Fibromyalgia Reading Room
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Latest Update: May 16, 2009
|Fibromyalgia Study: It's a Real Disease
||Travelers with Disabilities and Medical Conditions
|Electrotherapy Muscle Stimulation
||Nonpharmacological method in fibromyalgia:
the use of wool
|"Doubting doctors are ordered to take ME patients
||Novel Treatments for Fibromyalgia Syndrome.
|Yes,Virginia, there is Fibromyalgia. Suzi
||Targeted Gene Therapy Provides Relief For
Fibromyalgia Spectrum - Understanding Fibromyalgia
||Fibromyalgia Pain Is Real
|Fibromyalgia is not an imagined illness!
||Is Fibromyalgia Really a Rheumatologic
|Improving Sleep Quality - Fibromyalgia or Chronic Fatigue
||Neurobiology of fibromyalgia syndrome
|Treating Fibromyalgia with Testosterone
||Fibromyalgia Takes Different Tolls on Different
|Is fibromyalgia an organic disease?
||Fibromyalgia: an oxidative stress disorder?
|Fibromyalgia: Treatment Update -- Kim Jones,
PhD, RN, FNP
||Fibromyalgia syndrome in patients with hepatitis
|Remodeling ideas about stress and the brain
||Exercise for Patients with Fibromyalgia: Risks versus
|Office management of fibromyalgia.
||Antidepressants May Protect Brain from Damage
|Fibromyalgia: The Controversy Continues New
disagreements over pain syndrome
||Fibromyalgia: evolving concepts and
management in primary care settings.
|Neuroimmunologic aspects of sleep and sleep loss.
||Fibromyalgia Pain Isn't All in Patients' Heads
|Effective Treatment of Chronic Fatigue Syndrome and
||The contribution of pain, reported sleep
quality, and depressive symptoms to fatigue in fibromyalgia.
|Neurobiological Alterations That Result From Early Life
||Update on Mechanisms and Management Clauw,
Daniel J. MD
Studies and Trials
Links to More Articles.
Fibromyalgia Study: It's a
Kamiah A. Walker
don't know exactly what causes fibromyalgia, but now, thanks to French researchers, we
have a clue. Fibromyalgia may be related to abnormal blood flow in specific areas of the
Eric Guedj of the Centre Hospitalier-Universitaire de la Timone in Marseille, France, was
the lead researcher in a study examining blood perfusion (abnormal blood flow) as a
possible fibromyalgia cause.
imaging studies of patients with [fibromyalgia]
have shown above-normal cerebral
blood flow (brain perfusion) in some areas of the brain and below-normal in other
areas," explains Dr. Guedj in a press release about the study. "After performing
whole-brain scans on the participants, we used a statistical analysis to study the
relationship between functional activity in even the smallest area of the brain and
various parameters related to pain, disability, and anxiety/depression."
Dr. Guedj's team studied 30 women, 20 with fibromyalgia and 10 without it. The women
answered various questionnaires used in the medical research field to quantify such things
as pain levels and how severely fibromyalgia limits patients' lives.
the women underwent single photon emission computed tomography (SPECT)a special kind
of brain scan.
researchers analyzed the women's answers to the questionnaires in conjunction with
analyzing their brain scans.
what'd they find?
Dr. Guedj's team confirmed that women with fibromyalgia have abnormal blood flow in two
areas of the brain:
They have too much blood flow (called hyperperfusion) in the area of
the brain that's supposed to interpret the intensity of pain.
They have too little blood flow (called hypoperfusion) in the area of
the brain that's involved in the emotional response to pain.
Dr. Guedj's team found that if a participant's fibromyalgia symptoms were severe (as noted
by the questionnaires), then the degree of blood perfusion was severe. In other words, the
severity of the syndrome correlates with the severity of abnormal blood flow.
the team didn't find a correlation between blood perfusion and the participants' levels of
anxiety or depression. That's important to note because previously, it's been suggested
that fibromyalgia pain is linked to depression: fibromyalgia patients experience such
widespread pain in part because of depression or anxiety.
what's this mean for fibromyalgia sufferers?
Dr. Guedj sums it up nicely in a press release: "This study demonstrates that these
patients exhibit modifications of brain perfusion not found in healthy subjects and
reinforces the idea that fibromyalgia is a 'real disease/disorder'."
other words, this study could help move fibromyalgia from syndrome to disease status
because it has found a possible cause of fibromyalgia symptoms. Currently, fibromyalgia is
considered a syndrome rather than a disease because there isn't one identifiable cause of
it. Instead, there are signs and symptoms that point to a fibromyalgia diagnosis: for
example, widespread pain, fatigue, trouble sleeping, and headaches.
study could help the medical community better understand fibromyalgia and how to
effectively treat it.
is a complex condition affecting 3 million to 7 million Americanmost of them women
(hence why only women were used in the French study). Right now, there isn't one test used
to diagnose fibromyalgia; doctors have to diagnose it by eliminating other possible
diseases/syndromes and by paying careful attention to a patient's symptoms. This SPECT
study could lead to a way to objectively confirm a fibromyalgia diagnosis. Last Updated:
Return to Table of Topics.
Yes, Virginia, there is Fibromyalgia, Suzi Prokell,
still believe disease is a myth; sufferers say its no fairy tale.
DALLAS (January XX, 2008) Ads for a new drug recently approved by the U.S. Food
andDrug Administration to treat fibromyalgia are hitting the airwaves and sparking new
debates within the medical community over the very existence of the disease.
recently read, with great interest, an article in the New York Times over the
controversy surrounding fibromyalgia, said Dr. Arlyn LaBair of the
Fibromyalgia & Fatigue Centers Inc . and I found it almost amusing that this
kind of denial continues in the medical community.
the research and information provided by physicians, researchers, drug companies and every
expert under the sun, we can clearly see the disease does exist.
is characterized by muscle and joint pain, flu-like pain that can be severe andconstant, a
feeling of exhaustion, specific tender points,body aches and muscle stiffness. It can also
be accompanied by irritable bowel syndrome, sleep disturbance, headaches,
anxiety,depression and a variety of other symptoms.
Many patients suffer with these symptoms for years before getting help. Read entire
Return to Table of Topics.
Treatment of Fibromyalgia Syndrome With Antidepressants
Meta-analysis Winfried Häuser, MD; Kathrin Bernardy, PhD; Nurcan Üçeyler, MD; Claudia
Sommer, MD ;301(2):198-209.
Fibromyalgia syndrome (FMS) is a chronic pain disorder associated with multiple
debilitating symptoms and high disease-related costs. Effective treatment options are
To determine the efficacy of antidepressants in the treatment of FMS by performing
a meta-analysis of randomized controlled clinical trials.
Sources MEDLINE, PsycINFO, Scopus, and the Cochrane Library databases were searched
through August 2008. Reference sections of original studies, meta-analyses, and reviews on
antidepressants in FMS were reviewed.
Selection Randomized placebo-controlled trials with tricyclic and tetracyclic
antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and
noradrenaline reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) were
Extraction and Data Synthesis Two authors independently extracted data. Effects were
summarized using standardized mean differences (SMDs) by a random-effects model.
Eighteen randomized controlled trials (median duration, 8 weeks; range, 4-28 weeks)
involving 1427 participants were included. Overall, there was strong evidence for an
association of antidepressants with reduction in pain (SMD, 0.43; 95% confidence
interval [CI], 0.55 to 0.30), fatigue (SMD, 0.13; 95% CI, 0.26 to
0.01), depressed mood (SMD, 0.26; 95% CI, 0.39 to 0.12), and sleep
disturbances (SMD, 0.32; 95% CI, 0.46 to 0.18). There was strong
evidence for an association of antidepressants with improved health-related quality of
life (SMD, 0.31; 95% CI, 0.42 to 0.20). Effect sizes for pain reduction
were large for TCAs (SMD, 1.64; 95% CI, 2.57 to 0.71), medium for MAOIs
(SMD, 0.54; 95% CI, 1.02 to 0.07), and small for SSRIs (SMD, 0.39;
95% CI, 0.77 to 0.01) and SNRIs (SMD, 0.36; 95% CI, 0.46 to
Antidepressant medications are associated with improvements in pain, depression,
fatigue, sleep disturbances, and health-related quality of life in patients with FMS.
Author Affiliations: Department of Internal Medicine, Klinikum Saarbrücken, Saarbrücken,
Germany (Dr Häuser); Department of Anesthesiology, Emergency Medicine and Pain Therapy,
University of Saarland, Saarbrücken (Dr Bernardy); Department of Psychosomatic Medicine,
MediClin Bliestal Clinics, Blieskastel, Germany (Dr Bernardy); and Department of
Neurology, University of Würzburg, Würzburg, Germany (Drs Üçeyler and Sommer).
Return to Table of Topics.
Electrotherapy Muscle Stimulation
Many fibromyalgia sufferers become frustrated at the lack of effective
treatment available for their fibromyalgia symptoms. The chronic headaches, muscle
weakness and fatigue can often be too much to bear. However, if you are looking to try a
new treatment that can help relieve some of these symptoms, then you amy want to try
electrotherapy muscle stimulation. Electrotherapy muscle stimulation is a safe and
effective treatment for the chronic pain and fatigue associated with fibromyalgia.
What is Electrotherapy?
Electrotherapy, or electromedicine, is a class of treatment that uses electrical impulses
to improve symptoms of pain, muscle loss, and depression in patients. It may sound quite
scary to you to be treated using an electrical current, but, in fact, electricity has been
used in medicine for almost 2,000 years.
Electricity is actually one of the safest and most effective ways of
treating pain and other illness, because it is associated with so few side effects.
Electrotherapy delivers a small, pulsating current to a persons muscles and nerve
endings. This current causes the muscles to contract and then relax. Repeated stimulations
allow the muscles to strengthen, relax, and feel less painful.
What are the Benefits of Electrotherapy?
There are different types of electrotherapy but they are all associated with the same
benefits. Electrotherapy was introduced to American medicine in the 1950s, and used to
treat anxiety, depression, and insomnia Now, electrotherapy has proven effective in
treating other illnesses, including chronic fatigue, multiple sclerosis, and fibromyalgia.
Electrotherapy promotes nerve conduction, blood circulation, and also helps the body to
heal on its own. It is very similar to a deep tissue massage. The effects of
electrotherapy are cumulative, so you will see more benefits after repeated treatments.
Types of Electrotherapy
There are three main types of electrotherapy muscle stimulation available to fibromyalgia
sufferers. Before you begin electrotherapy treatment, speak with a licensed professional
and find out whether you are suited for the treatment.
Transcutaneous Electrical Nerve Stimulation (TENS)
TENS therapy is a non-invasive and non-addictive way to treat fibromyalgia pain and
fatigue. It delivers a current of about 60 milliamperes to muscles and nerve endings that
are causing you particular pain. It causes these nerves to contract and relax, allowing
for muscle stimulation and strengthening. It also reduces pain and restores mood.
