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REPLAY: Fibromyalgia: Central Sensitisation, Brain Architecture and the Pain Matrix with Dr. Michelle Woolhouse and Dr. Lily Tomas

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REPLAY: Fibromyalgia: Central Sensitisation, Brain Architecture & the Pain Matrix with Dr Lily Tomas

Integrative GP Dr. Lily Tomas dives into the many complexities involved in fibromyalgia, a condition underpinned by chronic, systemic inflammation and neuroinflammation. Our Ambassador Dr. Michelle Woolhouse opens the conversation discussing the many aetiologies of fibromyalgia which include oxidative stress, mitochondrial dysfunction, mast cell activation, microglia activation, peripheral and central sensitisation. They discuss common risk factors such as Vitamin D deficiency, gut health, and abnormal peripheral and central pain pathways, as well as others that can play a part in the development of fibromyalgia - which mainly impacts women aged 20 to 60 years of age. 

The gut is a major first focus for Dr. Tomas, who details connections between those with fibromyalgia and IBS, as well as how to investigate and treat through the gut. There’s also a deep discussion surrounding mitochondrial health and the development of fibromyalgia, due to the high concentration of mitochondria in skeletal muscle tissue as well as their impacts on damaging the nervous system and their ability to produce melatonin.  

Further to this, there is a fascinating technical discussion around gendered mast cells and microglia, and how they are shown to act differently depending on their sex, exposure to environmental toxins, dietary triggers, and sex hormones, all of which may be impacting patients with fibromyalgia. The brain and nervous system aspect can’t be forgotten as various areas of the brain known as the pain matrix contribute to both peripheral and central sensitisation with the focus on trigger points on reducing peripheral sensitisation having an upstream effect. 

This podcast is not to be missed for those who love technical details surrounding fibromyalgia and the multi-faceted aspects to treatment.  

Covered in this episode

[00:30] Welcoming Dr. Lily Tomas
[02:13] The multiple aetiologies of fibromyalgia
[03:49] Potential triggers of fibromyalgia
[07:19] Start with the gut
[08:41] Connections between IBS and fibromyalgia
[12:40] Microbiome testing
[14:10] The role of oxidative stress and mitochondrial function 
[19:22] Treatment options: how CoQ10 can improve symptoms
[21:28] Treatment options: Melatonin is more than a sleep hormone
[24:17] How mast cells affect nerve and neuroinflammation
[30:25] Hormonal influences on mast cells 
[34:37] The pain matrix
[39:57] The endocannabinoid system
[42:15] Topical preparations to reduce peripheral sensitisation
[45:53] Thanking Lily and final remarks

Key takeaways

  • Chronic systemic inflammation and neuroinflammation are the primary factors contributing to fibromyalgia 
  • Starting investigative points include vitamin-D status, gut dysbiosis, IBS, psychological history, environmental and dietary triggers, mitochondrial health and genetics 
  • Microbial balance has significant impacts where leaky gut, SIBO/SIFO can contribute to system inflammation, impacting mitochondria in the muscle causing peripheral pain 
  • Oxidative stress contributes to exacerbating fibromyalgia – consider glutathione and reducing oxidative load from internal and external insults. 
  • Central sensitisation results in a hypersensitive patient to pain stemming from excessively activated mast cells (MCAS), activated glial cells and long-term changes to nervous system signalling. Treatment can take years to wind-back neurological changes.  
  • Scans of the area in the brain called the “pain matrix” may reveal increased activity correlated with central sensitisation 
  • Microgenderome concept – where our gut microbiome interacts with sex hormones which might influence predisposition to certain conditions  
  • Sexual dimorphism in mast cells and microglia can lead to differences in severity of downstream effects I.e., female mast cells’ increased ability to store more inflammatory compounds with higher potential of anti-inflammatory effect on degranulation 
  • Genetic SNPs to consider 
    • COMT – may influence neurotransmitter levels of dopamine, adrenaline and noradrenaline 
    • GAD1 – may influence conversion of glutamate, an excitatory neurotransmitter, into gamma-aminobutyric acid 
    • DDR/ANNK2 - may influence dopamine receptor expression in the brain 
    • GPX1 – may influence free radical status load through expression of proteins from glutathione peroxidase family that catalyse redox reactions 
    • GSTP1 – may influence conjugation of glutathione to reactive metabolites and xenobiotics 
    • SOD2 – codes for an enzyme that produces master antioxidant superoxide dismutase  
    • 5-HTT – influences expression of serotonin transporters respsonsible to recycling the neurotransmitter  
    • 5-HT1A – influences expression of serotonin receptors 
  • Therapeutic Considerations 
    • Focus nutritional and compounds mentioned:  
      • Probiotics 
      • Vitamin-D 
      • Glutathione 
      • CoQ10 
      • Melatonin 
      • Topical preparations 
      • Lifestyle 
    • Psychological health – sleep (to relieve stress and anxiety, past trauma 
    • Identifying triggers – dietary, mycotoxins, mold, heavy metals, pesticides 
  • Testing 
    • Vitamin-D 
    • BioScreen 
    • Genetic SNP testing 
    • Referral for MRIs, and PET scans, NeuroQuant 


