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(Please note that I have added parts to this blog that were not covered in our talk.)

Daniel Claluw

Dr. Clauw helped lead the charge to institute fibromyalgia as a real disease.

It was great to get an opportunity to talk to Daniel Clauw M.D. who, with his hundreds of publications, was a key figure in helping drag the fibromyalgia field into the modern age. (In one of his talks, he recalled votes being taken at conferences as to whether fibromyalgia (FM) was a real disease…Those votes are no longer being taken.)

For all his work in FM, though, Clauw has never been simply a “fibro-guy” – his interests extend far beyond one disease. Clauw’s first paper, back in 1995, “The pathogenesis of chronic pain and fatigue syndromes, with special reference to fibromyalgia“, was on chronic pain and fatigue syndromes and included diseases like ME/CFS, irritable bowel syndrome (IBS), and migraine. (One can only conjecture how much further along these diseases would be if these fields had followed Clauw’s lead and studied them together…)

In that paper from almost 30 years ago, Clauw proposed that central nervous system hyperactivity affecting different parts of the brain was likely responsible for the different diseases.

Over time, Clauw’s focus has extended to many chronic pain conditions. The Chronic Pain and Fatigue Research Center (CPFRC) he established at the University of Michigan in 1998 has launched studies on fibromyalgia, interstitial cystitis, osteoarthritis, low back pain, and Gulf War Illness, and Clauw has published on chronic pain in such diverse diseases as multiple sclerosis, cirrhosis, endometriosis and chronic pelvic pain, rheumatoid arthritis, osteoarthritis, myofascial pain, TMJ, low back pain, environmental sensitivities, and others.