TENS electrotherapy equipment can be purchased and used at home, for
private, comfortable treatment. The TENS unit comes with a battery, electrodes, and an
electric signal generator. You simply place the TENS electrodes, which are usually rubber
or felt pads, over a painful area of your body. An electric current is then delivered to
the electrode, stimulating your muscle and blocking pain messages from being sent to your
brain. This allows your pain symptoms to improve. TENS units can be used once a week,
every other day, or as often as needed to provide relief. They cost between $400 and $700.
Percutaneous Electrical Nerve Stimulation (PENS)
PENS is a variant of TENS, only it uses a needle probe to stimulate nerve endings instead
of a felt pad. PENS treatments must be done by a licensed professional, either an
acupuncturist or general physician, and typically last 30 minutes. The physician first
locates sore or painful areas that require treatment. The physician inserts needles that
have been attached to electrical impulses 1 to 4 centimeters below the skin. Electrical
impulses are then delivered to the needles.
PENS treatments are thought to be more effective than TENS treatments.
This is because the needle electrodes are able to bypass your skin, providing less
resistance to the electric current. It allows for nerves to be stimulated more accurately
and efficiently. PENS treatments will probably only be available to you if TENS treatments
have provided you no relief. The procedure is not at all painful, and is associated with
few, if any, side effects.
Cranial Electrotherapy Stimulation (CES)
In the past, CES was used exclusively to improve mood and sleeping habits in ill patients.
Recently, it has been introduced as a chronic pain treatment for people with illness like
fibromyalgia. Cranial electrotherapy can be performed in the privacy of your own home.
This treatment delivers a very mild electric current (about a millionth of an amp) through
your head. Two electrodes are clipped onto your earlobes and a low electrical current is
transmitted back and forth through your head. There is absolutely no pain or discomfort
involved in this treatment.
Cranial electrotherapy stimulators work to relieve pain and improve
mood by stimulating the hypothalamus. This is the part of your brain responsible for
governing mood, cognitive function, and emotions. The electrical impulses stimulates your
hypothalamus to produce more neurohormones, helping to regulate your pain symptoms.
Complications and Side Effects
There a few, if any side effects associated with electrotherapy muscle stimulation. If too
strong a current is used, there is a risk that you could burn or irritate your skin.
Sometimes, people are sensitive to the glue or tape used to affix the electrodes to the
Complications can occur in some individuals, though. You
shouldnt use electrotherapy if you:
Electrotherapy and Fibromyalgia
Electrotherapy is often recommended to treat the numerous fibromyalgia symptoms. All types
of electrotherapy have proven beneficial to fibromyalgia sufferers in one way or another,
although more studies need to be done to conclusively prove the benefits of electrotherapy
One study found that the use of CES improved both the pain and sleep
problems caused by fibromyalgia. Participants reported a 28% drop in the number of tender
points as well as a 27% reduction in their overall pain after 6 weeks. 90% of participants
agreed that electrotherapy had helped to improve their quality of life.
A study on the use of TENS in fibromyalgia patients, found similar
results. After 6 weeks of TENS therapy, participants reported a 70% drop in their pain
symptoms as well as a 53% increase in their activity levels.
Return to Table of Topics.
Nonpharmacological method in fibromyalgia: the use of wool
Altern Complement Med. 2009 Apr;15(4):399-405. Kiyak EK. Atat=FCrk University, School of
Nursing, Erzurum, Turkey. email@example.com PMID: 19388862
OBJECTIVES: The aim was to assess the effect of wool use in patients with fibromyalgia.
BACKGROUND: Various studies concerning the treatment of patients with fibromyalgia using
nonpharmacological methods have been carried out. There are, however, no reports on the
use of wool clothing and bedding in treating these patients.
DESIGN AND METHODS: The study employed two-group, experimental design. A total of 50
patients with fibromyalgia, based on the criteria of the American College of Rheumatology,
were selected for the study. They were distributed equally into two groups: a control
group and a treatment group. The 25 patients in each group were randomly selected and the
compositions of the two groups were statistically identical. The patients in the treatment
group wore woolen underwear (which covered the body from the shoulders to the thighs) and
used woolen bedding such as woolen bed liner, woolen quilt and pillow during the
experimental period of 6 weeks. All patients were assessed at the beginning the trial
(pre-test) and the end of 6th (post-test) week. Data were collected using the visual
analogue scale (0-10), tender points count, and Fibromyalgia Impact Questionnaire.
RESULTS: Patients in the treatment group reported significant improvements in their
conditions including a reduction in pain levels,
tender point counts, and all scores of the Fibromyalgia Impact Questionnaire (p <or=3D
CONCLUSIONS: The use of woolen underwear and woolen bedding were effective in reducing the
symptoms of patients suffering from
fibromyalgia. The use of wool is recommended as a means of treatment for alleviating the
pain of fibromyalgia.
RELEVANCE TO CLINICAL PRACTICE: Nurses provide professional support to patients with
fibromyalgia. They select suitable clothes and sleeping materials for their patients with
this object in mind: to keep their patients warm and to protect them from the cold.
Return to Table of Topics.
Fibromyalgia Pain Is Real
Scan Proves What Sufferers Have Always Known By Daniel DeNoon
WebMD Medical News. Reviewed By Gary Vogin, MD
with fibromyalgia (FM) know their pain is real. So do FM experts. And now there's proof
that FM patients' extreme sensitivity to pain is no figment of their imaginations.
now possible to look at the brain and see exactly where it's active. This is done with a
sophisticated brain scan called functional magnetic resonance imaging or fMRI. And these
studies now are being done on FM patients.
a study reported in the May issue of the journal Arthritis & Rheumatism, FM experts
Richard H. Gracely, PhD, and Daniel J. Clauw, MD, gave fMRI scans to 16 FM patients and 16
healthy people. They did the scans under two conditions: first, when the person was
feeling slight pressure on the thumb; and second, when the person was feeling moderately
painful pressure on the thumb.
people's brains only became active when they felt the painful pinch. But the brains of the
FM patients became highly active even when there was only slight pressure. This activity
was very much like what happens in the brains of healthy people who are feeling pain.
it shows is that the brain response is consistent with what the patients report
verbally," Gracely tells WebMD. "Being believed is an extremely important issue
for these people. Now these physical findings are emerging, it is gratifying for these
patients. We doctors aren't surprised because we already knew. But for the patient, it is
just a terrible situation to be in. The general public doesn't really realize that pain
can be very severe -- and sometimes untreatable -- in a person who does not seem to be
John Russell, MD, PhD, is leading similar fMRI studies at University of Texas Health
Science Center, San Antonio. Russell is director of the university's clinical research
helps the patient to see that their pain is different from the pain of others and that it
is real," Russell tells WebMD. "Also, this gives us a window to look into the
brain at the responsiveness to and effect of pain on mood in people with FM."
notes that FM patients aren't just more sensitive to pain. Pain also affects the mood
centers of their brains in ways that it doesn't affect healthy people.
impressed by the new research is Terence W. Starz, MD, an FM expert at the University of
Pittsburgh Medical Center.
very, very sophisticated instruments may now help us describe different subsets of FM
patients," Starz tells WebMD. "The brain's processing information from the
senses is very complex. When one looks at fibromyalgia patients it is becoming
increasingly clear that there are variations in the processing of sensory
have been slow to accept FM as a real disease -- but that quickly is changing.
been in the pain field for 27 years," Gracely says. "Twenty years ago, pain
medicine was like a poor stepchild. It was not taught in medical school. Today, the number
of people in pain research is huge. FM has been a poor stepchild, too. It is like pain
research was several years ago."
formerly a researcher at the U.S. National Institutes of Health, and Clauw, formerly at
Georgetown University in Washington, have moved their research to the University of
Michigan, Ann Arbor.
Return to Table of Topics.
Targeted Gene Therapy Provides Relief For Chronic Pain,
(Jan. 24, 2008) Researchers in the Department of Medicine and Department of
Neurosciences at Mount Sinai School of Medicine have discovered that chronic pain can be
successfully treated with novel targeted gene therapy. In an effort to find a more
effective treatment for chronic pain, researchers at Mount Sinai developed a gene therapy
technique that simulates the pain-killing effect of opiate drugs. In the new study
researchers suggest that gene therapy for pain might in the future become a treatment
alternative for patients with severe chronic pain.
million Americans suffer from chronic pain. Chronic pain patients often do not experience
satisfactory pain relief from available treatments due to poor efficacy or intolerable
side effects like extreme sleepiness, mental clouding, and hallucinations," said Dr.
Andreas Beutler, MD, principal investigator of the study and Assistant Professor of
Medicine/ Hematology And Medical Oncology at Mount Sinai School of Medicine.
Sinai researchers designed a viral vector to carry the prepro-b-endorphin gene into
primary sensory neurons in order to activate opiate receptors selectively, in a rat model.
The agents were delivered directly into the spinal fluid of rats via a lumbar puncture, or
spinal tap with only one injection. Results showed that the rats remained symptom-free for
an extended period of time.
research found that treating chronic pain with Adeno-Associated Virus vector-based gene
therapy allows for pain relief for more than three months after a single injection,
targeting selectively the pain gate. The technique worked successfully with opioid- and
non-opioid therapeutic genes," said Dr. Beutler. "Targeted gene therapy will
likely avoid the unwanted side effects associated with opioid painkillers such as
morphine. Based on our findings, this targeted gene therapy via lumbar puncture appears to
be a promising candidate for bench-to-bedside research that might ultimately be tested in
patients with intractable chronic pain, e.g., to help patients suffering from severe pain
due to advanced cancer."
study "Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for
chronic pain" was published in the January 22, 2008 issue of the Proceedings of the
National Academy of Sciences (PNAS).
from materials provided by Mount Sinai Hospital / Mount Sinai School of Medicine.
Neurobiology of fibromyalgia syndrome
J Rheumatol Suppl. 2005 Aug;75:22-8. Price DD, Staud R.
From the Department of Neuroscience and Department of Medicine, University of Florida,
Gainesville, Florida, USA. PMID: 16078357
Accumulating evidence suggests that fibromyalgia syndrome (FM) pain is maintained by tonic
impulse input from deep tissues, such as muscle and joints, in combination with central
This nociceptive input may originate in peripheral tissues (trauma and infection)
resulting in hyperalgesia/allodynia and/or central
sensitization. Evidence for abnormal sensitization mechanisms in FM includes enhanced
temporal summation of delayed pain in response to repeated heat taps and repeated muscle
taps, as well as prolonged and enhanced painful after-sensations in FM patients but not
Moreover, magnitudes of enhanced after-sensations are predictive of FM patients' ongoing
clinical pain. Such alterations of relevant pain mechanisms may lead to longterm
neuroplastic changes that exceed the antinociceptive capabilities of affected individuals,
resulting in ever-increasing pain sensitivity and dysfunction.