Resources discussed and additional reading

Dr. Lily Tomas
Research: Perinatal androgens organize sex differences in mast cells and attenuate anaphylaxis severity into adulthood (PNAS, 2020)
Research: Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine (Front. Aging Neurosci., 2022)
Research: Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity (Pain., 2023)
Research: A systematic review of the association between fibromyalgia and functional gastrointestinal disorders (Therap Adv Gastroenterol. 2020)
Research: Roles of Sex Hormones and Gender in the Gut Microbiota (J Neurogastroenterol Motil. 2021)

Related FX Medicine Podcasts

Mast Cell Activation Syndrome with Dr. Michelle Woolhouse and Beth O'Hara
Emerging Importance of Psychoneuroimmunology Dr. Michelle Woolhouse & Professor Craig Hassed 


Website: BioScreen Medical
Research: Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study (Sleep Sci. 2015)
Research: Associations between self-reported psychological symptom severity and gut microbiota: further support for the microgenderome (BMC Psychiatry, 2022)
Research: Treating gut flora imbalances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A pilot open label trial examining sex differences and psychological symptoms (In progress)



Michelle: Welcome to FX Medicine, bringing you the latest in evidence-based, integrative, functional, and complementary medicine. I'm Dr. Michelle Woolhouse. 

FX Medicine acknowledges the traditional custodians of country throughout Australia, where we live and work, and their connections to land, sea, and community. We pay our respects to the elders, past and present, and extend this respect to all Aboriginal and Torres Strait Islander people today. 

Fibromyalgia is a chronic musculoskeletal disease characterised by multi-system issues, including chronic musculoskeletal pain, fatigue, sleep disturbance, depression, and cognitive issues.
It affects about 5% of the adult population, and is disproportionately higher in women aged 20 to 60 years. Given the complexities and recent breakthroughs, I've invited my esteemed colleague, Dr. Lily Thomas, to do a deep dive into the pathogenesis of this condition and to give practitioners some clinical pearls to help them support their patients with this often misunderstood and stigmatised chronic condition. 

Allow me to introduce Dr. Lily to you. She is an integrative medical GP working out of rural New South Wales. She's a regular keynote speaker, and a teacher of doctors and health practitioners in many areas of nutrition and environmental medicine. 

Welcome to FX Medicine, Dr. Lily. Thanks for being with us today.

Lily: Oh, thank you, Michelle. It's definitely my pleasure.

Michelle: So, fibromyalgia is possibly one of the most maligned conditions. Many sufferers still feel misunderstood, and it can devastate some people's lives, and not to mention their livelihoods. It's not a passing condition as a general rule. So tell us, Lily, what is going on for these patients, and what are some of the underlying causes we really need to know about?

Lily: Well, firstly, when we speak of fibromyalgia, like so many different chronic diseases, there really is no one cause. And rather, we have multiple aetiologies or multiple causes that differ from person to person. But there are two main explanations in fibromyalgia that do underpin all the others. And these are both chronic systemic inflammation as well as neuroinflammation. 

And we can break these down even further. We need to understand that there's varied conditions and they all sort of coalesce together. And that accounts for all the different varied symptoms we see in the people with fibromyalgia. And when we are talking about these conditions, I'm meaning things like oxidative stress, mitochondrial dysfunction, activated mast cells, activated microglia, and both peripheral and central sensitisation. And I'm sure we'll get a chance to discuss each of these in turn as we go along today in the podcast.

Michelle: Yeah. It'd be great to kind of break them down and kind of really understand A, how they interconnect, and B, it's like one thing kind of leads to another, and sort of it's why it's like looking at the hole and then diving in kind of. 

So it kind of begs the question, why does this happen for some people? Is there a trigger? Is there certain risk factors that we need to be aware of? What is that underlying kind of trigger point of that inflammatory response?

Lily: Yeah, and like I said earlier, I don't think there is only one trigger point. Every person is unique, and so there's different risk factors with every person. But in saying that, there are several common risk factors that we should really explore if we want to successfully help someone with fibromyalgia. And so we need to understand where the inflammation is coming from, both that chronic systemic inflammation and the neuro inflammation. 

So, the risk factors that I just want to bring up today. I mean, vitamin D, we've all heard so much about vitamin D.

Michelle: Yeah, absolutely.

Lily: It's so, so important for so many different things. We have to see if someone's vitamin D deficient, and it's important. We would all know as integrative doctors, when you look at reference ranges, the reference range in my lab goes from 50 to 140. And most integrative doctors and naturopaths would always aim for mid-range with most things. But truly after COVID, and after all the research that's pointing to increased severity of symptoms correlating with low vitamin D, an optimal level would be surely closer to 140. And the data clearly shows this with fibromyalgia as well. So, always considering vitamin D. 

We need to look at gut health as well, because we know that most diseases begin in the gut, and our gut contains at least 70% of our immune system. And so if our digestion is not good, like if we've got intestinal permeability or intestinal dysbiosis, that's certainly going to contribute to the symptoms of fibromyalgia. There's also evidence that people suffering with fibromyalgia have abnormalities in both their peripheral and their central pain processing pathways. And we can go into that a bit later on. You have to look at...