THE GIST

  • It was great to get an opportunity to talk to Daniel Clauw M.D. Clauw, with his hundreds of publications, was a key figure in helping drag the fibromyalgia field into the modern age. (In one of his talks, he recalled votes being taken at conferences as to whether fibromyalgia (FM) was a real disease…Those votes are no longer being taken.)
  • For all his work in FM, though, Clauw has never been simply a “fibro-guy” – his interests extend far beyond one disease and his first paper was on chronic pain and fatigue syndromes. In that paper from almost 30 years ago, Clauw proposed that central nervous system hyperactivity affecting different parts of the brain was likely responsible for the different diseases.
  • Over the past 5 years or so, Dr. Clauw has been focused on a new concept of pain, called nociplastic pain, that’s of particular relevance to diseases like fibromyalgia, ME/CFS, irritable bowel syndrome (IBS), migraine, etc. Echoing Clauw’s thoughts of 30 years ago, nociplastic pain is believed to originate in the central nervous system and particularly affects sensory processing.
  • The really intriguing thing about nociplastic pain – a condition that produces widespread pain, fatigue, sleep, cognitive, and mood problems (sound familiar?) –  is how widespread it is. It affects people with FM, ME/CFS, and long COVID but also a significant percentage of people with such disparate diseases as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, lupus, low back pain, multiple sclerosis, post-cancer, and sickle-cell anemia.
  • The longer you have a pain condition, the more susceptible you are to your nervous system going bananas and producing this symptom melange of widespread pain, fatigue, sleep, cognitive, and mood problems.
  • Exactly why this is happening is not clear, but Clauw referred to some recent studies from his lab in children that are helping to determine how it’s happening. The 2022 “Neurobiological antecedents of multisite pain in children”, which followed children for 9 years, found that increased activity in some brain regions (sensorimotor regions) and circuits (insula, sensorimotor, and the default mode network) occurred prior to and predicted which children came down with nociplastic pain later.
  • Studies indicate that pain-vulnerable brain networks may get activated prior to people becoming ill. The nodes in these networks regulate autonomic nervous system functioning and play key roles in pain perception, sensory signal integration, cognition, and emotion. The problem lies not in structural damage but in altered connections between brain regions. Activation of the insula, in particular, appears to play a major role in these diseases.
  • Studies of children show that sleep problems come first, then fatigue, cognitive issues, widespread pain, and finally mood issues.
  • Thirty years of research appears to have only strengthened Clauw’s original idea that fibromyalgia, ME/CFS, IBS, endometriosis, interstitial cystitis, migraine, and Gulf War Illness are all, at least in part, central nervous system drive sensory sensitivity disorders. Clauw believes the same process that’s producing pain is also causing the sensitivity to bright lights, noises, and odors, and even the hypersensitivity many people experience with drugs, foods, etc.
  • Early in the coronavirus pandemic, he warned that chronic pain conditions would likely increase. Studies indicate that 40-50% of the ME/CFS-like subset of long-COVID patients develop widespread pain and all of them experience the rest of the nociplastic syndrome (fatigue, sleep, cognitive and mood issues). ME/CFS got tagged early in long COVID because of the post-infectious element and because long COVID looks so much like it, but about half of the people with long COVID also fit the pain-added FM-like phenotype; i.e. they have nociplastic pain.
  • Clauw thinks the emphasis on fatigue – which he called one of the most difficult symptoms of all to assess – and the sidelining of fibromyalgia and chronic pain in long COVID has been unfortunate. Pain is so much easier to study. You produce a stimulus, remove it, and see what happens. With the recent adoption of nociplastic pain, three separate validated mechanisms of pain exist. None exist for fatigue.
  • Given the 200 other conditions that small fiber neuropathy is found in, he doesn’t believe it tells us anything significant about fibromyalgia. Citing his experience with fibromyalgia patients with autoimmune diseases, he doesn’t believe these diseases are autoimmune either. He noted we’re not seeing that kind of tissue destruction or the high levels of systemic inflammation found in diseases like FM or ME/CFS, and autoimmune drugs have not been helpful. He believes sex hormones. on the other hand, may play a significant role in FM and supports a testosterone supplementation study in fibromyalgia.
  • Clauw and his Chronic Pain and Fatigue Research Center’s (CPFRC) have studied many different treatment options, but Clauw agrees that the treatment options for fibromyalgia are “very inadequate” and only work in about one out of three patients. Clauw finds the cannabis and psychedelics studies his lab is engaged in “therapeutically fascinating”, however.
  • Clauw believes the inflammation in FM probably results from “neurogenic inflammation”; i.e. small, hard-to-detect amounts of inflammation produced by the agitated nerves.
  • Ion channel dysfunction, interestingly, given the Griffith University work on ion channels in ME/CFS, appears to play a major role as does the release of histamine from mast cells. Drugs to tamp down neurogenic inflammation response have been and are being developed. The most notable of these have been the highly successful anti-CGRP drugs developed for migraine which are also being trialed in fibromyalgia. Low-dose naltrexone may be tamping down neurogenic inflammation as well.
  • Tonix’s Tomnya – a reformulated cyclobenzaprine drug – that may help with sleep and pain will shortly be coming up for review at the FDA is another. Clauw said that cyclobenzaprine (Flexeril), a muscle relaxant, was his favorite FM drug 25 years ago, and is still his favorite drug. For one, it’s one of the rare drugs that improves deep sleep. The problem with Flexeril was that when used as prescribed (5-10 mg, 3 xs/day), a rapid buildup of toxic factors has prevented it from being used for more than a couple of days. When he cut down the dose to 5 or even 2.5 mg, though, fibromyalgia patients could tolerate it, use it long term, and benefit from it.
  • Microglial inhibitors, anti-CGRP drugs, microglial inhibitors, ion-channel drugs, low-dose naltrexone, Tomnya, cannabis, mast cell stabilizers, and psychedelics may help tamp down neurogenic inflammation.
  • In the end, it’s amazing how little play the nociplastic pain field, with its enormous overlaps, has received in ME/CFS and long COVID. Coming at these diseases from a nervous system/immune perspective, it provides interesting and new ways to look at them and potentially treat them.

