Richard G. Petty, MD

The Neurology of Fibromyalgia

Fibromyalgia can be a particularly nasty illness, not least because people who suffer from it have often been misdiagnosed and occasionally even accused of malingering. But the pain can be very real and very severe. There are some very good reasons for believing that it is a neurological problem involving regions of the brain and spinal cord that are involved in modulating pain.

A new study from the University of Bath and Royal National Hospital for Rheumatic Diseases in England has raised some intriguing possibilities for treatment. A year ago, researchers from the same institution reported that there is a reorganization of the sensory regions of the brain n people with chronic pain.

In this new study, researchers asked patients to look at a reflection of one arm while moving their other arm in a different direction that was hidden behind a mirror positioned in front of them at a right angle. So one limb was obscured from view behind the mirror while they could clearly see the other limb and its reflection.

This simple experiment created a mismatch between what the brain sees from sensory input and what it feels through the motor system that controls movement.

Of the 29 fibromyalgia patients involved in the study, 26 reported feeling a transient increase in pain, temperature change or heaviness in their hidden limb – all symptoms of a flare up of their condition.

This suggests that a mismatch between sensory and motor neurons could be at the root of the fibromyalgia.

This study adds to the growing body of evidence that many of the symptoms of fibromyalgia may be triggered or perpetuated by a sensory-motor conflict.

That opens up all kinds of new possibilities for treatment.

Fibromyalgia is Real! A Battle That Should Not Have To Be Fought Again

Fibromyalgia is a chronic, widespread pain in muscles and soft tissues accompanied by fatigue, it is a fairly common condition, affecting 3% to 6% of the general population, and is most commonly diagnosed in people between the ages of 20 and 50, though onset can occur in
childhood. The disease is not life-threatening, though the degree of
symptoms may vary greatly from day to day with periods of flares
(severe worsening of symptoms) or remission. The syndrome is generally
perceived as non-progressive, yet that issue is still a matter of debate.

The cardinal symptoms of fibromyalgia are chronic, widespread pain and
tenderness to light touch together with moderate to severe fatigue.
Those affected may also experience heightened sensitivity of the skin (“allodynia“),
tingling of the skin that is often needle-like, a deep ache in the muscle and , less often, the tendons, prolonged muscle spasms, weakness in the limbs, and nerve pain.
Chronic sleep disturbances are also characteristic of fibromyalgia, and
some studies suggest that these sleep disturbances are the result of a
sleep disorder called alpha-delta sleep , a condition in which
deep sleep (associated with delta EEG waves) is frequently interrupted
by bursts of brain activity similar to wakefulness (i.e. alpha waves).
Deeper stages of sleep (stages 3 & 4) are often dramatically
reduced, and that is the likely cause of the cognitive problems that so often accompany fibromyalgia.

There is not any structural damage in an organ, though it may sometimes start after trauma, such as a motor vehicle accident.

It is that last fact, that there is s often no obvious physical pathology, that has lead so many people to claim that fibromyalgia is “nothing more than” pain associated with depression. I have has some interesting “discussions” with health care professionals convinced that people wit fibromyalgia do not have a “real” illness, and that they need psychotherapy or antidepressants. Yet pain is pain, and the false dichotomy: “Is the pain my mind or in my body?” helps nobody.

Twenty-five years ago, Muhammad B. Yunus and his collaborators published the first controlled study of the clinical characteristics of fibromyalgia syndrome. That seminal article, published in Seminars in Arthritis and Rheumatism, led directly to formal recognition of this disease by the medical community. Last month, again in Seminars in Arthritis and Rheumatism, Muhammed makes another enormous contribution to the field of chronic pain and fatigue by meticulously synthesizing and interpreting the extensive body of scientific literature on fibromyalgia and his own insights into the concept of central sensitivity syndromes (CSS) that include irritable bowel syndrome, migraine and restless legs syndrome.

In fact there are at least 13 separate conditions that are related to central sensitization (CS), where the central nervous system becomes extremely sensitized with respect to certain parts of the body, so that even mild pressure or touch would cause much pain. This hypersensitivity may also be associated with other symptoms such as poor sleep and fatigue.

Muhammed took a rather more biological approach to fibromyalgia in the past, now emphasizes a biopsychosocial perspective:

“In my view, this is tremendously important because it is the only way to synthesize the disparate contributions of such variables as genes and adverse childhood experiences, life stress and distress, posttraumatic stress disorder, mood disorders, self-efficacy for pain control, catastrophizing, coping style, and social support into the evolving picture of central nervous system dysfunction vis-à-vis chronic pain and fatigue. Science and medicine now have rational scaffolding for understanding and treating chronic pain syndromes previously considered to be ‘functional’ or ‘unexplained.’ Neuroscience research will continue to reveal the mechanisms of CS, but only if informed through a biopsychosocial perspective and with the interdisciplinary collaboration of basic scientists, psychologists, sociologists, epidemiologists, and clinicians.”