Future research needs to address the important role of abnormal nociception and/or
antinociception for chronic pain in FM.
Return to Table of Topics.
Fibromyalgia: Update on Mechanisms and Management April
2007 Clauw, Daniel J. MD
the *Division of Rheumatology, Chronic Pain and Fatigue Research Center, Clinical
and Translational Research, University of Michigan Medical Center, Ann Arbor, Michigan.
From Rheumatology Grand Rounds at Rush University Medical Center, Chicago, IL, USA.
Editors: Robert S. Katz, MD, and Joel A. Block, MD. Reprints: Daniel J. Clauw, MD,
Director, Chronic Pain and Fatigue Research Center, University of Michigan Medical Center,
Ann Arbor, Michigan 48109.
ACR CRITERIA FOR FIBROMYALGIA: THE GOOD AND THE BAD The American College of Rheumatology
criteria have been both bad and good for fibromyalgia.1 When they were published in 1990,
this is what we thought fibromyalgia was: chronic widespread pain and the 11 of 18 tender
points. If this is your view of fibromyalgia, then fibromyalgia is really no different
than other rheumatic diseases like osteoarthritis or rheumatoid arthritis or lupus-a
1990, we also thought that the tenderness was confined to certain areas of the body, or at
least more accentuated in certain areas of the body, which we refer to as tender points.
Finally, another misconception that exists to this day in many people's mind is that
psychological and behavioral factors are always present in people with fibromyalgia and
always make them worse. A more contemporary view of fibromyalgia is that rather than being
a discrete illness, it is a part of a huge continuum of pain and somatic syndromes. It
happens to be what we, as rheumatologists, are most comfortable calling it. But these
individuals have pain throughout their entire body that isn't due to damage or
inflammation, and there's a great deal of scientific evidence that this is one large
spectrum of illness that includes fibromyalgia, irritable bowel, and temporomandibular
joint (TMJ) syndrome-as well as a number of other conditions that I'll talk about later.
if we use the American College of Rheumatology (ACR) criteria to diagnose fibromyalgia
(i.e., on the basis of widespread tenderness and pain), people don't just have tenderness
and pain. They have a lot of other somatic symptoms besides pain and tenderness. And,
again, psychological and behavioral factors only play negative roles in some individuals.
We also now know that the entire individual with fibromyalgia is tender, and that there is
nothing magical about tender points. These are merely areas where everyone is more tender.
But fibromyalgia patients are also much more tender wherever you apply pressure, including
areas previously considered to be control points. In fact, in our research group, when
performing sophisticated imaging studies, we push on the thumbnail because we found that
the thumbnail is just as tender (relative to that same region in a healthy control) as any
of the tender points. Fred Wolfe was the first to point this out. He suggested that we
should abandon this old term that used to be called control points and call them
high-threshold tender points; areas like the forehead and the thumbnail and the anterior
tibial region are just areas where all of us have a higher pain threshold.
are many other problems with ACR criteria and specifically with tender points. We didn't
know any of this in 1990, so I'm not being critical of the people who were involved in
developing the ACR criteria because they have been wonderful in standardizing research
into fibromyalgia. But we didn't know that tender points are actually not a very good
measure of tenderness. In 1997, Wolfe published an article where he looked at some of the
data that he collected in population-based studies. He had found that the number of tender
points an individual has is highly correlated with the number of measures of distress-of
anxiety, depression, and distress.2 What he said in that article was that tender points
are a sedimentation rate for distress.
then, our group and others have shown that other more sophisticated measures of
tenderness, such as where you give people stimuli randomly when they can't anticipate what
the next stimulus is going to be, are just as abnormal in people with fibromyalgia, but
these are not at all related to the level of distress of the individual.3 So people with
fibromyalgia are indeed much more tender, or they have what we would call a left-shift in
their stimulus-response function with respect to pressure.
the take-home message is that fibromyalgia patients are much more tender even using more
sophisticated measures that are not confounded by distress. However, tender points are not
a very good measure of tenderness. Tender points are part a measure of tenderness and part
a measure of how anxious and depressed an individual is. I might be the first author that
I know of that's been able to get away with writing a chapter in textbook regarding
fibromyalgia without having an illustration of a woman with 18 dots on it, because I think
that the longer that we highlight the ACR criteria and highlight these 18 areas of the
body, the longer physicians are going to think that there is something uniquely wrong with
those 18 areas of the body rather than realize that this is a diffuse, central problem
with pain processing. This gives an inappropriate impression about the nature of
fibromyalgia when you put those 18 dots and they all happen to be located over
muscle-tendon junctions and people sort of think, Well, that's where the problem is,
rather than realizing that this is a problem in the central nervous system with the way
people are processing pain or sensory information. Our group hypothesizes that this is
actually a more global problem with sensory processing, not just pain processing, because
people with this spectrum of illness are sensitive to a number of different types of
stimuli rather than just somatic pain.
think one of the other disservices that the ACR criteria has done is that they've deluded
us into thinking that fibromyalgia occurs almost exclusively in women. If you use the ACR
criteria, 92% of the people in the population who are identified as meeting those criteria
are females. But if you break down the criteria into the 2 elements, (1) chronic
widespread pain and (2) 11 of 18 tender points, women are only 1[1/2] times as likely as
men to have chronic widespread pain, but women are 11 times as likely as men to have 11 of
18 tender points. So what we've done with the ACR criteria is take an illness that is
probably only about 1[1/2] times more commonly in women and make physicians think that
this occurs only in females.
is similar to what we did a couple of decades ago when I was trained as a rheumatologist,
when we were taught that ankylosing spondylitis only occurred in males. When that's what
we were taught, then we only thought of the diagnosis of ankylosing spondylitis in men,
even though later data showed that the prevalence of AS is very similar in men and women.
The same thing happens now with women versus men in chronic pain. Men who come in with the
same exact symptoms and physical examination as women with fibromyalgia are more likely to
be labeled with regional pain syndromes such as osteoarthritis, because if you do X-ray
after X-ray (or worse yet MRI after MRI) you will always find something wrong. I used to
have a diagnostic test called the X-ray jacket sign because when we went to the VA clinic,
they would pull the X-ray jackets on all patients (before the X-rays were digitalized). I
joked that if you could pull 10 consecutive musculoskeletal X-rays out and none of them
were abnormal, that was a diagnostic test for fibromyalgia. And we had many men in the
rheumatology clinic that we were seeing who had been labeled as osteoarthritis or chronic
low back pain, who clearly had fibromyalgia. But the diagnosis carried for years and years
in their chart was a regional pain syndrome such as osteoarthritis, even though there were
inadequate radiographic findings to support this, and they typically did not respond very
well to treatments for peripheral pain. Then the last thing that people should be aware of
with tender points, and that is that 11 is a totally arbitrary number.
Katz has published articles recently talking about how different types of criteria
function equally well. And he and I, and almost everyone in the fibromyalgia field, agree
that the ACR criteria should not be used in clinical practice to diagnose fibromyalgia.
They never were intended for that purpose. They were intended to standardize research
studies. And they don't function very well at all when you use them in routine clinical
practice. Every subspecialist that I know, except perhaps radiologists and pathologists,
sees patients that was as rheumatologists call fibromyalgia and has one or more names for
the symptoms in the area of the body they are responsible for. It is not until you realize
the entirety of the problem, like the pharmaceutical industry now does, that you
understand that this is one large problem that needs to be addressed in primary care,
rather than something that's just been bestowed upon us in rheumatology because we have to
deal with these fibromyalgia patients.
IN FIBROMYALGIA So to summarize, there's nothing wrong with thinking that fibromyalgia is
a discrete disorder. But I'm going to talk of it as being more of the end of the
continuum, or the way the pharmaceutical industry is viewing this right now, which is that
it is the prototypical central pain state, where people can get pain and other somatic
symptoms without having anything really wrong in their peripheral tissues that would cause
a nociceptive problem. Regarding the underlying mechanisms in this spectrum of illness, we
didn't know in 1990 what we know now about pain sensitivity. In 1990, the thought was that
there were sort of 2 groups of people in the population: a small group of people who were
very tender and thus met criteria for fibromyalgia, and the rest of the population, who
had a normal pain threshold. But in the last 15 or so years, there have been a number of
different studies of pain sensitivity in the population. And we now know that pain
sensitivity in the population occurs over a wide continuum, a classic bell-shaped curve,
just like almost any other physiologic variable. We're also learning that genetics have a
lot to do with where you are on this continuum. I am quite comfortable saying that in 5-10
years we will have gene chips that will have been developed that will predict with a
reasonable accuracy where people are on this bell-shaped curve, because polymorphisms and
a number of different genes that involve the breakdown and metabolism of neurotransmitters
involved in sensory transmission will predict with a fair amount of accuracy where someone
is going to sit on this curve. And if you happen to be in the top quartile or tertile of
that bell-shaped curve, on the far right where you're very sensitive to pain, you probably
can develop pain without having any inflammation or damage in your peripheral tissues; and
that can either be regional or widespread pain.
this is really the emerging notion of what's going on in these fields like fibromyalgia,
TMJD, and irritable bowel. People, because of a combination of the genes they are born
with and the environment that they grew up in, move to the right end of this bell-shaped
curve and can develop pain and other somatic symptoms because of what's going on in their
central nervous system rather than because of any damage or inflammation in their
peripheral tissues. The best work showing the genetic and familial nature of fibromyalgia
has been done by Lesley Arnold and her colleagues.4 They showed that if someone has
fibromyalgia, the risk of one of their first-degree relatives having fibromyalgia is
8-fold greater. To put it in context, in lupus and rheumatoid arthritis, the odds ratio is
2 to 3; and we think of those diseases as being somewhat familial. But fibromyalgia is
incredibly familial. And one of the nice things about this study is that it somewhat
challenged an earlier notion that Jim Hudson, who was actually a coauthor of this study,
published in the mid 1980s where he called this an affective spectrum, because he felt
that depression and anxiety coaggregated strongly with fibromyalgia.
new studies, which he was also involved in, partially proved his theory, but the
coaggregate between these disorders and fibromyalgia is weaker than previously suggested
by studies done entirely in tertiary care centers. So there is a weaker coaggregation with
mood disorders genetically, whereas there is a very strong coaggregation with other pain
syndromes like fibromyalgia and irritable bowel syndrome and TMJ syndrome, and other
psychiatric disorders such as obsessive compulsive disorder and bipolar disorder.
of the best studies looking at the precise genetic cause of conditions related to
fibromyalgia was done by Luda Diatchenko and Bill Maixner at the University of North
Carolina.5 They looked at a large cohort of women who were pain-free and followed them for
3 years to see who developed the TMJD syndrome, and showed that how tender an individual
was at baseline, and polymorphisms in the COMT gene, predicted who went on to develop the
TMJD syndrome over the 3-year period. That's just one single polymorphism, and there are a
number of different polymorphisms that are probably playing a role in pain.
probably will be 20 or so genes that end up predicting with a reasonable amount of
accuracy where someone is on this continuum of pain processing. But where I think it's
going to be incredibly useful in 5 to 10 years is to figure out what drugs to give people
who have this spectrum of illness because if I see that one person might have developed
fibromyalgia because of an abnormality in catecholamine synthesis because of COMT or
ß-adrenergic receptors, then these individuals might respond very well to, for example, a
mixed reuptake inhibitor or low doses of a ß blocker. Whereas individuals who have
different polymorphisms might be more responsive to drugs like pregabalin or gabapentin,
or other classes of drugs, which will be developed in the future, that act on other
neurotransmitters that either increase or decrease an individual's pain sensitivity. Given
that nearly all illnesses are due to some combination of genes and environment, we also
are beginning to better understand the environmental factors that seem to be important in
triggering fibromyalgia. Most may be acting as stressors. One stressor that is clearly
capable of causing fibromyalgia is to begin by having a peripheral pain syndrome (i.e.,
pain due to damage or inflammation of peripheral tissues). I'm not sure what percentage of
rheumatologists are aware of this, but 20 to 25% of people with RA, lupus, and ankylosing
spondylitis, have comorbid fibromyalgia.6 I see young and old rheumatologists who make the
diagnosis of an autoimmune disease and then hone in and inordinately focus their treatment
on autoimmunity. Every time that patient has pain or fatigue, we raise their dose of
immunosuppressives because we think that's what is causing their pain and their fatigue.