A New Type of Pain – Nociplastic Pain

Over the past 5 years or so, Dr. Clauw has been focused on a new concept of pain, called nociplastic pain, that’s of particular relevance to diseases like fibromyalgia, ME/CFS, irritable bowel syndrome (IBS), migraine, etc.  Echoing Clauw’s thoughts of 30 years ago, nociplastic pain is believed to originate in the central nervous system and particularly affects sensory processing.

Diseases like fibromyalgia, ME/CFS, chronic pelvic pain syndrome, etc., paved the way for the rapid adoption of the nociplastic pain concept. Clauw noted, to his surprise, that he was recently asked to pen a review for a group that’s historically been hostile to fibromyalgia (and ME/CFS) – neurologists – for the Nature Reviews and Neurology journal. That’s progress.

The really intriguing thing about nociplastic pain – a condition that produces widespread pain, fatigue, sleep, cognitive, and mood problems (sound familiar?) – is how widespread it is. It affects people with FM, ME/CFS, and long COVID but also a significant percentage of people with such disparate diseases as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, lupus, low back pain, multiple sclerosis, post-cancer, and sickle-cell anemia.

So many diseases have nociplastic subsets that I was curious how many diseases Dr. Clauw thought it was present in. Clauw said that whether nociplastic pain was triggered by injury, inflammation, autoimmunity, or whatever, some degree of nociplastic pain is going to show up in a subset of people in every chronic pain condition. That’s good news for poorly funded nociplastic pain conditions like fibromyalgia and ME/CFS.

Nociplastic “pain” exists on a continuum; some people have more of it – some people have less of it. Just as he did decades ago, Clauw believes nociplastic pain is caused by a central nervous system amplifier that is ratcheting up signals coming from the periphery, or body. It can start in one of two ways: from the top down – that is, from the central nervous system down, as occurs in fibromyalgia and some people with ME/CFS, or from the bottom up – as in RA, OA, lupus, etc., where an injury in the periphery comes first and nociplastic pain, over time, develops.

The longer you have a pain condition, the more susceptible you are to your nervous system going bananas and producing this symptom melange of widespread pain, fatigue, sleep, cognitive, and mood problems.

Pain-Vulnerable Networks?

insula-fibromyalgia

The insula – a place where pain, stimuli, the autonomic nervous system, and mood issues come together – appears to play a major role in nociplastic disorders.

Exactly why this is happening is not clear, but Clauw referred to some recent studies from his lab in children that are helping to determine how it’s happening.  The 2022 “Neurobiological antecedents of multisite pain in children”, which followed children for 9 years, found that increased activity in some brain regions (sensorimotor regions) and circuits (insula, sensorimotor, and the default mode network) occurred prior to and predicted which children came down with nociplastic pain later.

This finding fits well with the idea that ‘pain vulnerable’ networks are present in people who come down with these diseases. The insula, for instance, regulates autonomic nervous system functioning and plays a key role in pain perception, sensory signal integration, cognition, and emotion. The default mode network promotes rumination, and the parabrachial nucleus – a recent finding – regulates the autonomic nervous system, processes sensory information, and triggers alarms.

The authors proposed that the increased Insula–DMN functional connectivity found primes the brains of children or adults to be “more sensitive to sensory inputs”.  Add in increased rumination, or alarm, to a brain being overwhelmed by sensory stimuli coming from the body to a hyperactive stress response system, and you have a pretty nasty picture.

Why this is happening is not clear. While early life stress can predispose these areas of the brain to become hyperactive, studies indicate they affect only a small percentage of people with nociplastic pain.

A follow-up study found that when this “blob” of symptoms, as Dr. Clauw put it, started showing up, sleep problems come first, then fatigue, cognitive issues, widespread pain, and finally, mood issues. (That’s reminiscent of studies showing that poor sleep rapidly increases pain sensitivities. Clauw said the two things he most wanted to be able to get his patients to do was to get better sleep and find ways to exercise.)

