a16z Podcast - a16z Podcast: The Biology of Pain

Episode Date: September 17, 2019

What is the nature of physical pain? Why do we even experience it? Is there one type, or many? Do people experience pain differently? What is happening in our brains and our bodies when we experience pain? What is the biological link between pain and addiction? In this episode Clifford Woolf, Professor of Neurobiology at Harvard Medical School and a renowned expert on understanding pain, shares with with a16z's Hanne Tidnam all we know about the biology of pain. Technology is enabling a new, deeper, and much more complex understanding of pain—which pathways and neurons are activated in the brain when, what patterns might represent which experiences of pain. We now understand that the notion of pain as a simple switch that can be switched on or off (you have pain/you don't have pain) and measured by categories like mild, moderate, or severe is just incorrect. Woolf describes the 4 different broad types of pain we in fact experience, what the purpose of each is, and what it means now that we can phenotype them and begin to understand them as distinct. Now that we have this deeper and much more complex understanding of pain, what does it mean for how we can treat pain in the future, and where we can intervene?

Hi and welcome to the A16Z podcast. I'm Hannah. In this episode, we talk all about the biology of pain with Clifford Wolf, professor of neurobiology at Harvard Medical School, who has dedicated his career to the subject. The conversation covers everything you ever wondered about the nature of pain, from why we even feel it and what the biological purpose of pain is, to whether or not all pain is the same, or if some kinds of pain function differently, feel different, have different purposes, or even if some people feel pain differently from others. Wolf describes the four different broad types of pain we experience, what the purpose of each one is, what it means now that we can phenotype different kinds of pain and begin to understand them as distinct and different from each other, and how technology is enabling this new, deeper, and much more complex understanding of the nature of pain. We also talk about what the biological link between pain and addiction really is, plus the one thing you might do that we know makes your experience of pain worse. You've been working on the subject of pain for your entire career. What drew you to that subject to begin with?

What was it that first sparked that initial interest for you and where you began investigating? When I was a medical student, I was on the surgical ward, and at that time, there was minimal treatment for post-operative pain. So I came into the ward, and there were a group of patients who had major surgery, and all of them were in severe discomfort. And I said to the attending a surgeon, what are you doing? Why, why aren't you treating them with pain? He looks at me as if I was crazy and he said, they've just had surgery. What do you expect? They were in pain. Even the idea of treating the pain was not. Absolutely. It was just thought you have surgery, have pain, and then you put up with it until the pain goes. And I, and I just thought to myself, that doesn't sound right. At that time, there was very little understanding of the mechanisms

of pain and indeed very few treatment options. Now, as we have, much greater understanding, but unfortunately, the treatment options haven't really expanded, and they are also accompanied by undesired effects, particularly in the case of the opioids. So let's talk a little bit about what the understanding looked like then and what it's beginning to look like now. So what was our understanding of the mechanism of pain back then when we just sort of assumed, okay, you have surgery, you're in pain? At that time, I just thought that all pain is similar that you either have no pain or you have pain. And if you have pain, it's an unpleasant sensation. The closest analogy, it would be like flicking a switch that switched on the pain

sensation in your brain. So we thought it was that simple. We thought there was a peripheral trigger which could be mild like a pinprick or touching something too hot or too cold or larger in the sense of major trauma or post-surgical. There was something that was activating that the pain switch and that all the triggers of pain acted on a single system in a single way and therefore pain really was not present or mild, moderate or severe. And that was the full range of the understanding of pain. Describe a little bit what the thought was around that system. Like how would that system be activated or how would, what was our understanding of that system? Well, it certainly was appreciated that pain has two facets. One, it is an essential early warning device.

It tells us of danger in the environment. And without it, there's a high risk that we may injure ourselves. So you need this alarm system, if you like. And in the case of surgery, that alarm system is going because you're vulnerable, you're exposed, you're healing. The alarm system is activated by the surgeon's damage that has created in the patient. And then the alarm system continues until that tissue injury is repaired. But what is happening in a patient who has persistent pain for years and years and years,

why is that pain alarm activated continuously? And there really was no explanation at the time. So that's where you began your research? Exactly. And at that time, if you had mild pain, then you took a non-steroidal anti-inflammatory drug like Tylenol or Advil. If you had more severe pain, you added a weak opioid to your ensade. And if you had severe pain, then that's the point of which you'd get. of a stronger opioid. And the World Health Organization had an analgesic ladder that it literally was