One of the reasons that I so like this new version of his model is because it fits so well with the concept of “Salience Disruption Syndrome.” A fancy name for a common problem that I talk about in Healing, Meaning and Purpose.

So very many people are super-sensitive to the environment and also have trouble in filtering out and deciding what is important. As a result pain, attentional problems, impulse control disorders, addictions and several other things tend to cluster together.

Happily we now have an array of novel techniques for dealing with these problems, and I plan to put out more books and papers on ways in which we can help.

Acupuncture, Qigong and Fibromyalgia

As we have discussed before fibromyalgia can be difficult to treat, so any decent research indicating a new approach is always welcome.

Two recent studies have indicated that acupuncture may be helpful in the treatment of fibromyalgia. In the first, published in Alternative Therapies in Health and Medicine, 21 patients completed the study, which consisted of 16 treatments in eight weeks. The patients all know that they were getting acupuncture, and there was no attempt to “blind” the study. The investigators used something called the Fibromyalgia Impact Questionnaire, and found an improvement. One of the problems with the study was that there were so many measurements done in so few people that there’s always a worry that something positive will turn up by chance. This may explain an odd observation: sicker people did better and it didn’t matter how long they had been in treatment.

The second study was a partially blinded, controlled, randomized clinical trial of 25 patients and 25 controls done at the Mayo Clinic. Acupuncture seemed to be more effective in improving pain, fatigue and anxiety, than putting needles at ineffective points.

One of the biggest practical problems is that some people with fibromyalgia are so sensitive that they cannot tolerate even the mild discomfort of acupuncture, which is usually all but painless if done by an expert.

So I was interested to see a small pilot study from the Department of Psychiatry in the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School in Piscataway, New Jersey, of the use of external qigong in fibromyalgia. A qigong practitioner worked to stimulate the flow of Qi in people with fibromyalgia, on the principle that in traditional Chinese medicine, pain is usually conceived as a blockage of the free flow of Qi. The results were very strongly positive, thought the trial only involved ten people.

Clearly more research is needed, but these preliminary results are all very encouraging.


Pramipexole is a remarkably interesting medicine about which you are likely to hear a lot in the near future. It is an agonist, which means that it has a positive effect, on D2 dopamine receptors and also on a little-known group of dopamine receptors, known as the D3 group. If you want to get really clever the dopamine receptor D3 group is abbreviated to DRD3. Pramipexole has been in use for almost a decade in the treatment of Parkinson’s disease, and approximately 9.1 million prescriptions for pramipexole have been written in the U.S. since its launch in 1997. It is not without its problems. In Parkinson’s disease it may cause dizziness, involuntary movement, hallucinations, headache, difficulty falling asleep, sleepiness, and nausea. Some people have also had behavioral dyscontrol while taking it.

At a meeting in Athens in February of 2006, we saw confirmation of something that had been shown in previous research: pramipexole seems to be a very effective treatment for restless legs syndrome (RLS). A study published in the journal Neurology has given us a more detailed understanding of the risks and benefits of pramipexole.

The investigators report a 12-week, multicenter, double-blind, randomized, placebo-controlled study of fixed daily doses of pramipexole (0.25 mg, 0.50 mg, and 0.75 mg) involving 344 patients with moderate to severe RLS. Data from 339 patients were analyzed to evaluate the effect of pramipexole treatment on efficacy and safety. The mean age of patients was 51.4 years and the mean duration of RLS symptoms was 5.1 years. The results were very promising, even though half of the patients on placebo also showed an improvement. The most commonly reported side effect included nausea (19.0%), headache (17.8%), insomnia (10.5%) and somnolence (10.1%).

In Europe pramipexole it has been approved for use in this indication. It is marketed as Sifrol® / Mirapexin® In the United States we currently only have one approved medical treatment for RLS, and that is the GlaxoSmithKline medicine ropinirole (Requip), that works at the same D3 receptors in the brain and spinal cord. Ropinirole is effective in a proportion of people with RLS, but it has also been linked to sleepiness, drops in blood pressure and fainting, so those are included in its label.