Michelle: Yeah, I'd like to look at that.

Lily: ...lifestyle. Yep. Yep. Like our diets, whether we smoke, how much exercise, how well we sleep. Of course, we've got to consider psychological factors. There is a higher incidence of fibromyalgia in those people who've been sexually abused in childhood, or who have experienced sexual violence in adulthood as well. 

Genes will have a part to play as well. There's more and more genetic things we're finding out about now. And there's a higher number of SNPs, so single nucleotide polymorphisms or mutations in people with fibromyalgia. And interestingly, they are all concerned with our serotonin receptor and transporter proteins, our COMT enzyme, which is really important as we know for mental health as well, and our dopamine receptor proteins. So, all of these things can add up. 

Oh, and one thing I definitely need to say here is environment, obviously, the environmental factors. We need to know, has this particular person been exposed to mycotoxins from mould or any tick-borne diseases? Do they have heavy metals, pesticides? We just have to look at it all together, and work out what those specific risk factors are for that specific person who's sitting in front of us.

Michelle: Yeah. Absolutely. So, with all that being said, I mean, it's almost...it's a seriously complicated deal, such interconnected systems. And we've got, almost like our mind-body medicine. We've got our digestive and our environmental aspects, and all these lifestyle factors. Where do you like to start with complex conditions like these?

Lily: Well, look, I suppose it really does depend upon the person that's sitting across from you as to what their needs and their priorities are. That's the first thing to consider. But for me, ideally, I always tend to like to look at gut health first. I like to look at what they're putting into their body. And I find that's really important because if every day they're eating things that are inflaming them, then any supplements that we might use may not be absorbed as well. And we have to fight against those foods, and we know how common food intolerances are in this society. My little mantra is anything can do anything to anybody at any time, and it's just so true. We know that food intolerances do far more than just digestion issues. There can be direct links between foods and pain, foods and energy, foods and moods, foods and sleep. So yes, I would have to say, for me, I tend to start gut first if I can.

Michelle: Yeah. So, there's a strong correlation between irritable bowel syndrome and fibromyalgia in the research, isn't there?

Lily: Absolutely. At least a third of the patients, and even up to 80% of patients with fibromyalgia actually meet the diagnostic criteria for irritable bowel. So there is really significant associations here. And besides the food intolerances that I was just mentioning before that we all know contribute to IBS, there's also the gut microbiome. And this is huge. This is such a growing area. We know that the studies have shown that supplementation with probiotics can significantly decrease pro-inflammatory mediators such as tumour necrosis factor alpha, interleukin-6. We've got specific bacterial colonisation patterns, which have been linked to chronic pain like clostridia, coagulase negative staph. And there was actually a new study that they presented, or paper they presented last year, which actually showed that people with fibromyalgia have different amounts and species of bile metabolising gut bacteria, and different concentrations of bile acids in the blood. And this is one way to distinguish. They're saying it's very important even as a biomarker now specifically for fibromyalgia, because it's different from, say, the people with IBS.

Michelle: Amazing.

Lily: And also, if you think of the gut microbiome, we all know about LPS, the lipopolysaccharides, those really powerful pro-inflammatory endotoxins that are produced from the gram negative bacteria in our gut. That's really important in fibromyalgia because if we're suffering with intestinal permeability or SIBO or SIFO, for instance, we know we are going to absorb those LPSs hugely. And it's been shown that the LPS actually causes mitochondrial dysfunction in the muscle. And it causes peripheral hyperalgesia, and this thing called central sensitisation, so it increases pain. Not only that, it activates our microglia in our brain and causes neuroinflammation. So...

Michelle: Wow. It's so important.

Lily: ...there's another concept as well, which is called the microgenderome, which proposes that our gut microbiome can actually interact with our own sex hormones. So this then gives insight into the certain sex discrepancies in susceptibility to particular disorders. And we know that fibromyalgia is definitely far more common in women than in men, for instance.

Michelle: Wow. That's amazing.

Lily: It is, isn't it? That's incredible.

Michelle: And I also love the fact that it's often a two-way street, too. You mentioned psychological factors before, and as they...which one's the chicken and the egg, and then how do they interact with that? It's all just a fascinating kind of enmeshment, so such a beautiful thing. But it's also really important to be able to kind of really show these inflammatory markers. And the way that this inflammatory, I guess, cocktail works for people with fibromyalgia, because they often feel disbelieved and they feel unvalidated in many respects, which actually almost heightens that psychological stress, particularly in the medical...it's almost like a medical trauma when people are disbelieved. So...

Lily: It's interesting now with the long COVID and everything surrounding that, how there's now talk of, well, I think we may have underestimated the effects of fibromyalgia, chronic fatigue, with more and more people suffering from a long COVID-type situation as well. People are now starting to be believed a little bit more, I would hope.

Michelle: Yeah. It may just open the door for this kind of level of understanding with so many people affected as well so that more money might kind of pour that way. 

