Fibromyalgia Trial Shows Promise...For Chronic Fatigue Syndrome? Mast Cells and Ketiotifen in FM an

Mast cell release could contribute to pain, fatigue, cramping, problems standing and more in FM and ME/CFS
An intriguing Fibromyalgia treatment appears, in its preliminary stages, to be working. A powdered form of Ketiotifen (which is not available yet in the US) may be turning down the activity of important immune cells called mast cells that recent research suggests could be contributing to the pain and fatigue in fibromyalgia (FM) and perhaps even chronic fatigue syndrome (ME/CFS).

When the Largest Organ Goes Bad

The road to the Ketiotifen FM trial probably began, oddly enough, with the skin and the recognition that high rates of allodynia (pain upon touching) occur in fibromyalgia.

Hyperalgesia (increased pain sensitivity) is present in ME/CFS but the allodynia in FM can be so severe that simply having clothing touching the skin can be excruciating…Adrienne Delwo at Aboutme.com describes the allodynia like this

" (it) makes your clothes hurt when they touch or brush your skin…(it) makes a sheet feel like sandpaper, and turns a light touch into searing pain."

Fibromyalgia Studies Suggest Mast Cell Link

1990 and 1997 skin studies found high levels of IgG deposits in the skin that appeared to be caused by mast cell activity. Nine years later a 2008 FM study suggesting immune problems in fibromyalgia pointed an arrow at mast cells, but it wasn't until 2010 that a Spanish FM study looked again at the skin - and found greatly increased levels of mast cells in the skin of every FM patient tested - a high positive rate for any disorder.

At that point, Ang, a frustrated physician/researcher not happy with a 30% success rate for FM approved drugs got busy. When preliminary results from his small NIH funded Ketiotifen FM study suggested the drug was working; he stated "I am quite excited. I think we are on the right track. The most rewarding thing I think that I can tell you being a physician scientist, is hearing from patients that they are responding to the medication that we are testing."

One patient who didn't know but assumed she was on the medication was pain free for the first time in years; "I was sure I had medicine, not the placebo. I was pain free. It was amazing. I was like I can't believe this, I think they're on to something."

Mast cells


Mast cell release can cause cramping, abdominal pain, diarrhea and other gastrointestinal symptoms

Mast cells have hardly been mentioned in ME/CFS or FM but they play an important role in inflammation and immune defense. Researchers know pain-production is up and pain inhibition is down in FM but the why this is happening is unclear. One theory suggests continuing pain signals from the body have put patients central nervous systems on alert and over-reacting ...and here's where mast cells come in.

Mast cells are found close to sensory nerve endings and blood vessels...When they're activated they dump large amounts of immune factors near them. That process has lead some researchers to ask whether chronic mast cell activation could be sending the central nervous system into a tizzy.

The large number of symptoms in FM and ME/CFS suggest problems with sensory data processing could be present. Both the Lights and Dr. Baraniuk believe sensory data filtering problems pay a key role in ME/CFS/FM. Ang's thesis was that if he could calm down the mast cells, their grip on the central nervous system might diminish, allowing it to relax and the pain to disappear.

"So my hypothesis is that if we quiet these immune cells then it will not send too many signals to the peripheral nerve endings and therefore would lessen the transmission of signals or pain to the brain and spinal chord and hopefully reduce the overall pain"

That's one part of the process and there may be another. The systemic effects of large-scale mast cell degranulation into the blood causes several symptoms very familiar to ME/CFS patients including fatigue, pain, dizziness, heart racing, etc.

The 'Grand Maestro's: ME/CFS Researcher Proposes Mast Cell Link

Enter Tufts University researcher Theorharis Theorharides. For years Theorharides has believed that mast cell activities play a role in a number of chronic illnesses including autism, fibromyalgia, ME/CFS, interstitial cystitus, IBS, migraines, cardiovascular disorders, asthma and multiple sclerosis.

With over 15 papers published thus far this year and over 300 to his credit, Theoharides is a busy researcher and in 2006 he was awarded an NIH grant (later extended) to study mast cells in ME/CFS (using an animal model). He spoke at the State of the Knowledge Conference on ME/CFS in 2011 and has developed a series of neutraceuticals to combat mast cell release for a number of disorders.

