Scientific American recently published an overview on fibromyalgia called “An Unnerving Enigma” suggesting that new clues may crack what’s going on in this mysterious, difficult-to-treat disorder and lead to new treatments.

This article gives us a good platform to look at where the science of fibromyalgia is now. As we do an overview of the article, we’ll be fleshing it out.

The article starts with Deborah, a mother, and author, who suddenly developed such deep muscle pain and fatigue that, in between her visits to doctors, she ended up spending entire days in bed. She ran through the usual gauntlet of doctors and specialists and was tested for multiple sclerosis, arthritis, cancer, lupus, Lyme disease, and a catalog of autoimmune disorders, only to be diagnosed two full years later with fibromyalgia.

The Trauma Connection

Like some other Fibromyalgia patients, Deborah had experienced a traumatic incident prior to coming down with Fibromyalgia. She appeared, however, to have recovered from her severe auto accident of a year earlier when Fibromyalgia struck.  While she fits a certain pattern in FM – a traumatic incident within a year of getting sick – how to translate that accident into her Fibromyalgia is entirely unclear

train wreck

Traumatic events such as an infection or injury often (but not always) precede FM

That has been done in other disorders.  In the case of chronic regional pain syndrome (CRPS) a small injury occurring just after an infection triggers an autoimmune response that attacks pain-sensing neurons in the spinal cord.  Take away the infection prior to the injury and the disorder doesn’t occur.

Similar patterns involving autoimmune responses and chronic pain are showing up:

  • Surgery that triggers an autoimmune response in the limb of the patient.
  • Autoimmune responses attack potassium channels and cause severe pain without showing any visible damage.
  • Autoimmune responses cause severe pain that occur out of the blue.

Most of these involve sudden onset, do not leave physical marks, baffle physicians and leave them prescribing antidepressants.  Understanding how these illnesses get activated will surely help inform our understanding of ME/CFS and FM.

Update – An Autoimmune Connection between fibromyalgia and long COVID?

Something in the Blood II: Long-COVID / Fibromyalgia Autoimmune Connection Found

Limited Effectiveness From Central Nervous System Approach


Brain abnormalities are present in FM but central nervous system acting drugs have had limited effectiveness thus far

Just getting the diagnosis helped Deborah, as did stress reduction, dietary changes, yoga, and mild exercise, but the FDA-approved drugs didn’t. The therapeutic approach to fibromyalgia has been largely built on the idea that FM is a brain disorder that causes pain sensations and other stimuli to be greatly magnified. Deborah’s muscles weren’t damaged; her brain was.

There’s certainly plenty of evidence for brain dysfunction in both FM and ME/CFS, but drugs designed to dampen central nervous system pain signals have generally provided only modest relief to some patients.

The fact that the central nervous system pain signatures, formerly thought to be unique to FM, are showing up in other pain disorders suggests they’re common endpoints of a variety of processes.  Chronic pain does appear to change the structure of the brain but that understanding, for the most part, has not left the medical field with better therapeutics (but see the end of this blog).

The Body Returns – Peripheral Nerve Destruction

It took oncologists treating cancer patients with ME/CFS on Rituximab to uncover that drug’s potential effectiveness, and it took neurologists finding misdiagnoses to understand the role the body may play in Fibromyalgia. Almost simultaneously, neurologists in three parts of the U.S. noticed a strange pattern; their small fiber neuropathy (SFN) patients tended to be first misdiagnosed as having fibromyalgia. (Note that this realization could never have come from FM specialists unless they were looking for SFN – which they weren’t.)

This suggests that the breakthroughs in FM, as with ME/CFS, may very well come from perceptive practitioners working outside the field.  Indeed one of the neurologists, Dr. Anne Oaklander, tried to find and failed to interest any rheumatologist in working with her to validate her findings.  In the end, she went it alone.