But if a quarter of the people with autoimmune diseases have comorbid fibromyalgia, maybe
they need a low dose of amitryptiline or some aerobic exercise rather than a cytotoxic
drug or 10 more milligrams of prednisone. Another stressor that can trigger this spectrum
of illness is infections.
different infections that have been shown in case-controlled studies to trigger either
fibromyalgia or chronic fatigue syndrome: Epstein-Barr virus, parvovirus, Lyme disease,
and Q fever.7 There are 2 studies published in the Lancet showing that the common cold
isn't capable of triggering either chronic fatigue syndrome or fibromyalgia. Now, in
almost all of my talk, you could substitute the word IBS for fibromyalgia and give the
exact same talk, and it would be accurate. But this is one area where fibromyalgia and IBS
would differ. The infections that trigger irritable bowel syndrome are virtually any
infections that cause acute infectious colitis-nearly all have been shown in case-control
studies to lead to the subsequent development of IBS. Likewise, a number of different
genitalurinary infections have been shown to be capable of triggering the development of
interstitial cystitis So depending on where in the area of the body responsible for one of
the syndromes, different infections that attack that area of the body seem to be capable
of triggering it. But only about 4 to 7% of people with these infections go on to develop
fibromyalgia, IBS, or interstitial cystitis, whereas the overwhelming majority of
individuals that have these same infections recover fully and go on to their baseline
state of health. So, again, it's probably some interplay between the genes the people are
born with and the infections that they get. Physical trauma is another stressor that is
capable of triggering the development of fibromyalgia. But one of the fascinating things
about this is that this occurs much more frequently in some countries than others. In
Lithuania, motor vehicle accidents trigger almost no chronic regional or chronic
widespread pain; whereas in the United States, they trigger a fair amount of it.8 It's not
the patient's fault. It has little to do with the insurance systems because this happens
in no-fault and in other insurance systems. And it probably doesn't even have much to do
with the disability and litigation systems. It may have more to do with what we as
physicians (and the healthcare system) lead people to expect what will or won't happen
after acute musculoskeletal trauma. In Lithuania, when you come in after a motor vehicle
accident, and you see an emergency room physician, there is no expectation that there will
be any chronic symptoms after that; you are given a few days worth of anti-inflammatory or
analgesic medications, and told to go back to work. In the United States and many other
countries, we give people opioids, tell them they might develop chronic pain, and tell
them to rest.
haven't learned our lesson from good research in conditions such as acute low back pain,
where we now know that the worst thing to do with someone with low back pain is to make
them expect they might develop chronic pain, and tell them to stop moving and rest. So it
may actually may be our health systems and the expectations that we as physicians set up
with our patients when they come in with acute pain rather than being litigation or
disability. With respect to stressors, there's actually weak data that psychologic stress
and distress directly causes fibromyalgia. One of the fascinating things is I'm always
surprised, being a scientist, at how often my clinical judgment ends up being wrong. When
I was first doing research in fibromyalgia, I, like many of you, was always smacked in the
face by the psychologic comorbidity that a lot of fibromyalgia patients come in and
express. But the data suggest that many types of psychologic stress don't seem to trigger
or worsen fibromyalgia. We were doing a study in Washington, D.C., where we were beginning
to work with a company that was doing clinical trials in fibromyalgia, and they wanted to
do more innovative outcome measures of fibromyalgia patients. So we were having
fibromyalgia patients in Washington, D.C., wearing Palm pilots that beeped 5 times a day
and they had to record their pain, their fatigue, their stress levels 5 times daily. As is
not unusual in research, some of the best things that happen to you are serendipitous; and
the 9/11 attacks on the Pentagon happened right smack in the middle of the study. So we
had about 20 people who had been recording their pain, their fatigue, and their other
symptoms, before and after the Pentagon attack, miles away from where all of these
patients were living. We expected that we would see pain, fatigue, and stress levels go
sky high in people with fibromyalgia after 9/11, but there was absolutely no change. Karen
Raphael was doing a population-based epidemiologic study in New Jersey where she had
collected baseline data in people right across the river from the World Trade Center in
New Jersey, and similarly found no increase in symptoms.9 So you have to be very careful
about attributing emotional stress to the development of fibromyalgia. It likely is very
important what type of stress, and interpersonal stress may be much more likely to
exacerbate or trigger fibromyalgia than the type of stress seen after 9/11. Finally, war
is another thing that triggers the development of this spectrum of illness.
Department of Defense provides funding for our research group and many others because of
the recognition that after the first Gulf War and, in fact, maybe after every war, one of
the major postdeployment health problems is the development of chronic pain, fatigue, and
what we would call either fibromyalgia, chronic fatigue syndrome, IBS, etc.10 RELATIONSHIP
BETWEEN NEUROBIOLOGICAL FACTORS AND PSYCHOLOGICAL, COGNITIVE, AND BEHAVIORAL FACTORS One
of the most controversial questions in this illness is what is the relationship between
physiologic or neurobiologic factors and psychologic and behavioral factors. If you do
research in this area, you quickly realize that the old dualist notion of organic versus
functional illnesses needs to be abandoned, because everything that is psychologic or
behavioral likely has neurobiologic and physiologic underpinnings, and psychologic and
behavioral factors play significant roles in even the most biologic of illnesses. In fact,
I think that one of the big tragedies regarding this spectrum of illness is that 30 or so
years ago, fibromyalgia was on had equally poor credibility as a real disease with mental
health disorders such as bipolar disease, major depression, and schizophrenia. But now
these latter conditions are more credible than fibromyalgia, in large part because
scientific studies have shown that there are strong biologic underpinnings to these
illnesses. The research showing strong biologic underpinnings is equally strong in this
spectrum of illness, but most physicians and the lay public are not yet aware of these
findings. This will likely change rapidly in the next few years as new drugs are approved
specifically for fibromyalgia, and the companies marketing these drugs will do a thorough
job of educating both physicians and patients about these conditions. Until then, though,
these patients are shunned and inappropriately treated in our current health care systems.
is averting their eyes and acting like they're not part of the problem here. But we are.
Rheumatologists don't want fibromyalgia. Gastroenterologists don't want IBS. None of the
subspecialties want this. So there never has been an advocacy campaign like the
psychiatrists and other mental health professionals mounted to legitimize psychiatric
conditions. Having said that I'm not a dualist, it can actually be very helpful when
you're sitting across the examination room from a fibromyalgia patient, to be a bit
dualistic, and ask yourself how much social, cognitive, behavioral, and psychological
factors are playing a role in symptom expression. Not all fibromyalgia patients are the
same. Some of them respond very well to a little bit of a tricyclic drug and a little bit
of education, and they never come back because they do fine. Others don't get better no
matter what we do. We did a study published in Arthritis & Rheumatism a couple of
years ago where we tried to develop subgroups based on 3 different domains. One domain was
neurobiological; that was how tender people were using these more sophisticated measures
of pressure pain threshold. One domain was whether they were depressed or anxious. And
then the third domain was cognition, how they think about their pain. There are 2
particular cognitive patterns that are known to be very negative in pain. One is
catastrophizing, which means that people have a very negative, pessimistic view of what
their pain is and what it's doing to them. The other is an external locus of control,
which basically means that people feel as though they can't do anything about their pain,
so they can't control their pain.
study that I referred to earlier looked at 97 patients that we had been seeing at
Georgetown, and 50 of them fell into the group we refer to as primary-care fibromyalgia
patients.11 These people all met ACR criteria for fibromyalgia, but this subgroup was not
depressed, they weren't anxious, they weren't very tender. They had enough tender points
to meet the ACR criteria, but they weren't very tender using more sophisticated measures
of pressure pain threshold. And they didn't have any negative cognitive factors, in that
they didn't catastrophize, and had a moderate sense that they could control their pain. So
in these people, they didn't have psychologic factors that seemed to be driving their pain
to be worse, yet they had fibromyalgia. These people likely do fairly well with the kinds
of treatments that we now recommend giving people with fibromyalgia. At the beginning of
this talk, I usually ask people to remember a fibromyalgia patient, and when I get to this
point of the talk, I say that that fibromyalgia patient that you remembered is in the
second subgroup, that we refer to as tertiary care fibromyalgia patients. You, as a
rheumatologist, are not well equipped to make this person better, because what's going on
in their spinal cord and brain with respect to their pain processing is the least of their
problems. In addition to being tender, they're depressed, anxious, they catastrophize,
they have no sense they can control their pain. These are people that have very prominent
psychological factors above and beyond what might be contributing to their tenderness.
These are people that even the best multidisciplinary pain programs have difficulty making
better, and they certainly are not going to get better by just giving them a drug that
somehow modifies pain processing in the brain or spinal cord. It is naive to think that
you're going to make this kind of person better by just giving them a drug, because
superimposed on a central nervous system problem with pain processing, these individuals
have had significant social, cognitive, behavioral, and psychologic consequences of years
or decades of untreated pain and other somatic symptoms. The third subgroup that we
identified in this study was very interesting. This group was the most tender of the
three, suggesting that there was something quite wrong with how they processed pain. But
despite this, these people were not anxious, they weren't depressed, they weren't
catastrophizing. They actually had a moderate sense they could do something about their
pain. These are individuals in whom psychologic resiliency seems to be buffering them
against the neurobiological effects of fibromyalgia. In spite of what's going on in their
brain and their spinal cord that is increasing their volume control setting and moving
them to the right side of the bell-shaped curve, somehow they're coping and they're
dealing with this condition much better than the other 2 groups. Several groups are now
exploring whether it is possible to instill this resiliency into chronic pain patients.