Theoharides also believes the almost ubiquitous problems with stress in CFS are caused by stress induced mast cell releases triggering abnormal neuronal activity and blood vessel problems. ( He also believes mast cell activity may cause leaks in the blood:brain barrier resulting in neuroinflammation. Interestingly, Theoharides has found that mercury, an oft tested substance by alternative doctors, but a ignored factor by the research community, can also increase BBB permeability.)

Theoharides theory is predicated, to some extent, on the success some people with ME/CFS have had with amytriptyline, an antidepressant his work suggests has anti-histamine factors. Dr. Cheney has speculated that another commonly used drug in ME/CFS, doxepin elixir, was effective because of its ability to control the histamine production in the brain. He called the histamine receptors 'the grand maestro's of the central nervous system.

Problems Standing Linked to Mast Cell Activation in POTS Patients

But that's not all. Earlier we noted that mast cell degranulation can cause dizziness and reduced blood pressure. Biaggioni, an ME/CFS researcher studying orthostatic intolerance noted that mast cells are "strategically positioned to modulate sympathetic (nervous system (SNS) activity" - a key system in ME/CFS. In a small 2005 study he described a process by which mast cell activation (MCA) caused orthostatic intolerance, particularly in patients who experienced 'flushing'.

Intriguingly neuropeptide Y - a proposed biomarker in chronic fatigue syndrome - can induce mast cell degranulation and a subsequent lowering of blood pressure. Biaggioni found that POTS (postural tachycardia syndrome) patients with mast cell activation experienced episodes of flushing, shortness of breath, headache, lightheadedness, excessive urination, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. These symptoms could be set off by such normally innocuous things as standing for long periods, exercise, premenstrual cycle, meals, and sexual intercourse.

Biaggioni triggered mast cell activation by having POTS patients stand for 30 minutes and/or exercising on a treadmill and then determining if they experienced flushing and high levels of methylhistamine.

Biaggioni noted that beta blockers should be used with caution as they can induce further mast cell activation in patients with MDA. He also noted a process whereby exercise could very well be causing mast cell activation in some POTS (ME/CFS) patient...which brings up the possibility of a condition called "Exercise Anaphylaxis" .

Exercise Anaphylaxis

Histamine release could contribute to flushing during exercise in people with Mast Cell Activation Syndrome

Exercise anaphylaxis occurs when exercise triggers mast cells to spill their guts causing itching skins, hives, flushing, wheezing, nausea, abdominal cramping, and diarrhea. When the activity stops the condition usually disappears which is very different than in ME/CFS,which is not to say that its not happening in some people with ME/CFS.

If physical activity continues, patients may experience reduced blood pressure, edema and ultimately cardiovascular collapse Liz at POTSRecovery.com describes a sudden drop in blood pressure while exercising that Dr. Levine suggested may have been due to exercise induced anaphylaxis.. It might be a good idea for any CFS patients experiencing flushing, cramping, wheezing, etc. during exercise to get some tests done.

Diagnosing A Mast Cell Disorder

First described in 1991 mast cell activation syndrome (MCAS) is certainly underdiagnosed and much remains to be learned about it. 150,000 mostly undiagnosed people are believed to have MCAS in the US. It has some intriguing commonalities with ME/CFS.

For one it can affect virtually every organ system without causing abnormalities on routine tests. Secondly, a recent overview suggested mast cell activation disorder should be suspected in patients who experience chronic multisystem involvement. Symptoms usually wax and wane quite a bit earlier in the disorder but often occur all the time later on.

Mast cell activation disease ….affect(s) functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing….Mast cell activation disease is now appreciated to likely be considerably prevalent and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity or patients in whom a definitively diagnosed major illness does not well account for the entirety of the patient's presentation. From Molderlings (Mast Cell Activation Disease -A concise practical guide for diagnostic workup and therapeutic options)

Symptoms can differ depending in which organ the over-active mast cells are present. Some of the major symptoms include fatigue, skin lesions and itching, abdominal discomfort, nausea, diarrhea and vomiting, intolerance of odors, low blood pressure, frequent infections, bone or muscle pain, malabsorption, headache...Skin lesions are common but they do not occur in all patients.