Hiding in Plain Sight – Peripheral Nerve Breakdown

The idea that FM might be affecting the nerves in the body, however, was not new. Caro’s 2008 study indicated that large fiber neuropathy was present in FM and that the symptom patterns in FM suggested a peripheral nerve disorder was present. It took neurologists working independently to validate his assertions years later.

skin anatomy

Early studies suggest two different types of nerve problems are showing up in the skin of FM patients

Three SFN studies in fibromyalgia over the past year suggested that a significant percentage of Fibromyalgia patients have small fiber neuropathy. They suggest that something – perhaps an immune response or toxin – has attacked and destroyed or damaged the small nerve fibers in their skin. Patients with SFN form the peripheral neuropathy subset in FM, and they may differ widely from other FM patients.   (About 45% of the FM patients in the limited studies done thus far have had SFN.)

Microneurography studies suggested that the surviving nerves were firing all the time, whether they were prodded by a stimulus or not. That suggested an ongoing stream of nerve signals to the brain could be causing central sensitization.

Researchers began to wonder if they were getting close to an important aspect of FM  for some patients. All they needed to do was to identify why the small nerves in the skin were being attacked. That’s not so easy, however. SFN can be caused by an injury, genetics, diabetes,  toxins, or an immune attack.   While the SFN findings open up some new treatment options such as IVIG, SFN has not been easy to treat.

Still, objective findings of physical damage are good news in fibromyalagia, a disorder many doctors still believe is not quite real.  (That disbelief does not extend to the research community anymore.  At a pain conference a year or so ago, Dr. Daniel Clauw noted that rheumatologists used to vote at their annual conferences whether or not fibromyalgia was a real disorder. That stopped a couple of years ago.)

Perhaps the most important aspect of the small fiber neuropathy findings is that they give researchers new targets – such as the immune system – to aim at. One of the neurologists cited in the article believes the nerve damage in FM extends to nerves serving the muscles and the tendons. That’s an intriguing notion given Dr. Rowe’s findings of impaired nerve elongation in adolescents with Chronic Fatigue Syndrome.

(Does SFN occur in chronic fatigue syndrome? Dr. Martinez-Lavin believes it may, at least in those patients who experience tingling sensations in their extremities. A personal aside:  At one time I regularly experienced tingling and numbness sensations in my hands and feet. Dr. Cheney described mercury poisoning, and when I stopped eating fish the sensations quickly disappeared. Peripheral neuropathy is a common symptom of mercury poisoning, yet my mercury levels did not appear to be high – they were apparently simply too high for me.)

Peripheral Nerve Buildup

The other major finding in fibromyalgia must have had FM researchers shaking their heads. Just as evidence surfaced that peripheral nerves were being destroyed, Dr. Rice’s team in San Diego published a study suggesting that too many nerves were being produced in FM.  In fact, the Rice team found ten times more nerve fibers than normal.  The catch was the nerve fibers they found were in the hands – an entirely different animal, it turns out, than the limbs.


A study suggests excessive nerve build up in shunts in the blood vessels in the hands may be hampering blood flows to the rest of the body

Using specialized techniques never used before in Fibromyalgia, Rice found an explosion of nerves had occurred at the junctures in the blood vessels that allow blood to flow into the hands. It turns out that, besides being adapted to picking up things, our hands also function as blood storage reservoirs that release blood to the muscles when we exercise. Rice’s finding suggests blood might have trouble flowing out of the hands to the muscles when we exercise.  That, of course, could explain much about the exercise intolerance in Fibromyalgia and perhaps in ME/CFS.

It could also explain the pain some FM patients feel when the weather changes. Our body adjusts our blood flows to compensate for temperature changes. If the blood is caught up in the hands it’s possible that the nerves in the skin elsewhere might go a bit bonkers when the blood flows they expect don’t materialize. That could cause pain.