that mild, moderate, severe pain, increasing the strength of the analgesic. And again, in keeping with this notion that pain was a unitary system activated by different triggers of different intensity. It's so simple. It makes me think of the signs in the nurses, doctor's office with the smiling faces. Like, even that is a whole order of magnitude above in terms of understanding. And unfortunately, the reality is those smiley faces would not be smiling if they saw how complicated pain was. The notion that there's a simple switch is just incorrect. The notion that pain can be defined by its severity as mild, moderate or severe is incorrect. And the notion that the treatment should be based on that is

also incorrect. What is it that has shifted in our understanding of the biology of how much more complex it is? Pain as an early warning device, a kind of radar for danger, if you like, is completely different from the pain that occurs in the setting of a patient who has persistent pain. The quality of the pain? No, that was the confusing element. We use the same word pain to describe both, and therefore physicians and patients felt this is the same phenomenon. But in fact, the pain that we experience does not reflect what is initiating and sustaining

the pain. In the case of a pain is a protective mechanism, you need just an intense stimulus, one of sufficient intensity that it potentially can damage our tissues, and we have this very elaborate system that has been designed to detect that danger. So we have specialized sensory neurons that are activated only by intense stimuli. And when they reach that threshold, which is just below the point of which damage can occur, we feel a pinprick or the point of which something that is too warm and it has the risk of burning us. And is that a problem? And is that a threshold the same for everyone or different for everyone? It's surprisingly similar that if you

measure it and in a situation where you remove all the emotional aspects of pain, the threshold at which someone feels something has been warm and then hotter, and then when it switches to actually painful, is 42 degrees with a surprisingly small variation. That is surprising. So the idea of being more pain tolerant because of your accumulated experiences or sensitivities, is that not? That is true, but that is not for that kind of pain. If you're drinking your coffee and it's too hot and it burns your tongue, you will stop drinking it immediately. You won't even aware of it. We've all learned to take a little sip and maybe not even put the coffee in our mouth. So we've been trained by our experience. We try and avoid that pain for that protective pain

to work, the pain has to be unpleasant. And in order for it to work, you can't say, I'll deal with it later. You've got to deal with it immediately. So it demands our attention and it's intense and it's unpleasant. And in that sense, it is that analogy of a switch. You have switched on something that focus your attention. I have to do something. I have to avoid this situation immediately. We're talking a matter of seconds. It's actually incredibly effective when you think about it, like that a very effective tool. The protective mechanism of pain requires an intense stimulus to activate it, a noxious stimulus. And we actually call this nocicept of pain, which is the pain that is initiated by a noxious stimuli. Now, the big difference

coming back to our post-surgical pain, we're now no longer dealing with protection from injury because the injury has occurred. It could either occur traumatically if you involved in a motor vehicle accident, or it could be because you have surgery. In both cases, there's trauma to your tissue. So you no longer need a protective system to prevent tissue damage because you have tissue damage. So what happens there? Instead of protecting you from tissue damage, evolution has developed a system that helps the injury to heal. And how does it do that? It makes the injured part hypersensitive. If you think about an injury or an inflammation, just touching that wounded sight will produce pain. So we're now got a complete shift. The pain is now activated

by a stimulus that would normally be innocuous, a sensation that would normally just be light touch, or in the case of a bad sunburn, a shower that would normally be pleasantly be warm, is now burning hot, even though the temperature is not in the hot range. So it's not about the stimulus, it's about the condition. Absolutely. The nervous system has changed. It's become hypersensitive such that normally inocular stimuli are now activating the pain system and we have tenderness, soreness, a heightened sense of pain. This is an adaptive thing. For example, after major abdominal surgery, if there were a way to completely eliminate the pain and you say, fine, I'll go for a jog, that would not be a good idea because you've got this

wounded tissue. It needs time for the wound to heal, to repair itself. And, you know, the same with if you've got arthritis, where there's damage to the joint. If you excessively use the joint, if you were pain-free, you would damage that joint. It's still essentially protective in nature. It's not protecting you from the external environment and potential danger to your tissue. It's protecting the injured body part from further injury, allowing repair to occur. And so, funny enough, the pain that I thought I first wanted to cure post-operative pain or post-traumatic pain, So you do want to try and reduce it to make people feel comfortable, but at the same time, if you eliminate it, that would be a real problem.