But I wanted to get back to your clinical expertise. Where do you start in terms of looking at the gut biome, or intestinal permeability and dysbiosis, what sort of microbiome test is your favourite, and why do you choose, or is there certain things that pique your attention that you kind of go, "Okay, well, I'm going to start there, or I'm going to start there."

Lily: Sure. I mean, there are so many different microbiome tests available these days. It's incredible. I suppose having done this for, at least the last two decades, like you Michelle as well, I tend to stick with one of the tests that was around back then, which is BioScreen based in Melbourne with Dr. Henry Butt. 

It's really interesting to see the same patterns popping up, whether you're dealing with someone with fibromyalgia, or whether you're dealing with someone with autism or chronic fatigue. The microbiome tests can just really tell you so much. And often times, you will see an excess of certain microorganisms, such as strep or clostridia that we mentioned, or perhaps a deficiency of E. coli, for example. And there are these specific protocols that you can follow to successfully balance the gut microbiome with great results. 

And I mean, I really should thank Dr. Henry Butt from BioScreen at the moment, who really taught me so much about these amazing links between the gut microbiome, and so many different chronic illnesses, not just fibromyalgia. So, that's my port of call. Yes.

Michelle: So, obviously treating gut dysbiosis, it then goes a long way to sort of settling down that micro-inflammation, and goes hand in hand with oxidative stress. It's almost like oxidative stress and fibromyalgia is interlinked. Is there truth in that kind of statement that you can almost assume that there's oxidative stress if somebody is presenting with fibromyalgia?

Lily: Sure. Most definitely. There's a clear relationship between oxidative stress, neuroinflammation, and pain in fibromyalgia. We all know that glutathione is one of the most important antioxidants in the human body. And studies have definitely shown that people with fibromyalgia have decreased blood levels of catalase, of glutathione peroxidase, and glutathione reductase. So what this means is they can't clear their free radicals, and you get increased lipid peroxides, and that's just resulting in higher levels of oxidative stress. 

They've also found reduced superoxide dismutase levels have been found in people with fibromyalgia. And that's been linked to chronic muscle pain as well as tender points. And what we know, even though we don't understand all the connections yet, and we're still learning, we know that the greater the abnormalities in our antioxidant and free radical status, the greater the severity of symptoms.

Michelle: It's almost like a really great clinical pill to kind of know that. Because if you sort of stumped, at least maybe sort of seeing whether you can increase some of those antioxidants, may just give you a little bit of a win to get you over to the next step. 

But let's talk oxidative stress and mitochondrial dysfunction. Because again, it's almost like, "Okay, well, here's the staircase. This is another step in..." Mitochondrial dysfunction has almost really been elevated to a really key point, I think, from my observations of the last kind of five years or so, or even more. 

But tell us about mitochondrial dysfunction and fibromyalgia. Because there seems to be a really significant kind of link that matches to a person's symptoms and how they're feeling.

Lily: Oh, absolutely. And again, it's the oxidative stress. We know that's one of those triggering mechanisms for mitochondrial dysfunction in fibromyalgia. And so when our mito aren't functioning correctly, what happens is we get increased glutaminergic transmission. And remember that glutamine is one of the body's most important excitatory neurotransmitters. So, it excites everything. We get activated microglia as well and this all results in neuroinflammation. 

And once we have that neuroinflammation, it contributes to peripheral muscle pain, but as well as central pain sensitisation. And that's one of the hallmarks of what we call wind-up pain in fibromyalgia. And it's also important to know that the expression of our pro-inflammatory cytokines that happens in fibromyalgia is both dependent upon and elevated by mitochondrial dysfunction and oxidative stress.

Michelle: Such a chicken and the egg, isn't it? It's like...

Lily: It is! Absolutely. That's right.

Michelle: So bidirectional.

Lily: Yes. And mito as well. When our mitochondria are not functioning properly, it's actually been implicated in damage to the axons of our nerve cells. And that's one of the potential underlying causes of allodynia, which is one of those characteristic symptoms of fibromyalgia. When you get the really severe pain from just slight touch or even a breath of wind. 

And once again, going back to gut health, we know that mitochondrial dysfunction can be triggered by those LPS, the lipopolysaccharides that I was just talking about before. D lactate, increased intestinal permeability, SIBO, and so forth. It's all connected. I was always fascinated by psycho-neuroimmunology. It was...

Michelle: My favorite.

Lily: Yeah, you too. I know.

Michelle: Loved it.

Lily: Psychoneuroendocrinology. It just...

Michelle: I loved it.

Lily: ...everything is connected and it is amazing, isn't it? It really is.

Michelle: Yeah. Gives me goosebumps.

Lily: Me too.

Michelle: I think though, what really strikes me listening to you talk about that microscopic neuropathy, because one of the things we know about neuropathies or nerve damage is that it takes a long time to heal. So it's a really good way of giving our patients kind of perspective, actually, of how long this will take to heal. Particularly, if you're doing all the right things, and you want to turn it around, it's still going to take a long time to turn around because you are dealing with the nervous system. And I think that's really... I mean, I often find setting my patients expectations is almost like the primary thing, because some people get off the bus too quick. It's like, it's not your stop, you can't just wait two stops and get off the bus. This is going to take years to unravel. But there's positive things that happen in those years going forward.