This is a relatively new thing in psychology; psychologists until recently focused on
psychopathology, on anxiety, on depression, on the bad things that happen in psychology.
I've noted several times that the fundamental problem with this spectrum of illness is in
pain processing or sensory processing.
of the things that you should be aware of is that in fibromyalgia, as well as in IBS and
most of the other conditions in this spectrum, it is not just painful stimuli to which
these people are more sensitive. They are more sensitive to auditory loudness, bright
lights, odors, and other sensory stimuli. In fact, accounts for the overlap between
multiple chemical sensitivity (which is a misnomer) and fibromyalgia. Thus, it is
appearing that this is not multiple chemical sensitivity; it is really multiple sensory
sensitivity. People are just sensitive to a lot of different sensory stimuli. Back to
talking about the sensation of pain, there are a number of different ways that people can
theoretically move to the right end of this bell-shaped curve, and have an increased
volume control in pain processing. Some of these mechanisms by which this occur involve
peripheral nerves, whereas others are central mechanisms, involving the brain or spinal
cord. One of the primary problems in fibromyalgia patients appears to be not that there is
too much input coming from the pressure nociceptors or the thermal nociceptors, but rather
that there is inadequate filtering of that activity, perhaps because of decreased activity
of descending antinociceptive pathways.12,13
pathways begin in the brain and brainstem and descend into the dorsal horn of the spinal
cord and are normally responsible for inhibiting the upward transmission of pain. It
appears that these pathways are not working properly in individuals with fibromyalgia. So
a lot of nociceptive information that may be filtered out in normal individuals may not be
filtered out in fibromyalgia patients. In addition to these studies that have used
experimental pain testing to elucidate some of the underlying mechanisms in fibromyalgia,
one of the other tools that you can use to look at pain processing in conditions like
fibromyalgia is functional imaging. Our group, led by Rick Gracely, has performed many
functional imaging studies in fibromyalgia. One of the big advantages of using functional
brain imaging is that, because of animal and then later human studies that have been going
on for the past 3 decades, we now know the regions of the brain that are involved in pain
processing. Thus, we can give people painful stimuli under different conditions and image
the neuronal activation patterns to infer how pain processing is different in fibromyalgia
patients and controls. The areas of the brain that are involved in the sensory dimension
of pain, which is basically where the pain located, and how much it hurts, are the primary
and secondary somatosensory cortex and thalamus.
are other regions of the brain that are more involved in the affective dimension of pain
or the emotional valance of pain, or in how they think about their pain, and these include
regions such as the insula, anterior cingulated, amygdale, and prefrontal cortex. In the
first study that used functional MRI to study pain processing in fibromyalgia, we gave
fibromyalgia patients a 2.5 kg stimulus to their thumb and asked them how much it hurt on
a 0 to 20 visual analog pain scale. We knew that they would experience moderate pain at
the same level of pressure that nonfibromyalgia patients, healthy controls, experienced no
pain. So we put the fibromyalgia patients in the scanner and gave them the low amount of
pressure, which in them led to moderate pain, and then gave a group of healthy controls
the same amount of pressure (which they rated as barely painful), and then the same amount
of pain (by giving them twice as much pressure). The hypothesis was very simple. If we saw
similar neuronal activation patterns in fibromyalgia patients getting the low pressure
(which they felt as moderately painful), and the controls getting the same amount of
pressure (which they barely felt), then that would indicate that fibromyalgia is some type
of a perceptual problem, because although the fibromyalgia patients were having the same
brain activation patterns, they were perceiving it differently. In contrast, we saw that
the fibromyalgia patient's brain activation patterns were very similar with 2.5 kg of
pressure as the controls getting 4.5 kg of pressure. This was the first objective evidence
that there is augmented central pain processing in people with fibromyalgia.14 We
published another functional MRI study a couple of years ago that showed that the level of
depression that a fibromyalgia patient has doesn't at all influence the level of pain in
the sensory areas of the brain.15 That suggests that depression and pain, when they are
present simultaneously, are really somewhat independent constructs. We also have seen
evidence of this in the clinical trials of drugs that are mixed reuptake inhibitors or
tricyclics in that whether someone is depressed or not doesn't predict at all whether
they're going to respond to one of these drugs as an analgesic.16 In contrast, how people
think about their pain might actually influence the sensory processing of pain.
another fMRI study, we showed that fibromyalgia patients that catastrophize actually have
augmented neuronal activation in the secondary somatosensory cortex.17 Dave Williams in
our group is just finishing a NIH-funded study that does functional imaging at baseline in
fibromyalgia patients who have an external locus of pain control and then gives them
several brief interventions to increase their locus of control. We hypothesize that
changing patient's cognitions (in this case locus of pain control) will change the
processing of pain in the brain, even in brain regions thought to be involved in the
sensory processing of pain. Finally, we performed another fMRI study showing that
individuals with chronic idiopathic low back pain (low back pain with normal lumbar MRIs)
were indistinguishable from fibromyalgia patients with respect to their pain sensitivity
at their thumbnail and with respect to their functional MRI findings.18 In aggregate,
these and many other studies in this spectrum of illness suggest that there is
neurobiological evidence of augmented central pain processing, and that in this setting,
individuals can experience pain even without appropriate peripheral nociceptive input.
TREATMENT Now that I have outlined some of the underlying mechanisms in fibromyalgia and
related conditions, I'll finish by discussing treatment. Clinical-based evidence advocates
a multifaceted program emphasizing education, certain medications, exercise, and cognitive
therapy.19 However, the overwhelming majority of fibromyalgia patients are not being
appropriately treated at present. Market surveys suggest that the no. 1 class of drugs
currently used to treat fibromyalgia in the United States is NSAIDs, whereas opioids are
no. 3 or 4, even though there is no evidence that either of these classes of drugs works
in fibromyalgia. Moreover, most fibromyalgia patients are not being adequate education
about their disease, nor are they given access to exercise and cognitive behavioral
therapy programs. So it should not be surprising that these patients are frustrated and
trying to prove that they really have something wrong with them when they come in to see
AND EDUCATION Once a physician rules out other potential disorders, an important and at
times controversial step in the management of fibromyalgia is making the diagnosis.
Despite some assumptions that being labeled with fibromyalgia may adversely affect
patients, a study by White et al. indicated that patients had significant improvement in
health satisfaction and symptoms after being given this label.20 Nonetheless, in certain
selected individuals, i.e., adolescents, or individuals who may use the label as an excuse
for maladaptive illness behavior, I prefer not to use this label but instead recommend the
same type of treatment I would for a fibromyalgia patient. Regardless of the label used or
not used, although the diagnosis of this condition should be coupled with patient
education, an intervention shown to be effective in many randomized controlled trials.
THERAPY The most frequently studied pharmacological therapy for fibromyalgia is low doses
of tricyclic compounds. Most tricyclic antidepressants (TCAs) increase the concentrations
of serotonin and/or norepinephrine by directly blocking their respective reuptake. Despite
tolerability issues, the use of TCAs (particularly amitriptyline and the biologically
similar cyclobenzaprine) to treat the symptoms of pain, poor sleep, and fatigue associated
with fibromyalgia is supported by several randomized, controlled trials.21 The
tolerability of TCAs can be improved by beginning at very low doses (e.g., 5 to 10 mg of
the above compounds), giving the dose a few hours before bedtime, and very slowly
escalating the dose. Because of a better side-effect profile, newer antidepressants, i.e.,
selective serotonin reuptake inhibitors (SSRIs), are frequently used in fibromyalgia. The
SSRIs fluoxetine, citalopram, and paroxetine have each been evaluated in randomized,
placebo controlled trials in fibromyalgia, and in general, the less selective drugs are
effective at high doses. The newer highly selective serotonin reuptake inhibitors, e.g.,
citalopram, seem to be less efficacious than the older SSRIs in both animal and human
studies, perhaps because these latter compounds have noradrenergic activity at higher
doses.22 Because TCAs (and high doses of certain SSRIs such as fluoxetine and sertraline)
that have the most balanced reuptake inhibition are the most effective analgesics, many in
the pain field have concluded that dual receptor inhibitors [serotonin-norepinephrine and
norepinephrine-serotonin reuptake inhibitors (SNRIs and NSRIs)] may be of more benefit
than pure serotonergic drugs. These drugs are pharmacologically similar to some TCAs in
their ability to inhibit the reuptake of both serotonin and norepinephrine, but differ
from TCAs in being generally devoid of significant activity at other receptor systems.
This selectivity results in diminished side effects and enhanced tolerability. The first
available SNRI, venlafaxine, has data to support its use in the management of neuropathic
pain, and retrospective trial data demonstrate that this compound is also effective in the
prophylaxis of migraine and tension headaches. Two studies in fibromyalgia have had
conflicting results, with the one using a higher dose showing efficacy. Two new SNRIs,
milnacipran and duloxetine, have undergone recent multicenter trials.16,23 In the phase II
trial evaluating milnacipran, statistically significant positive differences were noted in
overall improvement, physical functioning, level of fatigue, and degree of reported
physical impairment. In the trial of duloxetine when compared with placebo, participants
treated with duloxetine had decreased self-reported pain and stiffness and a reduced
number of tender points. In the 2 above studies as well as most studies that have used
antidepressants as analgesics, the benefits on pain and other symptoms were independent of
the drug effect on mood, thus suggesting that the analgesic and other positive effects of
this class of drugs in fibromyalgia is not simply because of their antidepressant effects.
Antiepileptic drugs are widely used in the treatment of various chronic pain conditions
including postherpetic neuralgia and painful diabetic neuropathy. Pregabalin is a
?-aminobutyric acid (GABA) analog and approved for the treatment of neuropathic pain. A
recent randomized, double-blinded, placebo-controlled trial demonstrated efficacy of
pregabalin against pain, sleep disturbances, and fatigue in fibromyalgia.24 Similar
results have also been recently noted with gabapentin, a compound with similar
pharmacology to pregabalin. Sedative-hypnotic compounds are widely used by fibromyalgia
patients. A handful of studies have been published on the use of certain nonbenzodiazepine
hypnotics in fibromyalgia, such as zopiclone and zolpidem. These reports have suggested
that these agents can improve the sleep and, perhaps, fatigue of fibromyalgia patients,
though they had no significant effects upon pain. On the other hand, ?-hydroxybutyrate
(also known as sodium oxabate), a precursor of GABA with powerful sedative properties, was
recently shown to be useful in improving fatigue, pain, and sleep architecture in patients
with fibromyalgia.25 Note, however, that this agent is a scheduled substance due to its
abuse potential. Pramipexole is a dopamine agonist indicated for Parkinson disease that
has shown utility in the treatment of periodic leg movement disorder, and a recent study
suggests that this compound may improve both pain and sleep in fibromyalgia patients.26
Tizanidine is a centrally acting a2-adrenergic agonist approved by the FDA for the
treatment of muscle spasticity associated with multiple sclerosis and stroke, and a recent
trial reported significant improvements in several parameters in fibromyalgia, including
sleep, pain, and measures of quality of life.27 There have been no adequate, randomized
controlled clinical trials of opiates in fibromyalgia, and many in the field (including
myself) have not found this class of compounds to be effective in anecdotal experience.