But that then leaves our patients who may not have any surgery, they have no tissue damage, and who have pain that just persists for years and years and years. One of the commonest causes of that is damage to the nervous system itself. And we call that neuropathic pain. And we now appreciate this is no longer telling us about. the presence of noxious stimuli or the presence of an injured part, it is the malfunction of the nervous system itself. It is a disease of the nervous system and is mechanistically quite different from either the two other kinds of pain. So there's three major categories of pain now. And there's one fourth one. And this is a group of patients who tend, not exclusively, but tend to be women. There's noxious

stimuli. There's no tissue inflammation. There's no damage to the nervous system, but they may have chronic widespread pain. And for a long time, this was labeled as psychosomatic, and there was almost a blame feature to that label to the patients. But now we realize they too have an abnormal nervous system. The reason they feeling pain is because it is as if someone has switched up the volume control in their central nervous system such that what would normally be a soft sound is now very loud and for them a soft touch now produces pain. So this is a pathological functioning of the nervous system in the absence of damage to the nervous system.

Is it congenital in those cases? Overall, for most clinical pain conditions, there is actually a very strong, heritable component. Something like 50% of the. the risk of developing pain is heritable. We know that from twin studies. So if you look at identical twins, if one of the twins has clinical pain, there's a very high chance that the identical twin will have it. If they're non-identical, it's lower. And if they're not related, then it falls way back. So something like 50% is driven by genetic variances that we get from our parents. You talk about phenotyping pain. That's what you mean essentially now, that we're able

to understand which type of pain and therefore treat it, presumably treat it differently. Right. What was behind the scientific breakthroughs that made that possible? Were there technological reasons or just sort of the accumulation over time of understanding? What were the pinnacle moments that shifted things? Technology now does enable us to interrogate the function of the nervous system in a way that wasn't possible. We can see activity using a number of indicators.

We can also opt to genetically activate specific parts of the nervous system. It is now possible in pre-clinical models to genetically target a light-sensitive protein into defined sets of neurons. And you can then use a laser light to activate those sets of neurons in a very controlled way. Super precise. Absolutely precise. And you can then dissect out the rule of each sets of neurons and particular circuits in a way that just wasn't possible. So this is a very exciting.

technological breakthrough. And the same thing with recording. We can genetically put calcium-sensitive dyes into specific sets of neurons and use little microscopes, and from that can see the activity of broad populations of neurons in different circumstances. So this is an extremely exciting time in neuroscience, but these technological breakthroughs are enabling us to dissect out the function of the brain. So what you're saying is essentially with these tools, we're seeing different areas light up in different ways than we once expected, which categorizes into different types of pain and reaction. Right.

The breakthrough came when we realized that acute, nociceceptive protective pain was different from inflammatory or neuropathic and then what we call dysfunctional pain. There's been a whole set of data looking at the mechanisms that drive each of them. What exactly happens when you have a noxious pinch? sets of neurons are activated? How does this environmental mechanical stimulus get converted into electrical activity? Which neurons transmitted? What are the signals that they use to transfer the input from the periphery to the central nervous system? Which parts of the brain do they activate? Which circuits? All of that, we're beginning to dissect out. And as we do that,

we're revealing potential points at which there could be therapeutic intervention. I think our greatest understanding now is the protected pain, how it switched on, which sets of neurons are responsible, which parts of the spinal cordon and brain are involved. We also know that in the presence of inflammation, as part of the tissue injury, there's a massive recruitment of the immune system. These produce signaling molecules that act on the neurons, but there are also changes in the central nervous system as well. As it becomes activated, there are changes such that the transmission of input can be amplified, it can spread so that, yes, at the site of the tissue injury there's, as expected, but actually the tissue surrounding it, which is not injured, that is

also hypersensitive. And that is a manifestation of the presence in the central nervous system of what we call central sensitization and abnormal amplificate. So it's happening both at the same time. There's both peripheral sensitization, where the threshold is reduced, and within the central nervous system, there is an amplification of the signals such that inputs that would normally not be painful now begin to drive pain. So now it begins to seem like our ways of treating pain have been just this huge hammer that we've been hitting all kinds of different things with this giant blunt instrument. Absolutely. So let's talk about the link between pain and addiction. We think about pain as being linked to addiction because of the category of

opiates largely. Can I ask a little bit about the science behind what we understand to be going on there, neurologically speaking, why those two tend to go hand in hand, or are we able to pull them apart? The big problem with opioids is that in addition to reducing pain, they produce a euphoria. The addiction comes from that euphoric signal, which occurs in the brain, in a different part of the brain, from where they act to reduce pain. And so you have two parallel systems. You have pain and it's a reduction by opioids and then you have the pleasure centers that are activated by morphine which gives someone a high and not everyone has it but those people who do then initiate a craving behavior and again there are certain individuals who have a high risk of