Lily: Oh, absolutely. And especially when that central sensitisation kicks in, because you know then things have gone far, and it does take a while to bring this back. And you're right, it is years in a lot of people.

Michelle: So, tell us about treatment applications, particularly for this, because we know coenzyme Q10 is a really important nutrient, and lots of vegetarians and vegans aren't getting enough. We make it ourselves, but it decreases with age. All of these kind of things. But it's often deficient in fibromyalgia, even if you've got a young patient, etc. Why is that, do you think? And is replacing it enough? Or do we have to do more?

Lily: Absolutely. And you're right, there's been so many studies demonstrating that people with fibromyalgia have low coenzyme Q10, and also just as many studies demonstrating the positive effect that CoQ10 can have on the symptoms of people with fibromyalgia. 

But once again, coming back to mitochondria, everything being linked. Our mitochondria depend upon CoQ10 or ubiquinol to function properly. And we don't totally understand all the mechanisms by which CoQ10 can do this, but we do know several things. Firstly, CoQ10 is absolutely essential to our mitochondrial electron transport chain. And we know that that's critical for creating ATP, which is the main energy source for us humans. And that we do know also that there's a high concentration of mitochondria in skeletal muscle. Now, of course, this is where most of the pain in fibromyalgia is.

We know that CoQ10 has potent antioxidant and free radical scavenger properties, and we know how the reactive oxygen species, the free radicals can create hyperalgesia in patients if there's too high levels. And there's one other effect that is considered here, that CoQ10 may be under the control of what's called our AMPK gene. And this is considered to be the overall regulator of our cellular energy levels. And so, it's actually thought to be another possible mechanism for why CoQ10 helps us to improve symptoms in people with fibromyalgia.

Michelle: And often, it's so interesting to me, I remember going to a lecture years ago about sleep, and we know how important sleep is. But often you need actually more energy to sleep than you do, say, sitting on the couch watching Netflix. 

So, there's a relationship between coenzyme Q10, and the use of melatonin. Is melatonin kind of an option to help support sleep? Or tell us about sleep and fibromyalgia because that seems to be a nice, good place to kind of start as well.

Lily: Absolutely. I mean, we all know that lack of sleep, just like stress, can make every single condition worse.

Michelle: Everything.

Lily: Everything, for sure. But we know melatonin is much, much more than just a simple sleep hormone. It's an antioxidant, it's an anti-inflammatory, and it's an antinociceptive, and analgesic in its own right. We do know that melatonin's produced in the pineal gland, but it's actually not just the only place it's made. It's actually made in our skeletal muscle as well as our GI tract, our immune cells, our liver, our spleen. And fun fact, it's not just humans that make melatonin. Melatonin is also found in plants, and animals, and insects, and fungi, and bacteria. So it just shows you then that melatonin's got to have many greater roles than the ones that we are just currently aware of now.

Michelle: It's like psycho-neuro ecology.

Lily: Neuro ecology. Absolutely. It’s a new phrase you've coined.

Michelle: Yeah, exactly. I'm going to patent it. Watch this space.

Lily: Absolutely. When we think about melatonin and fibromyalgia's role there, we know that obviously melatonin can help sleep. And when we are well-slept, then that can result in less anxiety. And so, therefore, that can reduce our perception of pain.

But once again, going back to our mitochondria, we know that mitochondria are strong producers of melatonin. And remember, our skeletal muscle has this high concentration of mitochondria. And so it's thought to be another mechanism by which melatonin exerts its positive effects on pain in fibromyalgia. 

But more and more studies are showing it's not just about this either. We've got melatonin receptors connecting with new opioid receptors, and they release beta-endorphins when they are bonded with melatonin. But melatonin can also affect our GABA-B receptors, which regulate anxiety and pain. And if we remember, GABA is our most important inhibitory or calming neurotransmitter in the body. So, all of these things combined, melatonin we know is just simply not about sleep and sleep alone, by any means.

Michelle: Yeah. So, we can't have a discussion on fibromyalgia without mentioning mast cells as a potential link. I mean, there's a... We've just released an episode on mast cells recently. Tell us about the role of mast cells, and how they play a role in the dysfunction, and how do you go about considering that as a key avenue to go down? What do you look out for in that clinical kind of situation?

Lily: Well, look, I suppose the most important thing to know about mast cells is they function as a critical bridge between our immune system and our nervous system. They actually connect the systems both directly. I mean, the mast cells actually abut our peripheral nerve endings, so they're right next to them. But it also connects them indirectly because the mast cells release their chemicals. 

And so the primary job of the mast cells in our body is to coordinate the body's immune response to toxins, to infections, to allergies, etc. But when they are inappropriately stimulated, so if there's too large a burden, which we think is one of the things happening in fibromyalgia amongst many other conditions, then they become activated, and they can start reacting to just ordinary stimuli. So, like foods that we eat, smells that we smell, light, touch, things that shouldn't be a problem, become a problem when these mast cells are really activated.

And themselves, we know mast cells, they produce far more than histamine. In fact, it's like more than 200 different biochemical mediators which can be released. And depending upon the conditions, and depending upon if a person is having a flare-up or not, the mediators can change. So, ultimately this can cause different symptoms for that person as well, which is what adds to the complexity of everything. 