The appearance of mood problems was never predictive of the development of pain, fatigue, sleep, etc., problems – it was always the other way around.

Sensory Disorders

Thirty years of research appears to have only strengthened Clauw’s original idea that fibromyalgia, ME/CFS, IBS, endometriosis, interstitial cystitis, migraine, and Gulf War Illness are all, at least in part, central nervous system drive sensory sensitivity disorders. Clauw believes the same process that’s producing pain is also causing the sensitivity to bright lights, noises, and odors, and even the hypersensitivity many people experience with drugs, foods, etc.

That made me think of all the weird and almost indescribable sensations associated with these diseases. The standard descriptions – stabbing, throbbing, aching, pinching, stinging, burning – often don’t apply. Many of my unpleasant sensations are so strange that I can hardly describe them. They feel like a nervous system run amok.

Twists and Turns on the Research Front

Then Dr. Clauw talked about the twists and turns of research funding – an apt subject for poorly funded diseases like ME/CFS and FM.  Clauw had been pushing for FM to be recognized as a real disease but needed proof, and funding was scarce. He got Department of Defense funding to assess brain functioning in GWI and was able to include FM patients as a control group. By the time the study was done, interest in GWI had evaporated, but the study found that a pain stimulus activated 13 regions of the brain in FM patients (but only 1 region in the healthy controls). The study’s clear biological evidence of central nervous system dysfunction helped pave the way for the recognition of FM as a real disease. (In 2020, Clauw showed that neuroinflammation was present in Gulf War Illness.)

MAPPING Chronic Pain

MAPP Research Network

The MAPP research network identified dysregulated brain pathways in nociplastic disorders.

In 2008, Clauw became part of the MAPP Research Network, funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDK) at the NIH. The MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) effort featured diseases that haven’t gotten much play on Health Rising but which bear close ties to fibromyalgia and ME/CFS. Like other nociplastic diseases, these chronic pain conditions show little or no evidence of pathology in the pelvic area.

MAPP focused on Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) but also, from time to time, hooked in diseases like irritable bowel syndrome and fibromyalgia. Using various types of brain imaging techniques, MAPP researchers found remarkably consistent alterations in the sensory and pain-integrating regions of the brain:

Note how brain regions (somatosensory cortex, insula/amygdala, motor cortex, default mode network) involved in sensory processing and perception, autonomic nervous system functioning, movement, and sleep show up again and again.

 A Key Player in the Brain

Speaking of the insula, Clauw described it as one of the most important regions of the brain for fibromyalgia. In the past year or so alone, seven studies have highlighted the insula in FM, and at least 5 studies over the past five years have done the same with ME/CFS. Sitting in a prime location, the insula has connections to the somatosensory cortex (sensory signals), thalamus (sensory processing, sleep, movement, alertness, automatic nervous system), and the amygdala (fear, anxiety).

The problems in FM, ME/CFS, etc., thankfully, do not appear primarily due to damage, per se, but in problems with connectivity: some brain regions (e.g. pain-amplifying ones) are too connected or activated, while other regions (inhibitory regions) are not activated enough.

The (Missing) Long-COVID Connection

Clauw was prescient when, early in the coronavirus pandemic, he warned that chronic pain conditions would likely increase. Studies indicate that 40-50% of the ME/CFS-like subset of long-COVID patients develop widespread pain and all of them experience the rest of the nociplastic syndrome (fatigue, sleep, cognitive and mood issues). ME/CFS got tagged early in long COVID because of the post-infectious element, and because long COVID looks so much like it, but about half of the people with long COVID also fit the pain-added FM-like phenotype; i.e. they have nociplastic pain.

Clauw thinks the emphasis on fatigue – which he called one of the most difficult symptoms of all to assess – and the sidelining of fibromyalgia and chronic pain in long COVID has been unfortunate, indeed, and recently made the argument that the long-COVID field is missing a potentially valuable connection.