craving who then become dependent and addicted but analgesia does not mean that there's going to be euphoria it just so happens in that one In the case of opioids, of which morphine is the typical example, not only does it reduce pain, but it produces the sense of well-being, of euphoria, of happiness. But you don't need to switch that system on to get the pain relief. So in a sense, it's extremely bad luck. The intertwining of pain and addiction now is largely through the fact that through opioid prescription has until very recently been the means by which people,

are introduced to opioids. So until literally a few years ago, if you had dental surgery, your dentist would give you 20 oxycodone. Why was it always so much? It always seemed like much more than one would need. Because what a big switch from your post-surgery beds where they, okay, well, pain's just part of it. So basically, this is not the first opioid crisis that.

we've had. In the 19th century, there was massive addiction, the famous opium wars. So the addictive qualities in the respiratory depression and all the other bad features of opioids have been around since the extract of the poppy was recognized. It was for that reason that in the middle of the 20th century, physicians were wary, highly wary of treating their patients with opioids. And that's why on my first exposure, there were patients. is literally crying in pain because the surgeons of that time. Because of the backlash. Because of the backlash.

Oh, how interesting is like a pendulum. So then what happened in the early 80s, the view came that if you gave morphine and its equivalent drugs to patients in pain, there was no risk of addiction. This came from palliative care because there was in the 80s a growing recognition that patients with terminal cancer did need very active treatment and a big part of that clearly is morphine. Those patients do need opioids, most of them in the lay stage of life. And from that very good use, it spread out to say, well, patients who don't have terminal cancer who have pain also need opioids and a belief appeared in the medical profession that if you gave morphine

or any other opioid to patients with pain, there was no risk of addiction. There was not based on proper studies, and it's turned out to be incorrect. So that led to an enormous expansion in the prescription of opioids. So it wasn't so much that there was any kind of intentional sort of extra. It was just thought not to matter, not to pose a risk. Not to pose a risk. It was done with the best of intentions. So the idea was if you have a patient with pain, give them appropriate treatment.

So the prescription opioids were the avenue initially in our current opioid crisis, the means by which people could become introduced to opioids. Although there have been many attempts to try and design drugs that only have analgesia, if they act through the mu-opioid receptor, I think in the end the risks are very high that you will always get the risk of addiction and abuse. But why is the euphoria addiction? I mean, I feel euphoria, you know, over, I don't know, emotional events and I feel that I can experience it and let it go. What is happening there that that kind of euphoria leads to the uncontrolled craving?

If you gave 100 people morphine, some of them would feel terrible nausea, some would feel they are floating on a cloud and happy and all their worries had disappeared and others wouldn't. And that again reflects out the genetic variation. But there are a group of people who, when they are exposed to morphine, feel so pleasant. And on top of it, when the morphine wears off, they feel so terrible that they develop that craving. So it's a combination of the positive feeling they get when they have the morphine and the terrible negative feeling when it wears off. it's actually the strength of a negative feeling that is one of the major drivers of addiction. If you ask addicts, they'll say their first exposure was intensely pleasant, and they've never been able to reach that same high again.

However, when they stop it, they feel so terrible, worse than they ever did starting off with, that they're now just trying to get back to a normal balance feeling. Now I sort of understand the confluence of cultural and what you grow up around or how whole of a person you feel you are, right? The psychological and the cultural stuff, it's about the contrast. It's not necessarily the euphoria, but the contrast of the euphoria and the lack then of it. If you have a job that is not satisfying, that if your family situation or your economic situation is dire and all these other features, then if you take a drug that makes you feel happy and then, you know, that becomes a driver of that. So when you start to get this level of detail and resolution sort of on understanding the different pathways and the different systems that are being triggered, what do you see going forward for where we intervene?

Are there solutions starting to change how we treat the pain as well? Absolutely. I'm very optimistic. I think we're going to move away from the blunt problem. where we see pain as a single box and we can throw only the same therapy at it to now having the means to identify in a patient what is the drive of their pain what is their particular set of pathological changes that are causing their pain and that will suggest what is the most appropriate treatment and that's called the phenotype is the total pain presentation in the patient and all its features that will reflect the mechanisms that are driving it And then we can use that to what we call segmentation.