We know that the mast cell mediators have been found in both the plasma, so the blood, and also the cerebrospinal fluid of patients with fibromyalgia. So this is going back to where we started, it's highlighting that importance of both the chronic systemic inflammation as well as the neuroinflammation that's happening simultaneously in fibromyalgia. And so we've got this crosstalk that's just going on between the two systems. And when we have these imbalances between our pro and our anti-inflammatory cytokines, then we're going to get disruptions in our inflammatory and our immune pathways. And once again, that's going to contribute to our neuroinflammation. 

Also our thalamus in our brain, it contains a significant number of mast cells, and they can cause neuroinflammation because, again, the mast cells activate our microglia, they can increase the permeability of our blood-brain barrier. And of course, they're releasing all those molecules. As I said, more than histamine, just Substance P, tumour necrosis factor alpha, interleukin-6, and so on. 

And then, once we've got this continued activation of mast cells, well, that can lead to MCAS or what we know as mast cell activation syndrome. Once we've got that, that's when, once again, it's like the central sensitisation, that it's far more complex. We've got far more blood-brain barrier dysregulation. We've got more microglial activation, we've got more neuroinflammation. And it's the neuroinflammation that actually turns acute pain to chronic and causes chronic pain to continue. It's very complex.

Michelle: And then we get that vicious cycle. Very, very complex and very difficult to unwind. 

But I guess, having a look at sort of the mechanisms kind of allow us, A, at least validation for the patient, but also, again, the expectation. These processes take a long time, but so long as the patient can acknowledge the complexity, but also understand the unraveling process, and using the things that are internal to them, their innate healing mechanisms can help a lot. 

So if you have that issue with mast cell overstimulation, for example, what's your kind of go-to starting point just from a practitioner perspective? What are these clinical pearls that you like to use in that particular situation?

Lily: So I suppose it's important to work out whether or not mast cells are involved with the particular patient that's sitting in front of you. We know that MCAS is such a chronic multi-system condition, it's going to have a wide variety of effects in a wide variety of organs. 

And so, you can think of the things that are happening with skin, so rashes and itching, dermatographism. It can affect our eyes by getting irritated eyes. Our ears, we can get tinnitus. Our respiratory system, we can get shortness of breath. Cardiovascular system, you think of palpitations. Neurological headaches, digestion issues, urinary frequency. It just goes on. Virtually every organ system can be affected. And that's, again, it makes it hard to...unless you're aware that MCAS could actually be happening, you're just trying to find a condition for every single one of those symptoms rather than putting it all together in a syndrome.

And so, as I said before, depending upon which of the mediators that are released by the mast cells at any one time, it's important to remember that each patient can present with different symptoms. But even the same patient can present with different symptoms at different times, depending upon their triggers. And so, I always think is mast cell being involved here if the patient has multiple symptoms in multiple systems in their body, symptoms that come and go, and also lots of different triggers. And there's always an inherent difficulty in trying to work out what those triggers are simply because they keep changing. So, that's what I would think to be aware, "Okay, our mast cells are at play here."

Michelle: So, one of the most fascinating parts of that recent presentation that I saw you at a conference recently was around the evidence between the difference between female mast cells and male mast cells. I thought that was absolutely incredible. Female microglia compared to male microglia. And this has some bearing on that predisposition of fibromyalgia and women with these kind of conditions. And so often there's this underlying kind of sense of that women are vulnerable and they get fibromyalgia or they complain of pain. It sort of feeds into a bit of a cultural, I guess, negativity around that. Tell us about that, because there's oestrogen, progesterone connection, etc. What is going on there? I find this fascinating.

Lily: Absolutely. It is definitely fascinating, I agree with you. It really is. In terms of mast cells, we know that there are both male and female mast cells. And the female mast cells are the ones that tend to have more aggressive immune responses. So, this is really good because it's better to fight infection on the one hand, but on the other hand, it can predispose females to suffer from more inflammatory and autoimmune conditions as well. So there's two sides of the sword, if you like. We know that female mast cells, they actually store and release more inflammatory substances than male mast cells. So, they release more proteases, more histamine, more serotonin, but what's also...

Michelle: So more allergy, more those kind of aspects too, so more allogenic, etc.

Lily: Absolutely. And what's even more fascinating is that mast cells have oestrogen receptors and progesterone receptors on their membranes, which then cause the mast cells to degranulate their contents, and release all those chemical mediators when bound to the sex hormones.

Michelle: Right. So, different times of the month they can change as well.

Lily: Absolutely. And also all those environmental oestrogens, the xeno-oestrogens, the BPA, the PCBs, just think, we are being exposed to those. They can also activate the mast cells. So, really, I think this is amazing and really significant, and it can really account for the female predominance in so many different autoimmune conditions.

Michelle: That's amazing.