It’s a shame the FM-nociplastic connection in long COVID has been almost totally ignored. The nociplastic element in long COVID provides not only an entrée into fibromyalgia, IBS, chronic pelvic pain, migraine, etc., but also to diseases like RA, OA, lupus, multiple sclerosis,  post-cancer fatigue, etc. It’s been a lesson in how oblivious research fields can be.

Clauw has always been interested in fatigue (his center is called the “Chronic Pain and Fatigue Research Center”, but pain provides an objective to produce a stimulus, remove it, and see what happens. With the recent adoption of nociplastic pain, three separate, validated models of pain exist. None exist for fatigue.

Body Map

A simple body map can quickly help a doctor tell if nociplastic pain is present. (from Clemens 2024, “Validation of a simple body map.”)

Body Mapping It

One of Clauw’s goals has been to show doctors how to tell if their patients have nociplastic pain. It couldn’t be simpler: have the patient fill out a body map of where the pain is. If pain shows up only in say, the pelvis, you have one set of options (surgery, physical therapy, drugs, etc.). If the pain shows up in and outside the pelvis, the patients probably have nociplastic pain and should be treated differently. No need for surgeries to try to fix problems that aren’t there, and no need to go the opioid route either – neither will work in this group of patients.

Take endometriosis. Clauw has found that in only a small percentage of women with endometriosis is the endometrial tissue causing most of their pain. We’ve known for decades that the same thing is true for people with low back pain. Some people with spinal issues don’t experience much pain, while other people with little discernibly wrong are in a lot of pain. Something else is playing a role in this set of patients, and Clauw believes that something is the central nervous system.

A Small Nerve Fiber Neuropathy Rabbit Hole?

Doctors and patients always look for a physical cause first. Take the small fiber neuropathy findings in FM, ME/CFS, and long COVID. These findings excited me because they seemed to promise a clear, physical cause. That simplicity is so alluring. If your body is in pain, the answer must lie in the body.

FM researchers jumped on the small nerve fiber findings, but Clauw doesn’t think they tell us anything significant about these diseases. He argues that the fact that they have been found in over 200 other conditions makes them about as non-specific a finding as you can get.

He suggested that the disappearance, or diminishment, of these small neurons is simply the result of the nerves being pruned back to reduce pain. He asked how a reduction in small nerve fibers (but no damage) could result in more pain. Even if reduced small fiber levels did result in pain, how could they affect the other symptoms in FM – the sleep, fatigue, and cognitive issues? Those are all central nervous system symptoms.

In 2017, Clauw published a paper showing that increasing activation of the insula – an important pain-processing area of the brain – resulted in reduced small nerve fiber density in the paws of a rat model (!). (That brought to mind a recent study showing that increased oxidative stress in the brain resulted in reduced energy production in the muscles.) In both cases, the brain was able to induce dramatic changes in the tissues of the body. Time will tell how much of a role the brain and central nervous system play in these diseases.

Hormones and Gender

I didn’t expect to be speaking about testosterone with Dr. Clauw, but it turns out that he believes the gender bias seen in diseases like FM and ME/CFS (more females than males) may reflect a withdrawal of male sex hormones. That’s an interesting idea given Dr. Klimas’s models suggesting that testosterone is protective in men against ME/CFS and that some doctors are treating female patients with testosterone.

Clauw stated that “a lot of evidence” suggests that sex hormones play a role in these diseases and that he felt that a research study assessing the effects of testosterone on FM is worth doing. Since testosterone can have very negative effects, he emphasized that it should be done in the context of a research study but conjectured that it might not take that much testosterone to provide help.

Studies exploring the effects of hormone-induced gender shifts in transgender individuals may be able to help us understand the role hormones play in chronic pain.

Treatment

Clauw and the Chronic Pain and Fatigue Research Center’s (CPFRC) investigations into treatment approaches seem to know no bounds. Besides more traditional approaches such as CBT, exercise, and mainstream drugs (Lyrica, Cymbalta, milnacipran), they’ve included acupuncture, transcranial magnetic stimulation, and cannabis. Clauw has even evinced an interest in psychedelics.