We can, instead of seeing the population as a whole, we can break it down. This is a patient where the pain is entirely periphery. It's been driven by, for example, if you had a thorn in your heel and you didn't remove it, whenever you walked, you'd have pain. But that pain has a definable cause. And in fact, all you need to do is remove that thorn and your pain will disappear. Well, then you'll have another kind of pain for a little. while.

Absolutely. You can identify the cause and you can target your treatment. What the challenge for us now is to find the equivalent of the thorn. These are changes in the function of the nervous system. But once we can find the mechanisms that are operating and use that to help us choose the most appropriate treatment for the patient, one of the big problems in pain management has been even those drugs that the FDA has approved, such as pregabalin, for treatment of neuropathic pain, the vast majority of patients, literally greater than 50%, do not respond

at all. They get no benefit whatsoever. Was the drug chosen because of its lack of side effects like addiction? So the FDA has two choices to make when they are proving a drug. The biggest factor is its safety. So if a drug has no minimal adverse effects or side effects, that is a very big plus. then they look for efficacy. You need that in order to get approval and put a label to say,

I can use this drug to treat neuropathy pain. But they don't require you to say it'll work in all patients with neuropathy pain. You just need to, the pharmaceutical company just needs to show that it is significantly better than no treatment. And that may mean literally it works in 30%. And what about the 70%? They get no benefit. But in the 30% that it did help, was that a drug? that intervened in the pathways in a different way?

It's a case of serendipity or empirical observation. Pregablin was a derivative of an earlier drug called gabapentin. Gabapentin, as its name indicated, was designed to be similar to one of the major inhibitory transmitters in the brain. It was designed in this way to switch off overactivity of neurons in the brain in the case of epilepsy and pain and other similar conditions. But it turned out that it didn't actually act in this way at all, but it did have some analgesic signal.

And even after it was marketed and approved by the FDA, it took a long time before it was discovered exactly what that signal was. And even to this day, it's not absolutely clear why activation of those particular targets produces analgesia in some patients and not in others. So how do you even begin? to consider new therapeutic approaches when you're at the stage of just sort of mapping? Or do you feel we're past mapping and we're starting to understand other kinds of interventions? What are the modalities of treatment for pain that we're going to start beginning to see?

A big part of my career has been trying to identify the mechanisms of pain as a basis for designing a new generation of treatments that would mean that we could make opioids obsolete. The technological advances in biomedicine as a whole have, really transformed the way we can approach even something as complicated as pain. We now know much more about the nature of tissue injury and the inflammation that occurs and the signaling molecules that are released and how to block them. We now know much more about the excitability of neurons and how they change and how we can target that whose signaling leads to the production of pain may be different from others and that enables us to get selectivity. But we also,

as I've indicated, can recognize that in patients who have neuropathic pain, we now know the downstream effects of that damage. What are the pathophysiological changes that have occurred and now can design our treatment to intervene? At the moment, most of that treatment just switches off those changes, so it's symptom control. But in the relatively near future, we will also get disease-modifying treatment

where we can recognize that if a surgeon damages a nerve during the surgery, there is a high risk, particularly in those people who have a genetic predisposition for the development of chronic neuropathy pain. And we will be able to say this person is at very high risk, therefore we can give a treatment that will prevent the evolution of those pathological processes in the brain that will cause that persistent neuropathy pain. So now you're shifting to kind of prevention. model from the very beginning, whereas almost by definition pain seemed like there was no possibility

for preventative unless you live in a bubble, right, that we by nature encounter this. I wanted to ask you something a little bit wacky about pain, which is if these are certain receptors and certain pathways, you have different types and we're beginning to understand what happens in these different systems. Do you believe in our psychological ability to manage pain? Is that a real thing? Ideas around self-hypnosis or meditation or what effect do those have on the brain or is it just are we just telling ourselves stories in the end what we feel is the net result of the totality of our brain function and so if you have pain and you're depressed those will be additive if you have pain and you are depressed and this interferes with your sleep that will increase your pain so

you can get into vicious cycles where your pain gets worse and worse and therefore your movement changes and therefore interventions such as distractions may not switch off your pain but can make it bearable and that certainly can be a big feature and should be part of the totality of treatment we shouldn't just rely on medication it's generally not enough one of the breakthroughs over the last decade or so has been the recognition that placebo we see that as a problem because it It makes it difficult when we do clinical trials to identify new treatments. In other words, you give a patient just a sugar pill and they respond well to that. And how are you going to differentiate that from an active compound?