Molderling reports MCAS has been associated with fibromyalgia, interstitial cystitis and irritable bowel syndrome.

Diagnosis

Some tests can aid diagnosis but Moldering notes that only a handful of the more than 60 substances released by mast cells are testable; a negative test result does not necessarily mean you don't have MCAS.

Darier's sign - high histamine releases can cause the skin of some people with MCAS to become itchy, swollen and red after its been stroked. (Note that histamine is just one of many substances released by mast cells and it may not always be released in MCAS.)

Blood and Urine Tests

Increased level of the following may occur

• Tryptase, histamine, heparin blood
• Eosinophilia, basophilia, monocytosis activity
• Serum chromagranin A
• Serum and urinary leukotriene and prostaglandin isoforms
• Urine methylhistamine (only elevated when people are experiencing flushing episodes. Biaggioni induced flushing in his study by having patients exercise).

The connection to exercise, the ability to cause dizziness, the possible connection to pain and sensory problems, the fluctuating symptoms...….the associations are intriguing. Dr. Janelle Sinclair reports that histamine levels can cause anxiety, depression and other problems misdiagnosed as mood disorders. There's a lot left to learn about mast cells and disease.

Treatment

Histamine Blockers and Methyldopa

Biaggioni reports the orthostatic intolerant patients improved when treated with H1 (eg Benadryl) and H2 histamine receptor blockers (eg. Claritin, Allegra) or with α-methyldopa, or with a combination of both. (His study examining methyldopa and other treatments in POTs patients is due to wrap up at the end of this year.) The use of β-blockers in MCAS patients, on the other hand, appeared to trigger more mast cell activity in some patents.
Quercetin and Luteolin


Theoharides believes quercetin may be a good mast cell stabilizer for disorders such as CFS

Thus far preliminary results suggest Ketiotifen may be helping in Fibromyalgia but Theoharides, believes better mast cell 'stabilizers' are available. Ketiotifen, he reports, is effective at blocking the release of allergy producing immune factors but does not block pro-inflammatory cytokines, which he believes are key in ME/CFS and other disorders.

Theoharides 2012 study found that quercetin and luteolin were more effective than cromolyn, a mast cell stabilizer, at reducing cytokine release and he's produced a patent-protected neutraceutical product called Neuroprotek (available without prescription) he believes will work better. The problem with many neutraceuticals is getting enough of their active factors into the system to make a difference. Theoharides believes using olive kernel oil in his products significantly increases the flavinoids availability.

Conclusion

The mast cell ME/CFS/FM theory is quite preliminary and mast cell research is a young field but with their fatigue and pain producing and vasodilatory properties mast cells could fit FM/ME/CFS very well. With mast cells firming up as a potential cause in FM and with Theorharides ongoing interest in ME/CFS it may only be a matter of time before we see more research and possibly treatment trials.

For interested fibromyalgia patients Ang's Indiana University study is still recruiting. For additional information about the study, contact the Indiana University Clinical Research Center for Fibromyalgia at 317-274-1755 or email jhilligo@iupui.edu.

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Hi cort,

Interesting article. Mast cell problems (mcad) are being seen in the dysautonomia arena too.

Can I ask you to please change the font to a darker bolder print ? Maybe
it's just me eyes this morning but I'm finding this hard to read.

Tx .. X

Hi Cort, fascinating stuff. It sounds plausible too, though I still wonder if it might not be just one more piece of the puzzle. It also fits with the long term benefits I have had with extra virgin olive oil, which quiets mast cells. Bye, Alex

Here's a link to a thread where we've been discussing mast cell issues:

ME/CFS is a mast cell disorder (hypothesis)

Xhoco - I changed the font - I hope it works better for you.

Alex - how much virgin olive oil are you taking?