Tramadol is a compound that has some opioid activity (weak mu agonist activity) combined
with serotonin/norepinephrine reuptake inhibition. This compound does appear to be
somewhat efficacious in the management of fibromyalgia, as both an isolated compound and
as fixed-dose combination with acetaminophen.28 Nonsteroidal anti-inflammatory drugs
(NSAIDs) and acetaminophen are used by a large number of fibromyalgia patients. Although
numerous studies have failed to confirm their effectiveness as analgesics in fibromyalgia,
there is limited evidence that patients may experience enhanced analgesia when treated
with combinations of NSAIDs and other agents. This phenomenon may be a result of
concurrent peripheral pain conditions (i.e., osteoarthritis, tendonitis), which may be
present in some individuals, and/or that these comorbid peripheral pain generators might
lead to central sensitization and worsening of central pain.
THERAPIES The 2 best-studied nonpharmacological therapies are cognitive behavioral therapy
and exercise. Both of these therapies have been shown to be efficacious in the treatment
of fibromyalgia, as well as a plethora of other medical conditions.29 Both of these
treatments can lead to sustained (e.g., greater than 1 year) improvements and are very
effective when an individual complies with therapy. Alternative therapies have been
explored by patients managing their own illness, as well as health care providers. As with
other diseases, there are few controlled trials to advocate their general use.
Trigger-point injections, chiropractic manipulation, acupuncture, and myofascial release
therapy are among the more commonly used modalities, which achieve varying levels of
success. Two recent randomized, sham-controlled trial of acupuncture in fibromyalgia
showed no difference between the efficacy in active treatment and sham groups.30,31 There
is some evidence that the use of alternative therapies give patients a greater sense of
control over their illness. In instances where this sense of control is accompanied by an
improved clinical state, the decision to use these therapies is between physicians and
patients themselves. SUMMARY Chronic pain and fatigue syndromes such as fibromyalgia
represent a part of a clinical spectrum of overlapping disorders that afflict a
significant portion of the general proportion. Data suggest that there is a familial
tendency to develop these disorders, and that exposure to physical, emotional, or
environmental stressors' may trigger the initiation of symptoms. Once the illness
develops, the majority of the symptoms are likely mediated by central nervous system
mechanisms. Management strategies are similar to other chronic illnesses, where empathetic
health care providers should develop a partnership with their patients. At one end of the
continuum, there are some individuals with fibromyalgia that respond to a single
medication or a graded, low-impact exercise program. At the other end of the continuum is
the tertiary care patient with high levels of distress who has no sense of control of
their illness, little social support, and has looked toward disability and compensation
systems to try to solve their problem. For this individual, and many in between,
multimodal programs that integrate nonpharmacological (especially exercise, CBT) and
pharmacological therapies are required.
Return to Table of Topics.
Is Fibromyalgia Really a Rheumatologic Diagnosis? A
nature and categorization of fibromyalgia has perplexed researchers for years. Researchers
at the Department of Rheumatology of the National Hospital Rikshospitalet, Oslo, Norway,
published an article this month in Rheumatology International (July 20, 2007) which is the
latest in the controversy over whether or not fibromyalgia can be classified as a
They describe fibromyalgia as "a medically unexplained or functional somatic syndrome
(FSS)" with two classification criteria: chronic widespread pain (CWP) and the
finding of 11 out of 18 tender points (TP). It overlaps, they write, with other functional
somatic syndromes. Ten of these FSS's aside from fibromyalgia also include chronic fatigue
syndrome, myofascial pain syndromes and irritable bowel syndrome. This makes it difficult
to effectively and consistently distinguish fibromyalgia from other syndromes.
The American Academy of Family Physicians defines functional somatic syndromes
(FSS) as "several related syndromes characterized more by symptoms, suffering and
disability than by disease-specific abnormalities of structure or function." It is a
diagnosis given to "patients with disabling, medically unexplained symptoms, many of
whom have already given themselves a diagnostic label for their complaints. These patients
resist information that contradicts attribution of their symptoms to a specific
The researchers go on to dismiss the validity of trigger points and suggest they be
excluded from testing. They write that trigger points "do not reflect demonstrable
pathology, and are locations where everyone is generally more tender. In [fibromyalgia]
they are more tender than normal due to lowered pain threshold. High TP counts are
associated with the extent of distress or unspecific somatic symptoms in the absence of
chronic pain. TP lack validity and should be excluded."
They conclude that chronic widespread pain and distress are "outside the domain of
rheumatology" and that the abnormal mechanisms found in fibromyalgia are related to
the central nervous system, which is not part of the field of rheumatology.
[Fibromyalgia] should not be considered as a rheumatologic condition but rather as part of
a broader spectre of [functional somatic syndromes]. Patients with [functional somatic
syndromes] should be considered and treated together across medical specialities by
general physicians in primary health care.
Return to Table of Topics.
Brain-derived Neurotrophic Factor Elevated in Fibromyalgia Patients
the October 2007 issue of the Journal of Psychiatric Research a study conducted by
researchers at the Department of Psychiatry and Psychotherapy, University of Tuebingen,
Germany, will discuss their research into the levels of brain-derived neurotrophic factor
in fibromyalgia patients and their conclusion that fibromyalgia is not a psychiatric or
psychosomatic disorder. The article, Increased BDNF serum concentration in fibromyalgia
with or without depression or antidepressants, describes the results of the department's
(FM) is still often viewed as a psychosomatic disorder. However, the increased pain
sensitivity to stimuli in FM patients is not an "imagined" histrionic phenomena.
Pain, which is consistently felt in the musculature, is related to specific abnormalities
in the CNS pain matrix. Brain-derived neurotrophic factor (BDNF) is an endogenous protein
involved in neuronal survival and synaptic plasticity of the central and peripheral
nervous system (CNS and PNS). Several lines of evidence converged to indicate that BDNF
also participates in structural and functional plasticity of nociceptive pathways in the
CNS and within the dorsal root ganglia and spinal cord. In the latter, release of BDNF
appears to modulate or even mediate nociceptive sensory inputs and pain hypersensitivity.
We were interested, if BDNF serum concentration may be altered in FM.
pilot study was the first to assess BDNF serum concentrations in fibromyalgia patients.
They studied 41 fibromyalgia patients and 45 age-matched healthy controls. They found that
the mean serum levels of BDNF in fibromyalgia patients were significantly increased as
compared to healthy controls. Fibromyalgia patients had a mean level of 19.6 ng/ml; SD
3.1. Health controls had a mean level of 16.8 ng/ml; SD 2.7; p<0.0001.
The researchers conclude that the study indicates that "BDNF may be involved in the
pathophysiology of pain in [fibromyalgia]. Nevertheless, how BDNF increases susceptibility
to pain is still not known."
Return to Table of Topics.
Sexual dysfunction in female subjects with fibromyalgia
J Urol. 2005 Aug;174(2):620-3. Tikiz C, Muezzinoglu T, Pirildar T, Taskn EO, Frat A,
From the Departments of Physical Medicine and Rehabilitation (CT, AF, CT),
Urology (TM), Internal Medicine (Division of Rheumatology) (TP) and
Psychiatry (EOT), Faculty of Medicine, Celal Bayar University, Manisa, Turkey.
PURPOSE:: We investigated sexual function in females with fibromyalgia (FM)
and evaluate whether coexistent major depression (MD) has an additional
negative effect on sexual function.
MATERIALS AND METHODS:: A total of 100 female subjects were enrolled in the
study, including 40 with FM only, 27 with FM plus MD and 33 healthy
volunteers as a control group. The diagnosis of MD was made according to
Structured Clinical Interview for Diagnostic and Statistical Manual-IV
interview and the Hamilton Depression Rate Scale was used to grade
depression. Widespread pain and quality of life were assessed with the
Lattinen Pain Scale and Fibromyalgia Impact Questionnaire, respectively.
The Female Sexual Function Index (FSFI) was used to assess sexual dysfunction.
RESULTS:: All subjects were comparable in age, occupation and education.
Mean FSFI total score +/- SD was significantly decreased in the FM and FM
plus MD groups compared with that in healthy controls (21.83 +/- 5.84 and
22.43 +/- 7.0 vs 28.10 +/- 6.52, respectively, p = 0.001). However, the
FSFI score was not significantly different between patients with FM only
and FM plus MD (p >0.05). Correlation analysis revealed a negative moderate
correlation between total Lattinen pain score and FSFI score in the FM only
and FM plus MD groups (r = -0.366, p = 0.047 and r = -0.403, p = 0.018,
respectively). FSFI score did not correlate with FIQ and HDRS scores
CONCLUSIONS:: This study demonstrates that female patients with FM have
distinct sexual dysfunction compared with healthy controls and coexistent
MD has no additional negative effect on sexual function. Thus, female
subjects with FM should be evaluated in terms of sexual function to provide
better quality of life.
Return to Table of Topics.
Does psychological vulnerability determine health-care utilization in
Rheumatology (Oxford). 2003 Nov;42(11):1324-31. Epub 2003 Jun 16. Dobkin PL, De Civita M,
Bernatsky S, Kang H, Baron M.
OBJECTIVES: Patients with fibromyalgia (FM) undergo multiple testing and referral to
specialists, and often use complementary/alternative medicine (CAM) services. The
objectives of the study were: (i) to
document health service utilization, and (ii) to examine whether psychological
vulnerability was associated with visits to physicians and CAM providers.
METHODS: Women (N = 178) with a diagnosis of primary FM completed a psychosocial test
measuring pain, perceived stress, global psychological distress, sexual abuse history,
co-morbidity and disability due to FM.
Subjects also completed a health services questionnaire, documenting visits to physicians
and CAM providers during the previous 6 months. Psychological vulnerability was
operationalized as obtaining high scores
on psychological distress, perceived stress and reporting at least one abusive event.
RESULTS: The average number of visits was 7.2 to physicians and 11.3 to CAM providers.
CONCLUSIONS: The number of physician visits was significantly associated with more
co-morbidity. Psychologically vulnerable subjects were more likely to use CAM services
than those not so classified.
Return to Table of Topics.
Person-centered approach to care, teaching, and research in
syndrome: justification from biopsychosocial perspectives in populations.