RLS may be associated with some other illnesses so I was very interested to see two reports of the use of pramipexole in bipolar depression as well as a report of its possible use in REM Behavior Sleep Disorder.

One of the most exciting potential uses for pramipexole may be in some people with fibromyalgia. I’ve mentioned that fibromyalgia, bipolar disorder and some other psychiatric illnesses may be connected. The idea that we might be able to use just one medicine to support our Integrated Medicine approach is very attractive, and also helps point us toward a deeper understanding of what exactly goes wrong at the physical level in RLS, depression and fibromyalgia.

I’ll keep you posted.

Vitamin D and Interstitial Cystitis

I think that interstitial cystitis (IC) must be one of the most distressing of conditions to have, and it is certainly one of the most challenging to treat. Outside the United States, it is more often called painful bladder syndrome (PBS).

IC is a condition that results in recurring discomfort or pain in the bladder and the surrounding pelvic region. The symptoms vary from person to person and even in the same individual. It can vary from an experience of mild discomfort, pressure, tenderness, to intense pain in the bladder and pelvic area. Symptoms may include an urgent need to urinate (urgency), a frequent need to urinate (frequency), or a combination of these symptoms. Both may be severe: I’ve seen people who had to urinate every ten minutes. Pain may change in intensity as the bladder fills with urine or as it empties. Women’s symptoms often get worse during menstruation, and some experience pain with vaginal intercourse. There is a good website provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), that is fairly up-to-date.

Because IC varies so much in symptoms and severity, most researchers believe that it is not one, but several diseases. There are clear links between IC and fibromyalgia, irritable bowel syndrome and chronic fatigue, and probably many other illnesses.

There is good evidence that inflammation in one pelvic organ can cause pain in other organs that share some of the same nerve supply. Inflammation of the colon may make some nerves coming from the spinal cord hyper-excitable, which in turn makes nerves running to the bladder hypersensitive. Because the same nerve plexus connects with the ovaries and uterus, it is no surprise to learn that phases of the menstrual cycle impact the way in which inflammation in one pelvic organ can cause inflammation in another.

IC appears to be becoming more common, although that is always a risky comment, because it was undoubtedly not often recognized in the past. The old teaching was that it was only something that occurred in menopausal women, but it is now being diagnosed in men as well as women, and in people as young as their late teens.

The cause of IC remains unknown, though there have been many theories: infections, allergy, autoimmunity, neurological and genetic. There have been recent claims of the discovery of responsible genes, but hey would most likely be susceptibility genes, rather than causative. Otherwise why should the rates of IC genuinely seem to be increasing? What seems clear is that the normal mucus lining of the bladder wall is damaged.

Multiple types of treatment have been tried, from medication to pelvic floor exercise, to neurological implants and homeopathy and acupuncture. The report of anything new that may help is always welcome.

So I was interested to see a report from investigators in Milan on the efficacy using a molecule that has been attracting a lot of interest recently: vitamin D. The active form of vitamin D is known as calcitriol or 1,25-dihydroxycholecalciferol (1,25(OH)2D3) that is manufactured in the kidney. Its in vivo biological effects include regulation of bone metabolism, control and modulation of the proliferation of cells and some aspects of the immune response. These characteristics have already led to therapeutic applications in osteoporosis, secondary hyperparathyroidism, and psoriasis. Many reports show beneficial effects of vitamin D in animal models of diabetes, organ graft rejection, experimental allergic encephalomyelitis, lupus nephritis, and in asthma. Despite what you may have seen in some advertisements, just taking extra vitamin D does not help, and may make matters worse: they key is to have the right form of vitamin D, that can reach and affect the right areas of the body.

The Milan team used a vitamin D3 analogue (BXL628) in a mouse model of chronic cystitis. What they found was that a specific inflammatory marker in the blood went down with treatment, and at the same time histological analysis showed a decrease in edema and white blood cell (leukocyte) infiltration in the bladder wall. This and some other biochemical evidence of what is known as “mast cell degranulation,”  is very encouraging and strongly supports the potential therapeutic use of BXL628 in diseases such as human interstitial cystitis.

This is the kind of mechanism-based research that holds out enormous promise for everyone’s welfare and will help us in our goal of using science to inform the development of the next generation of treatment, health and wellness.

A Missing Link: Serotonin, Inflammation and Psychiatric Illness

We have previously looked at the extraordinarily high rates of inflammation in psychiatric illnesses, as well as the evidence implicating disturbances in the serotonin transporter and an array of psychiatric and physical illnesses, including fibromyalgia and irritable bowel syndrome. Disturbances in serotonin homeostasis as well inflammation-promoting (pro-inflammatory) cytokines have both been implicated as causative factors in major mental illness. So the hunt has been on to see if there’s some way of uniting these two causative pathways.