Clauw’s longstanding interest in non-pharmacological approaches to chronic pain and fatigue diseases, including cognitive behavioral therapy and graded exercise therapy (CBT/GET), will likely rub some people with ME/CFS the wrong way. While noting the modest results of the PACE trial (15% showed improvement in ME/CFS symptoms), Clauw signed a critique of the new NICE guidelines, and supports the use of patient-tailored GET programs.

Perhaps because pain is better understood than fatigue, and because more treatment options are present for FM, CBT/GET never received the notoriety in FM that it did in ME/CFS. FM has had its share of behavioral trials, but the field never had to deal with the concerted attempt to psychologically define it that occurred in ME/CFS when federal funders poured tens of millions of dollars into biopsychosocial clinical trials while ignoring other treatment avenues.

This is not to say things are going well on the treatment end in FM. The Psychedelic Times in 2021 reported that Clauw stated that the current treatment offerings for fibromyalgia are “very inadequate” and only work in about one out of three individuals.

New Therapeutics

Psilocybin clinical trial

Preparing psilocybin for clinical trial. Several psilocybin trials are underway in fibromyalgia.

When I asked Clauw what excites him right now, he called “therapeutically fascinating” the cannabis and psychedelics studies his lab is engaged in. Since 2014, Clauw has co-authored no less than 14 cannabis papers and recently helped pen a guidance for doctors wishing to try cannabis products for chronic pain. He’s now testing different components of cannabis (CBD, THC, CBD + THC) in chronic pain.

One of his studies found that ingesting high levels of THC may actually increase pain levels but that lower levels helped. That makes sense given that THC is binding to the same receptors that opioid drugs are. Take too much of them and the endogenous opioid or endogenous cannabinoid system which reduces pain levels gets turned down. Smaller doses taken intermittently are fine, but higher doses over a longer period may blunt its effects. CBD is more expensive but doesn’t appear to have this problem. (He said the main side effect of high CBD use is cost :)).

Clauw isn’t the only one interested in psychedelics: Jared Younger is beginning a psychedelic trial in FM.

A Different Kind of Inflammation and a Different Approach

Nervous system

Clauw thinks nerve-associated inflammation, or neurogenic inflammation, is helping to drive the sensory issues in these disorders.

Clauw believes the inflammation in FM probably results from “neurogenic inflammation”; i.e. inflammation produced by agitated nerves – and is trying to understand that, and find ways to tamp that down.

On the inflammation front, Clauw noted that some people have proposed that FM is an autoimmune disease, but as someone who’s been trained to work with autoimmune disease, he doesn’t believe FM is an autoimmune disease, and none of the rheumatologists he works with believe it is either.

Some form of chronic low-level inflammation has been proposed for ME/CFS/FM for decades, yet we know that standard anti-inflammatories (over-the-counter drugs, prednisone, methotrexate) aren’t very effective. Time will tell with newer drugs that inhibit specific immune pathways like the TNF-a inhibitor etanercept that Dr. Klimas is trying out in GWI and ME/CFS, and the JAK inhibitor baricitinib that Ely is trying in long COVID.

From Skeptic to Advocate: Wes Ely, Long COVID, ME/CFS and his Big Baricitinib Trial

These drugs are commonly used in autoantibody-driven autoimmune diseases that produce a very vigorous immune response – the kind that can, in some cases, destroy joints. Clauw noted we’re not seeing that kind of tissue destruction or the high levels of systemic inflammation found in diseases like FM or ME/CFS. Blasting away at the immune system with autoimmune drugs in a person with autoimmune disease and fibromyalgia does not improve their fibromyalgia.

