From Mechanisms to Treatment of Pain: A Conversation with Clifford Woolf

Editor’s note: The 2025 North American Pain School took place June 22-27, 2025, in Montebello, QC, Canada, where four NAPSters also took part in the NAPS Science Communicators Program. This initiative helps the next generation of pain researchers and clinicians excel at communicating their own research and that of others to diverse audiences. As part of the program, participants interviewed visiting faculty and patient partners. Below is an interview with visiting faculty member Clifford Woolf, conducted by Julia Nickols, one of this year’s Science Communicators.

Clifford Woolf, PhD, MB, Bch, is director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, and a professor of neurobiology and neurology at Harvard Medical School, Boston, US. He is a pain researcher whose pioneering work on central sensitization and other aspects of pain has propelled the field in new directions over many decades.

Dr. Woolf’s lab studies how different forms of neuronal plasticity contribute to both adaptive and maladaptive changes in the mammalian nervous system in relation to pain, regeneration, and neurodegenerative diseases. His lab aims to develop novel therapies for neurological diseases by combining the best of academia and industry using new, unbiased, high-throughput phenotypic approaches to identify targets and screen for novel drug candidates.

In this interview, Dr. Woolf speaks with NAPS Science Communicator Julia Nickols, a PhD candidate at the University of Alberta, Canada, to discuss the arc of his career, the work he’s doing now, and much more. What follows is an edited transcript of their conversation.

You started your career studying medicine. How did you get into pain research, and when did you start considering yourself a pain researcher?

While I was a medical student, I went to the surgical ward for the first time and there was a resident looking after the patients who had just had surgery, and all of them were lying there crying in pain. I said, “What’s going on?” and he said, “What do you expect, that’s what happens,” and I said, “That’s crazy!” That triggered for me an interest in pain. I had done some research on fever before then, but I transitioned to studying pain and continued with it throughout my career.

What are the big questions that drive your lab today?

We’re trying to understand the mechanisms of pain, because, in the end, that will give us an understanding of the different drivers of pain for different individuals in different circumstances, leading to more effective and targeted precision therapies. That’s the motivation.

Do you think that those questions are any different from the ones you had when you started your research?

No, but the technology has changed very dramatically. When I started my career, the brain essentially was a black box – you knew what came in and what came out, but you didn’t know how the brain worked. Now we are beginning to really dissect out exactly how it works, and I’m very excited for the field because I am confident that in the reasonable future, we are going to fully understand both how the brain works in healthy individuals and what happens in disease states that drive conditions like pain.

In 1983, you published a seminal paper demonstrating post-injury central sensitization. Your recent work has largely involved peripheral nociceptors. Why has the periphery remained your focus in treating pain?

When I first joined Pat Wall’s lab at University College London, I started working on the dorsal horn with Maria Fitzgerald. At that time, we had developed a technique where we could record intracellularly from neurons, fill them with horseradish peroxidase [a neuronal tracer], and look at their receptive fields. But we had no idea if they were excitatory or inhibitory neurons, or if they were local neurons or projection neurons, and so we had absolutely no idea how they could function in spinal circuits. This really frustrated me.

That made me look at motor neurons, because you know what happens when a motor neuron fires – a muscle contracts. By looking at flexor motor neurons, which contract in the withdrawal reflex, I could at least get a sense of what was happening in a pain-related situation. While I was studying that, I discovered that repeated stimulation resulted in an expansion of the receptive fields and a reduction of the activation threshold of flexor motor neurons; I didn’t set out to discover central sensitization, but it emerged, and fortunately I identified it.

The reason that I’ve concentrated mainly on the periphery until very recently was the same problem: How do you identify neurons within the central nervous system and manipulate them? So, my focus largely remained in the periphery, and I’ve gotten so embroiled with it that I’ve continued to work on it.

But now, with genetic means, we can label specific subsets of neurons, we can use optogenetics to record from them, and we can use chemogenetics to manipulate the cells. I have a Neuron paper from earlier this year where we’ve gone back to the dorsal horn, but instead of just doing a single recording once, we can make repeated recordings over a year, and we can see the stability of the receptor field in a healthy state and the changes that occur, some of which are temporary and some that are permanent.