There’s an exceptional important paper out this week in the journal Neuropsychopharmacology.

Investigators from the Vanderbilt University School of Medicine in Nashville, Tennessee, have established that the pro-inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Using rat cells, they were able to show the precise mechanism by which these cytokines could regulate the activity of the serotonin transporter.

So why is this so important? Not only does it open up several new options for treating mental illness, but it may also explain some puzzles.

It’s recently been shown that mental illness is more common in overweight people. Large amounts of fat in the abdomen act as a kind of inflammation factory, soaking the circulation in inflammatory mediators. So here we have a link between ever expanding waistlines and the increasing rates of mental illness in the population. It’s not just stress and environmental overload; it is likely also fat causing inflammation.

Fibromyalgia and Childhood Abuse

There is a small and growing literature about a link between fibromyalgia and a history of abuse, primarily in childhood or early adolescence.

A new study has shown that people with fibromyalgia who had experienced physical abuse in childhood did not have the normal daily fluctuations in the stress hormone cortisol. They also had sudden surges in the hormone as soon as they were woken up, which can be a good stressor. People who had been sexually abused also had this odd cortisol response on being awakened. These findings suggest that severe traumatic experiences in childhood may be a factor in causing hormonal disturbances in people suffering from fibromyalgia. This adds to the growing body of evidence that in women having pain early in the day, there is a high likelihood that the entire stress hormone system does not function normally.

Colleagues from the Department of Psychiatry, UMDNJ-New Jersey Medical School in Newark, New Jersey have reported that women who have been raped are ten times more likely to experience chronic pelvic pain as well as generalized pain.

Another study has found close correlations between childhood abuse and the subsequent development of chronic pain. The link between rape and the subsequent development of fibromyalgia seems to be mediated by chronic stress, in the form of posttraumatic stress disorder.

What this means is that professionals need to consider this:

  1. It is important careful to inquire about any history of past or present abuse or other severe trauma
  2. That empathy and constructive validation of disease and suffering can be very helpful
  3. That dysfunctional pain behaviors and personality traits may be a consequence of abuse together with a lack of resilience
  4. That multidisciplinary treatments including psychotherapy may be the best approach to helping people. Using the methods of Integrated Medicine is often far better than reliance on potentially habit-forming medications.

If we remember that there is more and more evidence of inflammation and other physical problems in fibromyalgia, and that stress and maltreatment in early life can alter the structure and function of specific regions of the brain, what this all shows us is that abuse in childhood can have a long term impact on the way in which both the body and the brain functions.

Psychiatric Illnesses and Fibromyalgia

There’s an interesting and important article in last month’s issue of the Journal of Clinical Psychiatry, by a group of investigators from the University of Cincinnati.

They have shed important new light on fibromyalgia. We’ve recently learned how it is linked to disturbances of the serotonin transporter, as well as anti-inflammatory proteins, and that is may respond best to the kind of comprehensive multi-leveled approaches that we use in Integrated Medicine.

The new research compared people with fibromyalgia with people with rheumatoid arthritis, and it found that fibromyalgia, but not rheumatoid, may be associated with a range of psychiatric illnesses:

  1. Major depressive disorder
  2. Bipolar disorder
  3. Comorbid anxiety disorders including panic disorder, social phobia, posttraumatic stress disorder and obsessive-compulsive disorder
  4. Eating disorders and
  5. Substance abuse

What was particularly important in this study was that the psychiatric problems usually preceded the onset of fibromyalgia. So it wasn’t that people were developing psychological problems because they were in chronic pain.

It’s beginning to look as if fibromyalgia is part of a larger group of disorders that all share common etiologies or causes. Family studies have indicated that fibromyalgia and mood disorders share some of the same – perhaps genetic – determinants.

The study also confirms what we have said before: fibromyalgia is not only associated with some psychiatric problems, but also with other medical disorders, several of which may also co-exist with the same psychiatric problems. They include:

  1. Chronic fatigue syndrome
  2. Irritable bowel syndrome
  3. Interstitial cystitis
  4. Multiple chemical sensitivities and
  5. Migraine

Not only does this research highlight the need to check people with fibromyalgia to see if they might also be struggling with a psychiatric problem, but it is helping us home in on some of the mechanisms linking these apparently separate problems.

This particular study was done mainly in white women, and the investigators knew who had fibromyalgia, so there’s more work to be done.