Lily: One of the fascinating things also is not just the mast cells, it's the microglia in our bodies that can be also male and female. And so there's actually well-described sex differences in the microglia in male and female brains. So that, as far as the microglia, they've been found a different number, they have a different shape, they have a different morphology, and they certainly differ in activity. And it's interesting that female microglia are more active in regions involving pain processing than the male microglia. They also have a higher expression of phagocytosis receptors, and also a higher expression of cellular repair and inflammatory control genes. 

So just like the mast cells as well, the microglia actually also expressed steroid hormone receptors. So they're also sensitive to oestrogen, progesterone, testosterone. I just find it incredibly...

Michelle: Fluctuations by the month. It's amazing. Yeah.

Lily: Yes. Absolutely fascinating. And when you think about adverse drug reactions as well, what they've worked out is this sexual dimorphism of both our mast cells and our microglia can lead to sex-related differences in drug metabolism. So whether it's absorption of drugs, excretion of drugs, distribution of drugs. And we know that there's more adverse drug reactions have been reported in females compared to males, and this really could be one of the reasons why.

Michelle: Absolutely. And it's an interesting point to kind of know, because, I mean, back hundreds of years ago, we just used to sort of diagnose women with hysteria.

But you also talk about some of the dramatic changes in brain architecture, which is, I always find so fascinating. And I think the general kind of community don’t actually understand when we talk about brain plasticity, but really brain architecture almost gives it a sort of more of a sense of solidity and how long it takes to unwind that. We build up these almost like structures within our brain where signals from different parts of the brain can become dysregulated, and therefore unravelling from that takes a lot longer. And you talk about this concept of the pain matrix. Tell us a little bit about that in the concept of fibromyalgia as well.

Lily: Sure. Look, there've just been so many studies done now, using all sorts of different scanning techniques like MRIs, and PET scans, and NeuroQuant scans that they actually demonstrate the swelling or which we associate with neuroinflammation in certain areas of the brain, and atrophy in other areas in people with fibromyalgia. 

But not just fibromyalgia too. They're sort of seeing the same types of things in people with chronic fatigue syndrome, with CIRS, so chronic inflammatory response syndrome. These same sort of swelling or inflammation and atrophy are being highlighted in these other conditions as well. And the interesting thing is that the degree of glial activation of brain inflammation actually correlates directly with the intensity of fatigue. So the greater the neuroinflammation, the greater the fatigue. 

And there is one particular part of the brain you mentioned, the pain matrix. So the anterior singular cortex, remembering back our neuroanatomy from all those years ago.

Michelle: Loved it. Yeah, totally.

Lily: It's the part of the brain, which is most closely linked with chronic pain. And studies have shown that there's abnormally increased brain activity in this anterior singular cortex, but not just there, also the thalamus, the insular, and the prefrontal cortex in individuals with fibro. And this area of the brain is what's called the pain matrix. 

So, when we've got increased activity here, this can cause central sensitisation, and then that's going to lead to abnormal pain sensitivity and decreased pain modulation in both our ascending and our descending pain systems in the body. And what we're finding in fibromyalgia is that the signals from our prefrontal cortex to our limbic system in particular are dysregulated. And if we remember that our prefrontal cortex is our rational logical brain, whereas our limbic system, particularly our amygdala, actually runs on a fear-based system. This is really important because we can call the amygdala like the fire alarm of the brain, if you like.

And so, in people with these conditions, instead of the prefrontal cortex taking control, what happens is the fear-based amygdala can take over. And so we've got lots of different sensations which go through our amygdala, the scents that we smell, the foods that we eat, even the supplements that we take. So really anything can produce a fear response when the amygdala is hyperactive with microglial activation. And so, we start reacting to stimuli that would normally be considered to be non-noxious, if you like.

Michelle: Yeah.

Lily: And so this dysregulation between the limbic system and the prefrontal cortex can actually explain a lot of the other symptoms that people with fibromyalgia have, like cognitive dysfunction, fatigue, their emotional regulation or dysregulation, depression, anxiety, not just the chronic pain.

Michelle: Yeah, absolutely. It's so important to teach patients about this too, because often there still is that framework of when you talk about looking at, say, mental health, or anxiety management, or emotional regulation in the context of a chronic illness, it almost feels for patients that you disbelieve them if you're going to go down that particular avenue. 

But from a mind-body perspective or a psychoneuroimmunology perspective, we can do so much when we look at these particular situations, particularly when they're reacting to every supplement, or every thing that we are trying to give them, to see that we can wind back the chronicity of that inflammation neuro and systemic. 

So also looking at brain architecture, and seeing brain changes, and actually understanding that pain matrix can really give people something solid to hang on to that doesn't say, "We are disbelieving you here, and it's all in your head. And if you just manage your anxiety, it's all going to go away."

Lily: Exactly.

Michelle: But more so that if you can manage your anxiety and start working on some of these central mechanisms, these kind of brain mechanisms, that will actually wind back that inflammatory response as well.

So, there's heaps of research and excitement about that role of activating and stimulating the innate endocannabinoid system, still terrible at that word. Are these preparations...are they a good starting point? Is that something in terms of sort of winding back some of the chronicity, and some of these kind of enmeshment that we are seeing in such a chronic conditions such as fibromyalgia?

Lily: Absolutely. I certainly believe, and the research shows, our endocannabinoid…it is a hard word to say.