With neurogenic inflammation difficult to detect in standard blood draws, nociplastic researchers have found that stimulating whole blood with toxins such as lipopolysaccharide revealed it. (Studying the blood straight out of the body doesn’t work because the body quickly breaks down the immune factors. Taking the blood out of the body and then stimulating the immune response, on the other hand, allows researchers to assess which part of the immune is primed to go on the attack.)

Ion channel dysfunction, interestingly, given the Griffith University work on ion channels in ME/CFS, appears to play a major role, as does the release of histamine from mast cells.

Drugs to tamp down neurogenic inflammation response have – and are – being developed. The most notable of these have been the highly successful anti-CGRP drugs developed for migraine which are also being trialed in fibromyalgia. Low-dose naltrexone (LDN) may be tamping down neurogenic inflammation in the brain, although Clauw isn’t sure it’s working in the same way that most people think. Clauw’s studies suggest it’s acting as an opioid antagonist and increasing beta-endorphin and reducing enkephalin levels in the brain. (Beta endorphins are natural pain relievers. Enkephalins are activated by the stress response in the presence of pain and amplify the pain-producing circuits in the brain.) In other words, he believes LDN is resetting the endogenous opioid system in the brain.

My literature search suggests that anti-CGRP drugs, microglial inhibitors, ion-channel drugs, low-dose naltrexone, Tomnya, cannabis, mast cell stabilizers, and psychedelics may help tamp down neurogenic inflammation.

Tomnya – A New Fibromyalgia Drug?

Tonix’s Tomnya – a reformulated cyclobenzaprine drug – that may help with sleep and pain will shortly be coming up for review at the FDA. If approved, it will be the first drug in 15 years. It’s been a long, dry spell for a disease that got 3 drugs approved in short order in the late 2000s.

Clauw said that cyclobenzaprine (Flexeril), a muscle relaxant, was his favorite FM drug 25 years ago, and is still his favorite drug. For one, it’s one of the rare drugs that improves deep sleep. The problem with Flexeril was that when used as prescribed (5-10 mg, 3 xs/day), a rapid buildup of toxic factors has prevented it from being used for more than a couple of days.

Clauw found that FM patients were abnormally sensitive to Flexeril. At 10 mg, Flexeril was so sedating to FM patients that he believes sensitivity to it could be considered almost a biomarker for the disease. Even a milligram, more or less, can make a difference. When he cut down the dose to 5 or even 2.5 mg, though, they could tolerate it, use it long term, and benefit from it.

Tonix made a sublingual form of Flexeril called Tomnya, specifically aimed at the FM population. Clauw thinks it’s highly likely that Tomnya will be approved. If approved, it should be readily available from doctors. We should know about Tomnya in the first half of next year.

The Next Drug for Fibromyalgia? Tonix’s Tonmya Sleep AND Pain Drug Heads to the FDA

Conclusion

lone lighthouse

Clauw looks at these diseases in a different way than we’ve been used to.

Clauw comes at disorders like ME/CFS, fibromyalgia, IBS, long COVID, etc., from the perspective of a long-term chronic pain researcher. He sees them as primarily central nervous system sensory nociplastic disorders driven, in part, by difficult-to-detect nerve, or neurogenic, inflammation. Nociplastic disorders that feature chronic pain, fatigue, sleep, cognitive, and mood problems pop up in significant amounts in every disease associated with chronic pain, and simple body maps can reveal them.

He believes several themes in ME/CFS/FM and long-COVID research, such as autoimmunity and small fiber neuropathy, are either incorrect or irrelevant. On the treatment end, opioid drugs, heavy and light duty anti-inflammatories are generally not helpful. Clauw’s approach suggests that anti-CGRP drugs, ion-channel drugs, low-dose naltrexone, Tomnya, cannabis, mast cell stabilizers, and psychedelics may help tamp down neurogenic inflammation. Getting better sleep is a priority. Mind/body approaches are recommended. Hormonal manipulations could be helpful but need more study. The neurogenic inflammation field is still relatively new, but researchers are getting closer to the molecular roots of this kind of inflammation.

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