But if you or a loved one is struggling with fibromyalgia, it is good news to know that we are making rapid progress in unraveling this horrible illness.

Irritable Bowel Syndrome, Mood Disorders, the Serotonin Transporter and Integrated Medicine

Whenever we run into two common conditions, it’s easy to imagine links where none really exists. Three years ago some colleagues from Oxford reported on a person with bipolar disorder and irritable bowel syndrome, and commented that the association was uncommon.

However there may after all be a genuine link between mood disorders and irritable bowel syndrome, that is a disturbance in the “third arm” of the autonomic nervous system. The first arm is the sympathetic nervous system, the second the parasympathetic and the third is the enteric or gut nervous system that is closely linked with key regions of the brain.

Not long ago there was an interesting report of a woman who had multiple problems including environmental allergies, atypical bipolar disorder, irritable bowel syndrome and Raynaud’s phenomenon. Such odd constellations of problems are quite familiar to anyone working in the major referral centers around the world, and some can be exceedingly hard to treat. Tough cases like this often stimulate further research. I once tried and failed to treat a woman with a chronic illness. When she came back a year later to see if I had any new ideas, I told her that I now had a shelf of books and over a thousand reprint of papers about her condition: I don’t like failing someone. And I’m not unique in that.

A new study from the Karolinska Institute in Stockholm, has found that chronic widespread pain, which, as I explained recently, is the cardinal symptom of fibromyalgia, is prevalent and co-occurs with other symptom-based conditions such as chronic fatigue syndrome, joint pain, headache, irritable bowel syndrome, and psychiatric disorders.

There is more and more evidence of a link between fibromyalgia, irritable bowel syndrome and depression. It is not just that people are sick and get depressed: as we shall see in a moment, the link is more subtle than that. Another illness seemingly linked to these three is interstitial cystitis.

Now some colleagues at the National Institutes of Health have been looking at a serotonin transporter (SERT) that regulates the entire serotoninergic system and its receptors. This transporter is found throughout the animal kingdom, telling us that it must be important.

In humans the gene is located on chromosome 17, and disturbances in it have been found in people with autism, ADHD, Tourette’s syndrome and bipolar disorder. Experiments using genetic engineering suggest that SERT may be a candidate gene for several human disorders, from obesity to irritable bowel syndrome. People who have disturbances in SERT tend not to respond so well to the serotonin reuptake inhibitors (SSRI’s) antidepressant medicines.

SERT is not the whole story. Some geneticists from Los Angeles have found evidence linking irritable bowel syndrome, depression, migraine and inheritance of mitochondrial DNA.

Many approaches have been tried to help people with these groups of problems. I always find it remarkable that psychological treatments can be so effective in conditions with a genetic component, for this once again proves that biology is not destiny.

The best approaches to conditions like irritable bowel syndrome and coexisting mood disorders is to use medications and psychological approaches. Many of us have also found that the addition of nutritional, environmental and subtle energetic approaches have been of great help, together with some work to uncover the meaning and transpersonal value of a chronic illness. That last piece is not the first priority, which is to help the person gain control of his or her life. But if we don’t do something to work with the meaning and purpose of an illness, it will usually come back in some form or other. This comprehensive approach differentiates Integrated Medicine from many other types of therapy.

Chronic Widespread Pain, Fibromyalgia and Anti-inflammatory Proteins

Chronic widespread pain is a common and distressing medical condition that can be difficult to treat and is usually associated with fatigue, poor sleep and depression. One major subgroup is fibromyalgia. A connection between fibromyalgia and cytokines – small proteins that act as messengers between cells – has been suspected for some time, since some cancer patients treated with the cytokine interleukin -2 develop fibromyalgia-like symptoms. A new study from Wurzburg in Germany, published in the August 2006 issue of Arthritis and Rheumatism examined cytokine profiles in patients with chronic widespread pain and found that they had significantly lower levels of the anti-inflammatory cytokines IL-4 and IL-10.

This is an important finding: Previous research has shown that IL-10, administered as a protein or via gene transfer, reduces sensitivity to pain. Similarly, IL-4 has been shown to dull the pain response. There is also another piece to this: genetic variations in different cytokine genes are associated with distinct diseases, such as the association between IL-4 gene variations and asthma, Crohn’s disease, and chronic polyarthritis.

Although low levels of anti-inflammatory cytokines could be a consequence of chronic widespread pain and its treatment, it is much more likely that these proteins actually play a role in the causation of chronic widespread pain.

This new research raises all kinds of possibilities for the physical treatment of a particularly horrible set of illnesses.

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