But that placebo is not wishful thinking. It is the activation, and we know that from functional imaging, of very specific parts of the brain, which then suppress or reduce the activity of those parts of the brain that generate the sensation of pain. So it is having a biological effect. It is a biological effect. And certainly anything that can switch it on

is beneficial. It's more variable. It's more difficult to manage. But interventions such as acupuncture are very good at switching on the placebo. That's fascinating. What you're saying is that that actually could in turn cycle back

into how you experience the physical pain, just that in the overall composite of how your brain, as a system is behaving. There's been a lot of work in this, trying to identify all these confounders or contributors to pain.

And the one that seems strongest is something what we call catastrophization. This is a definable feature of our makeup, that there are some people who, if they have a problem, make it worse.

It's a kind of anxiety. It is exactly that. And that definitely is highly correlated with the intensity of pain that people experience. And if you can target that catastrophization where you can get people to overcome that anxiety, the sense of powerlessness

and lack of ownership of that pain, then that is, again, a very good treatment modality. It's not a magic switch. It's a cycle that you're interrupting. And what needs to see it in the context, it's more useful in the setting if you have daily pain that you can control and suppress

and deal with. In the next five years, how does our current framework need to shift in the system again in order to allow this different kind of understanding of pain to have actual effect in the clinic and in the hospital? The greatest challenge for pain is that it is a subjective experience. I can't know your pain, you can't know mine. When I say my pain is 9 out of 10 on a 0 to 10 scale, and tomorrow I say it's 5 out of 10, and how accurate do you think that is?

There's a smiley faces in the picture, yeah. And it's extremely difficult. And what if the patient is a neonatal baby or an adult who has Alzheimer's disease who cannot report their pain? How do we measure that? So I think a crucial element is we need new objective ways of surrogates of pain, pain biomarkers.

One of the most promising ways, there'll be others for sure, but is to use functional brain imaging to look at the changes in the activity patterns in the brain. This has been around for some time. The signals have been very noisy, but using artificial intelligence as a tool to help us measure pain. Now, instead of having a human look at the patterns of changes of activity and say, that constitutes the presence of pain, machine learning algorithms that are picking up patterns that we wouldn't even have detected. And correlating them to pain.

correlating. So it is reaching a point now that the signals we can get from those functional image will tell us that there's a very high likelihood that the patient has pain or not pain. That also raises ethical issues because if someone says they have pain and your functional imaging says there's no equivalent, how do you deal with that? But the positive is that we now have tools to go beyond just relying on someone saying, I have very bad pain or I have no pain, to a point at which we can understand the changes that underlie that pain and the associated features, because not only do you pick up the sensory experience, but you do pick up the changes that reflect the anxiety, the helplessness, the other features that constitute the entire picture

that a patient has. And to take it from the realm of purely subjective to objective. Exactly. And that's helping us in our pre-clinical studies because, again, we, Pain is extremely complex. There are many different features. If we study those neurons that are the prime initiators for pain, and we can actually grow using stem cell technology, we can take patient stem cells, we can convert them into neurons,

we can look at the features of the function of those neurons. In the past, we used to look at one feature, say the firing of action potentials as a surrogate for their activity. Now we recognize there are tens of features of phenotypes, we call it, that constitute the entire functional repertoire of these cells. And again, machine learning is helping us see the patterns and how they correlate with a normal state, a disease state, what kind of disease state, and the response to treatment.

So we now have tools at last to embrace complexity and from that define what are the components and which ones are relevant and important and which ones to go for. And where to go next. And where to go next. We are identifying other targets that are looking very promising, and I'm optimistic that in consequence I think we are going to be able to make choices about which are the best targets to go for, find the means to identify the best modalities to go for those targets, to develop new ways of running clinical trials, that will be more sensitive, both to suppress symptoms, but also to prevent the evolution of permanent changes in the function that nervous system that is a big drive of the crinicity of pain. Do you think that if we are able to get to that stage, it would just roll through the

system and become adopted? Or would there be challenges? They're always challenges. As is typical in biotech, there are going to be many failures. I think it is important that we go for risky because some of them will pan out. But the portfolio of potential possibilities is sufficiently exciting now that I'd do think this is, that we'll be able to look back in the near future and say, at last, we both understand pain and we can now control it in a way that has just simply not been possible before. I feel like we need a new thing in the doctor's office that says you're experiencing one of these four different types of pain, for starters. Thank you so much for

joining us on the A16D podcast. It's a pleasure.