For example, in amputees, neuromas developing at the site of amputation may be a cause of this spontaneous activity. On the other hand, there are the studies like Marshall Devor's that suggest the dorsal root ganglion may be a site. And even in the dorsal root ganglion, there are studies showing that changes may occur at the level of the injury, but also at adjacent uninjured neurons and the uninjured dorsal root ganglion. Similarly, in peripheral nerves, both the injured afferents as well as adjacent uninjured afferents, seem to show neuroplastic changes. There may also be neuroimmune interactions, or many genetic and epigenetic mechanisms that could play a role.
I was recently looking at a nice paper in Neurotherapeutics that reviewed novel peripheral targets for pain. Over the last three years, there were more than 1,600 publications on peripheral targets. This review classified potential targets into broad groups – the protein kinases, enzymes that work on endocannabinoids, prostaglandins, nitric oxide pathways, G protein-coupled receptors, opioid receptors, voltage- and ligand-gated ion channels – the list goes on. I think there's a broad variety of targets and strategies being explored, which makes me very optimistic that something will come out of all of this research in the coming years.
Given the broad range of potential targets and mechanisms, do you think focusing on a combination of these will lead to the most promising therapeutics rather than on a single pathway or channel?
That's an excellent question, and one I've been thinking about from a different perspective. I was thinking about that review I mentioned on the 1,600 publications relating to novel targets. I looked closely at the FDA over the last decade to find out how many new drugs had been approved for clinical use. Over 400 had been approved, with more than a quarter of them for oncological indications. Do you want to take a guess what percentage of these drugs were for pain?
It was 2% – there were eight drugs approved. Interestingly, seven were for migraine prevention or treatment, and the majority of those targeted the CGRP receptor. The other drug was a biased opioid agonist, so that makes it eight drugs. But there have not been any drugs approved for neuropathic pain in the last decade. There's clearly a big dichotomy between what the preclinical experts have identified as potential targets and, clinically, what we've been able to show as beneficial.
What sparked your interest in this line of thinking?
It's clear that we have a set of approved drugs for neuropathic pain. Through my involvement with the IASP Neuropathic Pain Special Interest Group (NeuPSIG), in 2014 or 2015 we were investigating the evidence base for neuropathic pain drugs. Nanna Finnerup and Nadine Attal wrote a review paper, and it was clear that there were limited choices available. My clinical experience was consistent with what the review found – that there are few first-line drugs, and they work in less than 50% of patients, and they provide less than 50% relief of their pain. That got me curious to see what was happening in the drug development field, and if there were any drugs in the pipeline.
Switching gears, what were some of the more challenging aspects of leading the IASP Definition of Pain Task Force?
It was clearly one of the most challenging but also the most gratifying tasks that I've taken on in my career. The most daunting aspect was that we already had a well-established definition that was widely accepted, including by the World Health Organization and many disciplines, including veterinary medicine. The main question I had was, Is there scope for improving on something that’s so widely accepted?
It was also a challenging task to accurately define pain, as pain ranges from short, stabbing pains all the way through to distressing chronic pain states. So we focused not only on the definition but also the accompanying notes that expanded on the definition.
Unlike prior attempts, this group sought input from the broader pain community as well as the IASP Council. It was interesting to get those perspectives, including the views of people experiencing pain, and then bring that into this definition. And finally, when you have a group of 14 experts in the field and broad areas of interest and expertise, bringing the group together to a consensus was an interesting and challenging aspect of it. But it was a smooth process.
What does winning the John J. Bonica Distinguished Lecture Award mean to you?
It means a lot. It’s very humbling, and it's more than I ever dreamed of in my career. I say this because as I was preparing my lecture for the Virtual World Congress, I was reviewing the accomplishments of John Bonica as a clinician, as an educator, and as a visionary leader. But I also talked to his daughter to get a feeling for who John Bonica, the man, was. He made enormous contributions despite very challenging personal life experiences. He immigrated to the US when he was 10, and lost his father when he was 14.
After he lost his father, he kind of assumed responsibility for the household by taking odd jobs, shining shoes, hawking newspapers, and selling produce. Then later on he had a life as both an amateur and professional wrestler to support himself through college. On top of that, nearly 50 years ago he had the foresight to bring a wide spectrum of people together and form this international organization, IASP. He was way ahead of his time in that respect. So to have my name associated with somebody of that stature, who has accomplished so much, is truly very humbling.
What was it like to work with John Bonica?
John was involved in one of the most important transitions of my academic career, which was switching from surgery to anesthesiology. He was the chair of anesthesia at the University of Washington at the time, and he gave me the opportunity to switch specialties by offering me a position in his program. I like to think this helped me transition from being a physician who was inducing pain in patients to one where I was dedicated to preventing, treating, and understanding pain. It was a big transition for me, and I'm very grateful to him.
I clearly remember that, on the very first day I started in the anesthesia program, John lectured us on the use of regional anesthesia. John was interested in promoting the use of regional anesthesia compared to general anesthetic techniques. However, he wanted to make sure that regional anesthesia was performed in a safe manner, taking the same precautions as you would when using general anesthesia. I remember he started his talk by saying, "You are at an institution where regional anesthesia will be emphasized. You'll be trained in it, but I want to make sure that with every patient you treat with regional anesthesia, you use the same precautions and the same monitoring that you would do when you're doing general anesthesia. If I don't see that, you will not be in the program anymore." After meeting him once, it was clear how much the ethical aspects meant to him, and how much empathy he had for his patients.
Do you have any secret talents or interesting hobbies outside of research and your clinical work?
Most of what I've done in my career has been exercising my left brain. To try and balance this out and exercise my right brain, I've been interested in photography, especially nature photography. When I was young my uncle gave me a camera, but I had to use it sparingly because at that time film was expensive, and you had to take great care in developing and printing photos. But once the digital era came, I started taking it a little more seriously. I use photography to relax and see objects that the naked eye doesn't see or capture as well. And I get to combine my interest in photography with my love of travel – I’ve visited six of the seven continents and more than 50 countries. Hopefully I’ll get the opportunity to tick Antarctica off the list one day.
Lincoln Tracy is a researcher and freelance writer based in Melbourne, Australia. You can follow him on Twitter @lincolntracy.