So, at last, I think we now have the tools to really dissect the central nervous system out, and that’s why my lab is now working half-half between the central and peripheral nervous systems.

Your lab is interested in screening for and identifying novel analgesics. Can you tell me a bit more about that?

The more we understand mechanisms, the more potential we have for identifying potential novel therapeutic strategies. When I started my career, for the first 18 years at University College London, I didn’t file a single patent, and I never met anyone who was associated with or initiated a startup.

When I moved to Mass General Hospital in Boston, suddenly I was exposed to a translational environment and that led me to suddenly say, “Well, instead of just doing the research, can we also ask the question of whether this is potentially relevant for developing either new biomarkers or new therapies?” That really changed my whole approach.

Then, as you discover something that has translational potential you can, if you wish to, initiate a startup, and you start working with venture capitalists and other investors, which is a whole new world. But in the end, it’s a way of taking your ideas and leading to something that will impact patients. I feel that will be the reward of my career if something positive comes out, and that’s what I’m trying to do.

You’ve expressed criticism in the past towards the use of mu opioid receptor agonists for pain treatment. What place do you think mu agonists have in the treatment of pain today, and do you imagine a future where these drugs fall out of use entirely?

At this present time, they do have a role because they are effective, particularly in relatively acute pains like postoperative or post-traumatic pain. But they have such toxicity and abuse liability that if there’s a way that we can eliminate them, we should. And that is a big part of my research – it’s not only to develop new therapies that are beneficial for patients but to eliminate the risk of abuse-liable drugs.

When I started my career, the World Health Organization had a scale for treating pain: For mild pain you took NSAIDs, for more severe pain you took a weak opioid, and for intense pain you took a strong opioid. Frankly, that was a step ladder to opioid addiction, and at that time medical professionals said that patients never become addicted, but in fact that was not true at all.

Often, you’ll find patients who have had chronic exposure to opioids, and their pain has come back, but if they try and stop their opioids, they get enormous withdrawal symptoms, so they stay on them just to avoid that – and that’s terrible. That is a case of medical intervention that has led to problems rather than solve them. There’s also been quite a large attempt to try and develop new opioid receptor agonists that don’t have abuse liability, but so far, none of them have worked.

It’s been argued that part of the reason mu opioid receptor agonists are effective is because of their rewarding properties, in that they alleviate pain unpleasantness. With this in mind, is a non-rewarding analgesic that performs comparably to opioids attainable?

In principle, yes, absolutely. The mu opioid receptor is widely expressed – it’s on primary afferents, on dorsal horn neurons, in the brainstem, and in the cortex. And yes, the agonists produce euphoria, and certainly an element of the experience that patients have is, “I have the pain, but I don’t care about it.” But if we can find a way of just switching off the pain, then you don’t have to have the euphoria, and frankly the euphoria is the bit that leads to addiction, and heroin and fentanyl use. I definitely want an analgesic that is as effective as the opioids but with no euphoria. To me, euphoria is the risky part of the opioids that leads to abuse and dependence.

The opioid crisis has been devastating for the pain community. What are the lessons that pain researchers should take from it?

Opioids have been used for over a century now, but the lesson was in the 90s when oxycodone was introduced with the claim that it had no euphoric features because of slow release, which is not true. Even worse than that, patients could take a pill and crush it, snort it, or inject it, and get a very high, potent dose.

It’s part of our responsibility as physicians to ask the question of what the risks of this therapy are. Frankly, I see that as being as important as the efficacy profile. If you look at opioids, there’s just no question that they are very high risk for respiratory arrest, severe pruritus, or constipation, never mind the euphoria and addiction. If you happen to see heroin addicts in a place like San Francisco, lying in the street, it is so awful seeing opioids destroying their lives.

One of the problems is that there was a time when almost all opioids were prescription opioids, but with fentanyl and heroin available now, even if we eliminate prescription opioids, opioids are not going to disappear. But it’s the responsibility of the medical profession to eliminate prescription opioids.