Unnerving Complications

Tim will tell which nerve problem is most prevalent and important in FM. Rice’s work is more detailed than the small fiber work done thus far.  He’s also found excessive nerve loads in a much higher percentage of FM patients (@75%) than have the small nerve fiber studies (45%).  (The microneurography study also found much higher percentages of FM patients with excessive nerve firing than with SFN.) (Meanwhile, Dr. Martinez-Lavin believes nerve ‘sprouting’ in the spinal cord plays a role in fibromyalgia as well.)

In contrast to the possible autoimmune causes of SFN in FM, Rice’s work suggests estrogen may contribute to the nerve fiber explosion he’s found (and could help explain the female dominance in the disorder). He’s applied for a major grant to extend his work. An interview with him is coming up soon.

Are two subsets of patients with different kinds of nerve damage showing up in FM or do some people with fibromyalgia, paradoxically, have too few nerve fibers in their torso and too many nerve fibers in their hands?

The Chicken and the Egg

The chicken and egg discussion in FM is a sign of a maturing field that's willing to look at new options

The chicken and egg discussion in FM is a sign of a maturing field that’s willing to look at new options

The debate over what is causing what in FM has begun.  Longtime FM researcher Dr. Daniel Clauw of the University of Michigan believes a hyperactive central nervous system is causing the nerves to go bonkers in the periphery.  He believes the central nervous system holds the key.

Equally longtime FM researcher, Dr. Roland Staud, believes healing the nerves will reduce the pain. Staud has published several studies showing that lidocaine applied to the nerves in the torso could reliably reduce FM pain – something that shouldn’t happen in a disorder purely caused by central sensitization. He believes treating nerve damage could help FM patients.

New Therapeutic Approaches Emerging

It’s clear that some rethinking of Fibromyalgia is going on and new therapeutic approaches are emerging.

Dr. Xavier Caro reports that immune-modulating treatments have been much more effective in his patients than the traditional central nervous system-acting drugs most doctors are familiar with. Caro has been suggesting this for decades (he proposed in 1989 that ‘fibrositis’ (e.g. fibromyalgia) had an immune component) but there’s some evidence that his peers may be listening now.

A chronic pain workshop recently called for the use of immune therapies in a wide range of chronic pain disorders including chronic regional pain syndrome (CRPS) and Fibromyalgia.  The reports from the clinics on the success of these therapies in some patients are simply too positive, they assert, to be ignored.

If autoimmune processes are responsible for the small fiber neuropathy group and IgG subclasses are found to be low, then IVIG can be very helpful.

If the Pridgen antiviral study is as successful as reports suggest, then antiviral therapy will open an entirely new door on FM pathophysiology and treatment.  A report from Dr. Pridgen is due in November.

FM patients need new and better treatment options

FM patients need new and better treatment options

A different kind of anti-inflammatory approach might be helpful as well. Studies and patient reports suggest FM is not a typical inflammatory disorder and anti-inflammatories are not generally effective, but some researchers believe the inflammation may be in the brain, not in the body. That could call for microglial inhibitors such as LDN, medical marijuana, and others.

Finally, brain stimulation therapies are emerging that may be helpful. New advances in the field of transcranial magnetic stimulation are allowing researchers to reach deeper into the brain where many of the CNS problems in FM are believed to occur.  Recent studies suggest this may be a promising therapy for FM patients.

Even newer to the field and as yet untested in FM or ME/CFS, vagal nerve stimulation (VNS) via the ear may be able to suppress a hyperactive sympathetic nervous system that’s believed to contribute to the pain, poor sleep, and cognitive problems found in FM and/or ME/CFS.  Since the stimulus passes through the central nervous system on the way to the vagus nerve, auricular stimulation of the vagus nerve is actually a form of central nervous system stimulation.

Clinical trials underway in fibromyalgia include a variety of different treatment approaches that are being tested. From norepinephrine agonists (Droxidopa) to dopamine enhancers (Ropinirole) to glutamate inhibitors (memantine) to brain stimulation (rTMS), clinical trials are exploring different options for Fibromyalgia patients.

The Next Generation of Fibromyalgia Treatments – The Clinical Trials


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