Michelle: Yes, it's hard.

Lily: It's intricately related to the symptoms, people with fibromyalgia experience. And it's thought that there's possibly an endocannabinoid deficiency in people with fibromyalgia. 

So, we know that both CBD and THC have anti-inflammatory, they've got analgesic, anti-anxiety effects and sedative properties. We know by the research that both CB1 and CB2 receptors can assist in reducing pain because they directly affect the nociceptors, the pain neurons in our muscles. CB1 is actually found in the nerve terminals in our central nervous system and our peripheral nervous system, so it can modulate the neurotransmitter release. And CB2 is found primarily in the immune system cells, and also in the microglia in our brains. So, THC also, we know can act as a partial agonist at both the CB1 and the CB2 receptors. 

And the endocannabinoids, I mean, again, there's so much we're still learning about it, but they can also interact with so many other pathways which are involved in pain perception, such as our 5HT, our noradrenaline, dopamine, GABA, and also our opioid receptors. So, effectively, these endocannabinoids can work synergistically with our own endogenous opioids.

Michelle: That's so important too, particularly because pain is just so difficult to focus, concentrate, even have confidence and self-esteem when pain is just so omnipotent in somebody's life. 

And you've spoken about the centralisation of pain, and brain architecture, and pain matrix, but you also mentioned that it often starts as a peripheral wind-up. 

So, peripheral preparations that target peripheral nociceptors are becoming more widespread, and there's so much variety in these preparations. And is this designed for more localised pain syndrome or for widespread application? If we are looking at using some of these things, what is your thinking in clinical experience here, and what have you found to be effective going down that particular pathway?

Lily: Look, absolutely, I've certainly found topical analgesic therapy, it's effective in so many different conditions, including fibromyalgia. And basically, it's because we know that the propagation of pain starts in the periphery. So by using topical therapy, our aim is to reduce the excitatory influences or the excitatory signals, and increase the inhibitory influences or the inhibitory signals in the periphery, because if we can reduce or even stop peripheral sensitisation, then we can reduce, or even stop central sensitisation, and that's really important. There's so many different excitatory influences in our peripheral system if we think of glutamate, and histamine, and Substance P, and so on. And so, by understanding pharmacology, we can use different drug preparations to target different areas in order to reduce the hypersensitivity of pain.

For example, we could use a topical preparation of an anti-convulsant to reduce both peripheral and central sensitisation, as well as to target our descending inhibitory pain pathway. And that's the body's natural way of reducing pain. The most obvious benefit when you're using these topical therapies is that we avoid the side effects and the drug interactions, which is so common with our systemic analgesics. 

We can go local and focal, but in terms of treating a more systemic disorder like fibromyalgia, we can actually use these topical preparations on our trigger points and also the appropriate dorsal horn level in our spinal cord. And so the dorsal horn corresponds with a particular area that is innovated by this. And if you remember back, again, anatomy at dermatome, and now, myotomes. Fibromyalgia can follow...

Michelle: I might have missed that lecture, Lily.

Lily: We know that fibromyalgia can follow these specific myotomes. And if we can identify that particular single nerve that is being activated here, we can actually use the topical therapy on the level of the dorsal horn, and that activates that descending inhibitory system. And it's really significant in fibromyalgia because most of the tender points in fibromyalgia have actually been found to be myofascial trigger points. 

So, even though that fibromyalgia is rooted in the central nervous system with its central sensitisation, trigger points have a peripheral origin. And they can be targeted through this topical therapy. So the whole aim is to provide analgesia by desensitising our peripheral nociceptive receptors, so our peripheral pain neurons.

Michelle: Yeah. It's so important to have some of those really targeted, really almost like...I mean, it's not an easy win per se, but it's almost like an instant kind of supporting agent, just to give people some trust back into their body, some trust back into therapy, and into that therapeutic relationship, which we know, is so critical for the longevity, particularly on long journey such as fibromyalgia. 

And today, you've just given us such an incredible journey through things like the causes, and the issues, and the course treatments, and where to start, whether we start with the gut, or whether we start with these peripheral preparations. And also just most importantly, understanding the intricacy, and the duality, and the dramatic nature of what people suffering with fibromyalgia are going through.

And I think from a practitioner perspective, it's like, wow, A, there's so much that we can do. B, it's so deep and almost, I think, people with fibromyalgia need that respect from their clinicians in which to do that. But I particularly loved the research on the female microglia and muscles. It just really does offer that insight into the way women work and really there's just so much need for research to help de-stigmatise these kind of issues for women. 

So, I just want to thank you so much for your clinical expertise and your research around this area. It's really been a fantastic listen, fantastic podcast. Thanks.

Lily: Thanks, Michelle. Look, honestly, it's just been a pleasure to be here today. So, hopefully, people can learn some clinical gems from this and look at the links, etc. And, yeah, take treatment to another level, if we can.

Michelle: Thank you, everyone, for listening today. And don't forget that you can find all the show notes, transcripts, and other resources from today's episode on the FX Medicine website. I'm Dr. Michelle Woolhouse, and thanks for joining us. We'll see you next time.


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