There was a time when both my sons had their wisdom teeth taken out, and instead of getting one or maybe two opioid pills to help them relieve the pain, they were given twenty, which is unbelievably crazy and ridiculous! There was a time when people were not aware of, or didn’t think about, the risks of the treatment, and they just went ahead with it. When I was at Mass General Hospital, I’d go to the pain clinic and we reached a point at which I’d say the majority of patients would come in just to get their prescription opioids – it wasn’t about their pain, it was just, “I need my prescription.” That was a problem that physicians had created.

A lot of the discovery research being done to develop non-opioid analgesics has focused heavily on targeting nociceptors directly. However, there’s an increasing appreciation for the neuroimmune contribution to pain. At a preclinical level, how do you take this into account?

Instead of us only looking at the nervous system, we should look at both the nervous system and the immune system. That means that we need to collaborate with the immunologists and bring people who’ve been trained in immunology into our labs. There’s a reciprocal interaction where the immune system creates ligands that act on neurons, and neurons release many factors that act on immune cells; they don’t act separately, they work together.

The evolutionary development of both systems was to protect us from dangerous environments and pathogens, but, unfortunately, they also interact to drive disease and death. It’s absolutely crucial for us to incorporate that into our research, and so we can’t be neuroscientists exclusively anymore. And that’s true of so many other neurological conditions beyond pain.

Your lab uses a wide array of techniques, from single-cell RNA sequencing to AI-based assessments of behavioural responses in rodent models. Of these new techniques, which one do you find the most exciting or promising for advancing pain research?

I don’t rank them – it’s a matter of finding the ones that can help you address issues in a new way. There was a time when bulk sequencing was the standard way of measuring mRNA levels in different tissues, and then single-cell profiling comes along, and then bulk sequencing becomes obsolete overnight. Frankly, I think the same thing is going to happen with ways of measuring mouse behavior using machine learning algorithms. Soon we’re also going to have single-cell proteomics, spatial transcriptomics, and all of these enable us to do things that we couldn’t do before.

I’m not someone who devotes my lab, in a fixed way, to one technique. Instead, it’s about having a question that needs to be answered and having a technique that can help us answer it, and then we collaborate with someone who has the expertise in that. So that’s the approach – it’s still trying to deal with the actual problems and the solutions, rather than being obsessed by the technology for its own sake. But at the same time, the technology is advancing so rapidly, and there are so many novel aspects, and that’s wonderful.

If you were a prospective graduate student interested in pain today, what would you want to be working on – what would you be trying to learn, and what models would you want to use?

The advice I give to people who are applying for graduate programs is when you do your PhD, you don’t have to be locked into what you do for your thesis after you have completed it. It is a training experience. So, find a lab that you feel comfortable with – find one where the challenges are exciting for you, where the technology is cutting edge. And then, later on, when you’re a postdoc, you can move on from that project and either do something similar or completely different.

As long as you can really get the skills to become, in due course, an independent scientist, who knows how to define questions and use the appropriate techniques to address them – if you can learn all of that, that’s the point at which you can then decide exactly what challenge to work on.

You’ve been a major figure in pain research for a long time. How has pain research changed over the course of your career?

When I started my career, pain was a big challenge and people knew very little mechanistically about it, in terms of how the nervous system was driving pain. At that time, pain was almost seen as a unitary experience, rather than as a consequence of quite diverse pathological situations. We have, over my career, now moved to a point where we are beginning to really understand pain, define the mechanisms, and reveal potential therapeutic opportunities from that.

When I first moved to the US 27 years ago, the NIH spent a tiny fraction of its research grants on pain. And now, with the HEAL program, pain is one of the biggest elements. That is because we’ve made so much progress in understanding pain. Pain is no longer something out there that people think is bad, but we don’t know anything about it, that we don’t know what it is and how to address it. Now we do know what it is, and we have the tools now to know even more. When I did my PhD, things were so crude; the techniques were so awful, frankly. When I look at my graduate students now, at the advanced work they’re doing, I’m very excited. We have made enormous progress, and I hope it continues, and our communities recognize its value and importance.