Semin Arthritis Rheum. 2002 Oct;32(2):71-93. Masi AT, White KP, Pilcher JJ.
Department of Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL
OBJECTIVES: To describe complex interactions of multiple factors believed to contribute to
fibromyalgia syndrome (FMS) at a person-centered level to enhance approaches to care,
teaching, and research. The main factors addressed were central nervous system sensory
sensitization, autonomic nervous system (ANS) activation, neurohumoral perturbations, and
psychosocial and environmental stressors. A person-centered approach is defined as
attention to major biopsychosocial issues of affected individuals.
METHODS: Literature on classification, mechanistic pathways, course and outcomes, and
management of FMS was reviewed to assess applications of person-centered approaches to
care, teaching, and research. Various
biopsychosocial influences were considered in relation to the heterogeneous subjective
manifestations of this illness, including central hyperalgesia, ANS and other neurohumoral
perturbations, functional hyperexcitability, nonrestorative sleep, and psychologic
RESULTS: A person-centered approach to FMS can expand on and strengthen traditional
biomedical concepts. Adding such a focus can help to untangle current controversies in the
course, outcomes, and treatment of
FMS. A person-centered approach can also help in the subgrouping of affected patients for
greater specificity in care programs and in improved clinical investigations. In the
biomedical model, diverse symptoms of FMS are often addressed separately and apart from
their interconnectedness and linkages to the patient's individualized
biopsychosocial factors. However, the causes of FMS symptomatology are not likely to be
caused by uniform biologic abnormalities across populations. Rather, the syndrome likely
results from personal reactivities to varied multifactorial biopsychosocial influences.
Common denominators among individuals may include varying degrees of ANS activation (or
personal susceptibility to ANS activation), nonrestorative sleep, negative affectivity,
and other central pain sensitization mechanisms, among the pathways reviewed.
CONCLUSIONS: Innovative analytical methodologies will need to be developed to more
effectively investigate complex interacting biopsychosocial dynamics at a person-centered
level, including qualitative research, and multifactorial and multilevel techniques.
Adding person-centered approaches to biopsychosocial concepts of FMS
promises to show new physiopathogenetic insights and more effective treatment than current
biomedical models alone. Person-centered approaches enhance patient-physician
relationships and help prioritize patients' goals in mutually derived treatment plans.
Copyright 2002, Elsevier Science (USA)
Return to Table of Topics.
High rates of autoimmune and endocrine disorders,
fatigue syndrome and atopic diseases among women with endometriosis: a
survey analysis. Hum Reprod. 2002 Oct;17(10):2715-24. Sinaii N, Cleary SD, Ballweg ML,
Nieman LK, Stratton P.
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and
Human Development, NIH, 10 Center Drive, Building 10,Room 9D42, MSC 1583, Bethesda, MD
20892-1583, USA. firstname.lastname@example.org
BACKGROUND: Women with endometriosis may also have associated disorders related to
autoimmune dysregulation or pain. This study examined whether the prevalence of
autoimmune, chronic pain and fatigue and atopic disorders is higher in women with
endometriosis than in the general female population.
METHODS AND RESULTS: A cross-sectional survey was conducted in 1998 by the Endometriosis
Association of 3680 USA members with surgically diagnosed endometriosis. Almost all
responders had pain (99%), and many
reported infertility (41%). Compared with published rates in the general USA female
population, women with endometriosis had higher rates of hypothyroidism (9.6 versus 1.5%,
P < 0.0001), fibromyalgia (5.9 versus
3.4%, P < 0.0001), chronic fatigue syndrome (4.6 versus 0.03%, P <0.0001),
rheumatoid arthritis (1.8 versus 1.2%, P = 0.001), systemiclupus erythematosus (0.8 versus
0.04%, P < 0.0001), Sjogren's syndrome
(0.6 versus 0.03%, P < 0.0001) and multiple sclerosis (0.5 versus 0.07%, P <
0.0001), but not hyperthyroidism or diabetes. Allergies and asthma were more common among
women with endometriosis alone (61%, P < 0.001
and 12%, P < 0.001 respectively) and highest in those with fibromyalgia or chronic
fatigue syndrome (88%, P < 0.001 and 25%, P < 0.001 respectively) than in the USA
female population (18%, P < 0.001 and 5%,
P < 0.001 respectively).
CONCLUSIONS: Hypothyroidism, fibromyalgia, chronic fatigue syndrome, autoimmune diseases,
allergies and asthma are all significantly more common in women with endometriosis than in
women in the general USA
Return to Table of Topics.
Peripheral blood mononuclear cell beta-endorphin concentration is
decreased in chronic fatigue syndrome and fibromyalgia but not in
depression: preliminary report. Clin J Pain. 2002 Jul-Aug;18(4):270-3.
Panerai AE, Vecchiet J, Panzeri P, Meroni P, Scarone S, Pizzigallo E, Giamberardino MA,
Department of Pharmacology, Istituto di Ricerca e Cura a Carattere Scientifico, University
of Milan, Italy.
OBJECTIVE: The aim of this study was to examine the possible role of the immune system in
the pathophysiology of chronic fatigue syndrome and fibromyalgia syndrome and in the
differential diagnosis of depression by
investigating changes in peripheral blood mononuclear cell levels of beta-endorphin, an
endogenous opioid known to be involved in regulation of the immune system function.
DESIGN: Beta-endorphin concentrations were measured by radioimmunoassay in peripheral
blood mononuclear cells from healthy controls (n = 8) and patients with chronic fatigue
syndrome (n = 17), fibromyalgia syndrome
(n = 5), or depression (n = 10).
RESULTS: Beta-endorphin concentrations were significantly lower in patients with chronic
fatigue syndrome or fibromyalgia syndrome than in normal subjects and depressed patients
(p <0.001 and p <0.01,
respectively). They were significantly higher in depressed patients than in controls (p
CONCLUSIONS: Evaluation of peripheral blood mononuclear cell beta-endorphin concentrations
could represent a diagnostic tool for chronic fatigue syndrome and fibromyalgia and help
with differential diagnosis of these syndromes versus depression. The results obtained are
also consistent with the hypothesis that the immune system is activated in both chronic
fatigue syndrome and fibromyalgia syndrome.
Return to Table of Topics.
Attentional functioning in fibromyalgia, rheumatoid arthritis, and
musculoskeletal pain patients. Arthritis Rheum. 2002 Dec
Dick B, Eccleston C, Crombez G.
Dalhousie University/IWK Health Centre, Halifax, Nova Scotia, Canada.
OBJECTIVES: To investigate whether chronic pain patients have deficits in attentional
functioning compared with pain-free controls, and whether fibromyalgia patients have
larger deficits in attentional functioning
compared with rheumatoid arthritis and musculoskeletal pain patients.
METHODS: Sixty patients (20 in each of 3 patient groups) and 20 pain-free controls
completed measures assessing pain intensity, mood, pain-related disability, somatic
awareness, and catastrophic thinking
about pain. Attentional functioning was assessed using an age-standardized, ecologically
valid test battery. Analyses were made of between-group differences.
RESULTS: Sixty percent of patients had at least one score in the clinical range of
neuropsychological impairment, independent of demography and mood. Fibromyalgia patients
were more anxious and somatically aware than rheumatoid arthritis or musculoskeletal pain
patients, but did not show larger attentional deficits than other
CONCLUSION: All 3 groups of chronic pain patients, regardless of diagnosis, had impaired
cognitive functioning on an ecologically sensitive neuropsychological test of everyday
Return to Table of Topics.
Fibromyalgia: evolving concepts and management in primary care settings.
Medsurg Nurs. 2003 Jun;12(3):145-59, 190; quiz 160.
Lash AA, Ehrlich-Jones L, McCoy D Northern Illinois University School of Nursing, DeKalb,
During the last 10 years, fibromyalgia (FM) research shifted focus from psychological and
behavioral issues to sleep, nociception, and neuroendocrinology. Although there are still
no definitive markers of the disease, a barrage of studies in physiological,
psychological, and behavioral sciences have now dispelled the belief that FM is solely
in the late 1990s as well as in the early part of the current decade reaffirm earlier
research that sleep abnormalities and alterations in nociception may partly be responsible
While sleep research shows that FM patients typically are deficient in stage IV
(restorative) sleep, most current studies in nociception now affirm that patients with FM
exhibit low serum serotonin in combination with increased substance P levels in the
cerebrospinal fluid. Although there is still no cure, treatment
aimed at promoting sleep, interrupting nociception, and actively involving patient and
family in FM management can bring lifetime control for the disease. PMID: 12861752 [PubMed
- in process]
Return to Table of Topics.
Fibromyalgia syndrome in patients with hepatitis C infection.
Rheumatol Int. 2003 Sep;23(5):248-51. Epub 2003 Mar 18. Kozanoglu E, Canataroglu A, Abayli
B, Colakoglu S, Goncu K. Department of Physical Medicine and Rehabilitation, Cukurova
University Faculty of Medicine, Adana, Turkey, email@example.com
Fibromyalgia syndrome (FS) is characterized by widespread pain and tenderness at specific
anatomic sites. Different theories have been proposed in the etiopathogenesis of this
syndrome, and besides genetic,
neuroendocrine, psychologic, and traumatic causes, infections have also been reported. The
aim of the present study was to evaluate the presence of FS in patients with hepatitis C
virus (HCV) infection.
patients with chronic HCV infection and 95 healthy controls were enrolled in the study.
The 1990 American College of Rheumatology classification criteria were used for the
diagnosis of FS. Tender point
count, pain intensity, sleep disturbance, stiffness, headache, paresthesia, fatigue,
irritable bowel syndrome (IBS), and sicca- and Raynaud-like symptoms were assessed.
Fibromyalgia was found in 18.9% of
patients and 5.3% of healthy controls.
tender point count, pain intensity scored on a visual analog scale (VAS), sleep
stiffness, paresthesia, and fatigue were higher in the HCV group. No significant
relationship was observed between the two groups regarding headache, IBS, and sicca- and
Raynaud-like symptoms. In addition, mean
tender point count and pain intensity scores were also significantly higher in HCV
patients with FS than in control subjects with FS.
of the symptoms except stiffness were not statistically significant between the HCV and
control groups with FS.
results demonstrate a tendency toward higher prevalence of FS in patients with HCV
various extrahepatic features, musculoskeletal disorders including fibromyalgia might be
expected in the progression of HCV infection. Detailed examination of the patients helps
to differentiate FS from
other musculoskeletal complications of HCV infection. This will provide appropriate
management approaches and better quality of life for them.
PMID: 14504918 [PubMed - in process
Return to Table of Topics.
Is fibromyalgia an organic disease?
Issue: April, 2003 (See JAMA, 2003; 289(11): 1385.)
There is still heated debate as to whether fibromyalgia and chronic fatigue syndrome (CFS)
are discrete pathological conditions or simply common human complaints.
