Sean Mackey, M.D., Ph.D.
speaker
373 appearances
1 recordings
1 series
first heard Apr 2025
last heard Apr 2025
Sean Mackey, M.D., Ph.D.’s voice in public audio — every appearance, attributed to the second.
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Gabapentin, I think you've had perhaps some experience with. Turns out it's a lousy anti-seizure drug. Terrible. But it's a pretty good anti-nerve pain drug. Four grams a day. Four grams a day. Yeah. Drowsy though. You know who gets credit by the way? I give credit to making gabapentin the blockbuster drug. George Clooney. How? You ever watched ER? Yeah. He was a pediatric ER doc.
Kid comes into the ER with a skateboarding injury. George Clooney puts the kid on gabapentin. Now, where that had all started was a case report from a couple of ED docs who had noted by putting people on gabapentin that their acute pain got better. So,
I felt like beforehand when I was practicing medicine, around the time I saw you practicing pain medicine, that I'd look like a genius if I put somebody on gabapentin because nobody heard of it. And then after that came out, floodgates opened, primary care docs started using it. Now everybody's tried it. And it's a very safe medication.
I should also make a mention when I'm talking about these meds or any treatments. I have zero industry relations with anybody. Nobody. I don't take any industry money. You can go look me up on Open Payments CMS, which is a public database. Okay. Neuropathic pain. There's another one. There's a new kid on the block called nociplastic pain. I don't know if this one has made much traction yet.
This is a newly introduced category of pain, which is thought to represent dysfunction in the central pain processing system. And I'm not precisely defining it, but that's the gist of it. It means that in the absence of an identifiable peripheral cause, There is dysfunction in the brain and the spinal cord that is causing pain, perpetuating and amplifying pain. Nociplastic pain.
And it has been tied in with conditions like fibromyalgia, temporomandibular disorders, some aspects of chronic low back pain, irritable bowel syndrome, interstitial cystitis, and more. It's slowly starting to get traction. When we talk about pain, both to study it, but also ideally to treat it, we put them in these categories that we just described.
You're absolutely right. And I think the verdict is still out. In the end, does nociplastic pain stick around? Or is the problem that in these conditions that we associate with nociplastic pain, medical science hasn't caught up to identify a specific peripheral driver? I'm of the opinion it's that latter. I think we're going to find peripheral drivers for fibromyalgia.
There's some controversy right now as to whether fibromyalgia represents a small fiber neuropathy. And just because we may not be able to identify a lesion doesn't mean that there's not something there. But, as in all things, the truth will weigh out. We'll see how the story plays.
Oh, the last 15 years of my career has been spent on doing that very thing. And where do you think we are in that regard? Much further along than I ever would have predicted. So a large chunk of my research early on, my early research was in neuroimaging of pain. It was opening up windows into the brain to see where people were thinking, processing, perceiving, magnifying pain.
And I spent much of that publishing work to understand the mechanisms of that. And we haven't yet actually finished our story of pain going up to the brain and what's going on. And we'll get there. Over the years, I migrated into the space of developing objective biomarkers of pain. So I love working with young, smart people. I bet against it.
I had some young grad students and others who said that they thought they could do this. I told them how you would do it. And I said, it won't work. And I'm going to pay you. I'm going to give you money to go scan people. And you're going to learn how it doesn't work because failure is a great lesson in life. And they came back and they showed... they could do it.
And it was all through developing patterns in the brain and using machine learning models to then take that pattern, that signature, and be able to predict in other people whether they were experiencing pain. I didn't think we could do that because of the hugely individual nature of pain. It's so different from person to person.
But it turns out that there are core patterns in the brain that represent that experience of pain.
FMRI? Functional magnetic resonance imaging. It is a standard MRI that people go into, but we do some fancy pulse sequences. We play some physics tricks where we can see where nerves, the brain's being activated. And we've taken this, we and others have taken this from being able to determine whether somebody is in a state of pain to predicting their long-term trajectory.
We're working right now, a big grant that I have is to actually create composite multimodal biomarkers to predict their future state. We're getting there.
you'd see rather dramatic increases in activity in brain regions such as the thalamus, the posterior insular cortex, the anterior cingulate cortex, the dorsal anterior cingulate cortex, and a number of other areas.
You would also see it in S1. You're right. And indeed, what we've learned through this, that there's no one single pain region in the brain. That's another mistake that was made along the way. We all thought we were going to find a brain region. Then we can knock it out, right? Just go cut it out. And it turns out that didn't work. It's not one brain region. that generates the experience of pain.
It is a distributed network. It's all of these regions coming together and working in harmony. Doing what? Generating the experience of pain and then generating typically a response to that. Let me be very clear because there was a lot of controversy when we and others initially published our papers. We are not trying to take away the autonomy of the patient and the self-report.
I don't need an fMRI to see a patient and know if they have pain. I can just ask them. I can use self-report measures to get it. That's another part of the research. Where we're working to build these objective markers, this objectifying pain, is not to see what they're in now, but can it give us useful information? to predict treatment to a particular therapy?
Can we use it to predict their future state? Can we use it to predict their vulnerability to an injury or surgery? Those are things that just asking a patient right now probably not going to get there. I don't know if you want to go back to the brain.
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