Cort, I use it in cooking (the minimum I need and not at high temp), and add extra at the end (just a splash). Its still less than most people use with vegetable oil (based on what I see of TV chefs) but not by a lot. I have been using it for way over a decade now. Its the green stuff in the oil that is the chemical compound that helps, not the oil itself. Its very important the oil is not old or rancid. Locally made oil is the best bet - imported oil might be any age. Its best bought in small bottles unless you use a lot, as this way it is used up before the air can really damage it. Bye, Alex

PS This applies to extra virgin olive oil. I am not sure virgin olive oil has the same properties, its a lower grade.

I've been using Dr. Theo's luteolin with a perceived reduction in symptoms. He has a Facebook group too called Fans of Dr. Theo

https://www.facebook.com/groups/350125058387434/

Thanks K-day. Is the luteolin in his Neuroprotek pack or from somewhere else?

Thanks for trying cort, but it didn't help. The print in the majority of the article is too light and fuzzy.
All other posts on the board are ok tho. I'm clueless on fonts so I have no idea how to fix this. I'm using
my tablet but I'll check it on my laptop later.

I wouldn't be such a pest but I've always enjoyed reading your articles. I like the way you sum things up
for us. Tc .. X

Here's an interesting interesting illustration that goes well with Cort's article, me thinks:

http://forums.phoenixrising.me/inde...-disorder-hypothesis.18437/page-3#post-287227

Cort, it's in his Neuroprotek. I am currently trying another product called Lutimax while waiting for Fibroprotek (which should be more economical and contain more Luteolin I think). I am on another treatment that could make me feel worse, but it is of my opinion the Lutimax doesn't work well. I had no idea this was being discussed on this forum, and it looked like nanonug had the same experience with Lutimax?

Note that quercetin's oral bioavailability is really low ( around 1%), so the in-vitro results of Theoharides research are very hard/impossible to reach with oral quercetine supplementation. This could definitely explain the very few positive logs of quercetin supplementation. Another explanation is that Theoharides is wrong and mast cell activation is not really a problem in the majority of ME/CFS cases. (Are there any positive reports about using mastocytosis medications?)

BTW, some 'special formulas' claim to have increased oral bioavailability, but AFAIK evidence is lacking. Caveat emptor.

Yes, see this post.

hey this is super interesting to me, i havent read the add'l links people posted yet after corts article but i will eventually, however i recall posting in another mast thread this spring here because I had come to conclusion mastocytosis plays some role in my issues, not nec. skin sort of type a big problem with me but i suspect my increasing reactions to so many foods had to be something with histamines, i was never allegic when younger to anything, except alcohol

so that methyldopa sounds nasty at wikipedia; i have noticed that hypertensive type meds can sometimes be helpful in literature i read for cfs/fm but we tend to have low b/p so its a dilemma

Also interestingly quercetin is one supplement i have returned to loyally over years, i thought it marginally helps me with mcs, marginally, however i also suspect it lowers my b/p which is why i dont take it at times cus that increases a dif kind of malaise since my pressure already low, paradox again

havent tried luteolin
benadryl is my sleep aid and one of only things besides a drop of gabapentin that helps squelch certain headaches

i dont take claritin often or in high dose because it makes me feel gross, going to experiment with tiny fraction again, sometimes helped stamina slightly

here is the old post i resurrected in april, maybe its been linked to here too
http://forums.phoenixrising.me/index.php?threads/doctor-suggested-mastocytosis-anyone.5181/

I went to the website for Neuroprotek and found that there are actually 2 versions of the product. The regular version and one called Neuroprotek LP (low phenol). I am thinking about trying it and am wondering which one to get. I have severe chemical sensitivities and phenol is one chemical I have problems with but I think that is only the man-made chemical version and not the natural version that sounds like is contained in this product. Any thoughts?

As an aside, they have a product called ArthroSoft, which I am assuming is for arthritis? Wondering if that might help my Mom. Anyone know anyone who has tried it?

I've been on the regular Neuroprotek for a few days without any reactions, but if you have phenol problems it would seem the LP version would be the way to go.

Not a pest at all xchoco..I wonder what's going on...it may be a browser issue or something...the posts on the blog may be better. http://phoenixrising.me/

This often seems to be a problem Theoharides does have a Facebook group that is using his formulas...http://www.facebook.com/pages/Fans-of-AlgonotNeuroprotek/362134783843386 might be good to check them out.