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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It's more than diabetes, heart disease, and cancer combined. Fibromyalgia, again, I'm escaping the prevalence. Many millions of people. Huge societal burden. It is... Historically, a disease of histrionic housewives is how they were mislabeled, tragically. And we're having now a greater appreciation for what it is, what's affected.
What we have learned is that there are brain systems that are clearly abnormal in the processing of pain in people with fibromyalgia. We find that for the same pressure stimulus, if you apply something like four kilograms per square centimeter, healthy people will give a range of reporting in a certain range. People with fibromyalgia, much, much higher.
Here's another, I think this is an interesting pain concept to introduce and talk about it. There's something called conditioned pain modulation. In the animal world, we call it diffuse noxious inhibitory controller, DENIC. CPM. Think back to when you were a kid. Your arm hurt. You walk up to your buddy. You say, hey, man. And he's like, how you doing?
It's like, well, my arm's kind of hurting a lot. And what would he do? Hit you? He would hit you, of course. He'd hit you in your other arm. He'd stomp on your foot. And you're like, why the hell did you do that?
This is what little boys do. I was guilty of a lot of that. But then you'd say to your buddy, like, don't you feel better? And the truth is you did. Because pain in another area reduces the primary pain site. It's called conditioned pain modulation. We're all wired. It is
a network predominantly, we think, in the brainstem involving some of this periaqueductal gray rostral ventral medullary regions. Labar's first described this in the mid-70s in animals. So we all do it. We all have it. It's this endogenous tonic inhibitory tone that you can activate when you cause pain in another site, unless you have fibromyalgia.
If you have fibromyalgia, particularly if you're a woman with fibromyalgia, you have impaired CPM. You don't inhibit
Yeah. We used to think that there was a high preponderance of anxiety and depression with fibromyalgia. And I think the current data... doesn't support that there's any higher prevalence than particularly any other pain conditions. I think you tend to see more of the anxiety, depression, broadly speaking, in things like low back pain.
I think what you see more of in fibromyalgia is fatigue, unrelenting fibro fog is what they call it, and then the sleep disturbances.
Yes and no. What do I mean? Well, one, we don't know exactly the mechanisms. There's different prevailing thoughts. One thought, again, is it's a disruption in your central brain processing of pain through reasons unknown. There are some that believe it is a disease, a condition of small fiber neuropathy, because you can do punch biopsies, little, little skin biopsies here.
And what they find in some subsets of people with fibromyalgia is those C fibers... That there is alterations, abnormalities of the C fibers in the skin. And that is synonymous with a small fiber neuropathy that neurologists typically see.
That's the thing. Is this infectious? What do people think is going on? So fibromyalgia is frequently preceded by some event, something traumatic. That traumatic can be physical, motor vehicle accident, but it could also be some emotional or sexual abuse. It can be an infection. We frequently also hear that story. So there is some insult that people will frequently identify.
Getting back to your question on managing this, we frequently use the same medications that we've described before, but we rely on more of those brain modulatory drugs. Another one's like duloxetine, which is in the class of antidepressants, but it's a little cleaner, fewer side effects. It's a serotonin norepinephrine reuptake inhibitor. This is actually a drug that got FDA approval for pain.
And so we go to this a lot. One of the drugs that I have studied with Jared Younger, who's now at UAB, is a drug called low-dose naltrexone. This is a fascinating drug. It's got like this underground reputation out there. It's all over the forums. The reason for it is because it's been around for decades and off patent, there is zero money for any pharmaceutical company for it. What is naltrexone?
Naltrexone, when given at 50 milligrams, is used to block opioid receptors. It's an opioid blocker. And so we use this in the treatment of opioid and alcohol addiction because it blocks the rewarding experiences of alcohol or opioids. And so it's used as a treatment for addiction. 50 milligrams.
At four and a half milligrams, one-tenth of the dose, it has been shown to block Toll-like-4 receptor on the microglia. Now, I just introduced this really technical concept, so allow me to briefly explain. The microglia are these cells that hang around nerves but are not neurons.
And when I was in medical school, a few years, several years before you, what I was taught was these microglia were like the warm fuzzy blanket that propped up the nerves. I don't know what you were taught, but they provided structural support to the nerves. What I learned is that was only part of the story, that they're key neuroimmune modulators.
And so what I mean by that is, in times of stress, injury, fever, these microglia get activated. They release all sorts of inflammatory mediators, chemicals, that sensitize the central nerves responsible for pain perception, pain transmission, pain perception. So you give low-dose naltrexone, it blocks that neuroinflammatory soup. And in some patients, Peter, this drug's been magical. Magical.
I give it in four and a half milligrams.
All right, here's my story. Linda Watkins and Mark Hutchinson did some of the early work in the animal studies on this and showed this microglial effect. And they did it at a certain dose. And so what we did is we did a milligram per kilogram conversion to 70 milligram.
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