Rheumatologist George E. Ehrlich, MD, did not mince words in weighing in with his opinion
in a recent issue of JAMA. "Fibromyalgia and CFS describe sociopathies, chronic pain,
and tiredness in an urban social
context much given to imitative behavior and symptom amplification. The patients truly
have pain, but I believe that its severity and persistence are iatrogenic, promoted by
patient support groups, lawyers,
and their allies in the medical profession," according to Ehrlich. He asserts that
authors from several disciplines "have effectively denied the existence of
fibromyalgia and CFS."
A more moderate view is that these syndromes do exist. It seems beyond dispute that the
central hallmarks of fibromyalgia and CFS--widespread pain and fatigue--are common
symptoms even outside of medical settings.
Population-based studies suggest that substantial numbers of individuals in the community
pass in and out of these symptom states with regularity. Why some individuals develop
intractable symptoms remains a
No one has yet identified a single pathological entity that clearly separates fibromyalgia
and CFS sufferers from their nonafflicted peers. And given that these syndromes have loose
and variable definitions, it
may be unrealistic to expect that a common pathological thread runs through all of
them--anymore than it would be realistic to expect that all nonspecific back pain has a
COPYRIGHT 2003 Lippincott/Williams & Wilkins
Return to Table of Topics.
Oral symptoms associated with fibromyalgia syndrome.
J Rheumatol. 2003 Aug;30(8):1841-5. Rhodus NL, Fricton J, Carlson P, Messner R.Division of
Oral Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Studies have described oral problems associated with fibromyalgia syndrome (FM), including
sicca, oral ulcerations, and orofacial pain. We evaluated the prevalence and profile of
various oral symptoms in a population of patients diagnosed with FM.
METHODS: Subjects diagnosed with FM by American College ofRheumatology criteria (n = 67;
all women, mean age +/- SEM 47.6 +/- 2.3 yrs) were enrolled in the study after meeting
strict exclusion criteria (i.e., oral mucosal conditions, Sjogren's syndrome,
anemia,inflammatory bowel syndrome or other gastrointestinal disturbances,and other
disorders that may manifest oral symptoms). Subjective oral evaluations were carried out
for each subject, including oral pain (Melzack scale) for glossodynia, throbbing, aching,
etc.;temporomandibular joint dysfunction (TMD); xerostomia (including intake of fluids,
functional problems, etc.); dysphagia; dysgeusia;and information about frequent oral
ulcerations or lesions.Psychological tests included Beck Depression Scale (BDS) and
Spielberger Anxiety Scale (SAS) were administered.
RESULTS: The results indicated a significant prevalence in some subjects'
oral symptoms, compared to age and sex matched control data (mean +/-
SEM) for xerostomia 70.9% vs 5.7% (p < 0.001); glossodynia 32.8% vs 1.1% (p <
0.001); TMD 67.6% vs 20% (p < 0.01); dysphagia 37.3% vs 0.4% (p < 0.001); dysgeusia
34.2% vs 1.0% (p < 0.001). Other findings were not significantly different from
controls: oral ulcerations/lesions 5.1% vs 4.4% (NS); BDS 34% vs 30% (NS); SAS
21% vs 19% (NS). The average visual analog scale (100 mm) for
burning pain was 53.0 +/- 5.6 (p < 0.001). Anxiety and depression scores were no
different in the FM subjects compared to controls with chronic pain conditions.
CONCLUSION: These data indicate that patients with FM have significantly increased
prevalence of xerostomia, glossodynia, dysphagia, dysgeusia, and TMD compared to
controls, with no significant difference in clinical oral lesions or psychological status.
Return to Table of Topics.
Fibromyalgia: Treatment Update -- Kim Jones, PhD, RN,
If you are one of the 4 million Americans suffering from the chronic
pain of fibromyalgia, see what researcher and WebMD message board expert Kim Jones, PhD,
RN, FNP, had to say. She joined us to answer your questions and share the latest treatment
information about this debilitating disorder.
to read the transcript of the chat, it is very informative.
Return to Table of Topics.
Antidepressants May Protect Brain from Damage
Fri Aug 1, 5:47 PM ET Add Health - By Karla Gale
NEW YORK (Reuters Health) - Antidepressants may do more than improve the symptoms of
depression. According to a new study, these drugs may actually protect the brain in
individuals who have repeated bouts of major depression.
Previously, investigators have reported that the size of the hippocampus, the brain area
involved in learning and memory, is smaller in people who have experienced depression.
This may be why patients with depression have trouble concentrating and paying attention,
Dr. Yvette I. Sheline told Reuters Health.
Sheline, of the Washington University School of Medicine in St. Louis, and her colleagues
speculated that the length of time a person is treated with antidepressants may affect the
loss of hippocampal volume.
To investigate, the researchers interviewed 38 women with a history of depression. They
used magnetic resonance imaging (MRI) to compare the size of the hippocampus in the
depressed women with those of women who had never been depressed.
On average, the hippocampus was 10% smaller in the depressed subjects.
However, when they looked at the effect of antidepressants, they found that the
hippocampus had not shrunk as much in patients who had been on antidepressants for a
longer period of time.
Some of the subjects had never gone into full remission from their depression, Sheline
told Reuters Health. But even among these subjects, she said, "there does seem to be
a protective effect."
Psychiatrists now recommend that patients who have multiple episodes of depression remain
on antidepressants for the rest of their life, because they are less likely to relapse,
Sheline noted. However, many patients don't
want to take antidepressants or don't want to stay on them long enough. Her group's
findings suggest that, not only do patients feel better when taking the drugs, their
physical brain is actually better off.
A lot of previous research in animals has shown that antidepressants do not harm the brain
or the neurons, but that instead, there is a clear-cut benefit, Sheline noted. Her team's
study now shows the same is true for
Her group now plans to invite the same women back for repeat MRI, in hopes of determining
if the hippocampus shrinks more as time goes by, and if antidepressants "improve the
SOURCE: American Journal of Psychiatry, August 2003.
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Remodeling ideas about stress and the brain
Investigator: Bruce McEwen 22 May 2003 by Tabitha M. Powledge
Stress swells the amygdala, shrinks the hippocampus, and may underlie several psychiatric
disorders, says one researcher, who is trying to trace the neuroendocrine pathways
triggered by this stimulus.
It can be a messy and imprecise concept, but researchers say they are making progress in
sorting out how stress affects body and mind. One of them is Bruce McEwen of The
who has introduced the idea of allostatic load - the price the body pays for mounting
adaptive responses to stress.
There are many systemic mediators of allostasis, notes McEwen, among them the
hypothalamic-pituitary-adrenal axis, the sympathetic and parasympathetic nervous systems,
and cytokines - systems that talk to and regulate each other. Glucocorticoids -
the so-called "stress hormones" - are just the tip of the iceberg; the
neuroactive "excitatory amino acids" and their receptors, for example, play a
major role too, he says.
The hippocampus, central to learning and memory, is full of adrenal steroid receptors, and
is therefore targeted by glucocorticoids. Stress also causes changes in the amygdala, the
seat of potent emotions such as fear. In these two areas, stress remodels the brain, says
McEwen, but has opposite effects. In the hippocampus, neurons get shorter and branch less,
suppresses the production of new neurons in the dentate gyrus. In the amygdala, by
contrast, stress causes neuron hypertrophy. Recently, McEwen and his collaborators have
mechanisms for dendrite remodeling in the hippocampus and amygdala, a process that is
characteristic of prolonged stress. A protease common to both brain areas is
tissue plasminogen activator (tPA), which McEwen says is crucial for remodeling.
In response to mild stress, wild-type mice show increased anxiety. tPA-knockouts, however,
are not anxious, even after three weeks of being confined to a plastic tube for several
a day. This, suggests McEwen, is evidence that without tPA, remodeling does not occur.
However, the precise role of tPA in these brain areas is still a bit of a mystery. The
neuronal remodeling stimulated by tPA does not appear to require plasminogen as a
substrate, says McEwen.
This, he says, indicates the existence of another mediator, although the role this plays
alongside glucocorticoids and excitatory amino acids is still unknown, he says.
These molecular mechanisms in mice are likely to inform how stress affects on the human
brain. In major depression, the amygdala is active, even when depression is in remission.
Researchers also see amygdala enlargement in patients experiencing their first episode of
By contrast, in a recent study of the effects of depression on the hippocampus, there was
shrinkage as well as evidence of abnormalities of memory. Hippocampus volume was decreased
major depression, but no atrophy was apparent during a first episode of depression.
Both hippocampal atrophy and amygdala hyperactivity and hypertrophy are seen in many
psychiatric disorders, notes McEwen, such as bipolar disorder, Cushing's syndrome,
stress disorder, and borderline personality disorder.
"Maybe in order to successfully treat one of these disorders we're going to have to
develop interventions that affect that structural plasticity as well as the more immediate
neurotransmitters that we've been thinking about for decades," he told BioMedNet
"The excitatory amino acid transmitters or glutamate, the major neurotransmitter in
the brain, are extremely important in depression," he said. "We know that in our
animal model, it's the
excitatory amino acids that are involved in causing neurons to shrink and also in
suppressing neurogenesis aided by circulating stress
This, says McEwen, suggests that modification of excitatory amino acid receptors could be
a promising therapeutic option. However, there's a lot of research still to be done.
"There's a lot of
discussion, [but] not a lot of specific drugs yet," he said.
Return to Table of Topics.
The Effects of Sodium Oxybate on Clinical Symptoms and Sleep Patterns in
Patients with Fibromyalgia 08-25-2003
Source: Journal of Rheumatology. 2003;30(5):1070-1074 Scharf MB, Baumann M, Berkowitz DV
Scharf and colleagues report a double-blind, randomized, placebo-controlled cross-over
trial of sodium oxybate in patients with fibromyalgia (FM). They evaluated the effects of
sodium oxybate, a commercial form of gamma-hydroxybutyrate (GHB), on the subjective
symptoms of pain, fatigue, and sleep quality and the objective polysomnographic sleep
variables of alpha intrusion, slow-wave (stage 3/4) sleep, and sleep efficiency in
patients with FM. They studied 24 female patients of which 18 completed the trial. The
patients who dropped out were in the active medication portion of the study, and none of
the side effects were considered serious events (transient episodes of headache, anxiety
attack, or paresthesia). In the intention-to-treat analysis of all patients who entered
the protocol, tender-point index was decreased from baseline by 8.5, compared with an
increase of 0.4 for the placebo (P = .0079) portion of the cross-over trial. Sodium
oxybate was associated with relief of 29% to 33% of 6 of the 7 pain/fatigue scores
(overall pain, pain at rest, pain during movement, end-of-day fatigue, overall fatigue,
and morning fatigue), compared with relief of 6% to 10% with placebo (P < .005).
Slow-wave (stage 3/4) sleep was significantly increased while alpha intrusion, sleep
latency, and rapid eye movement (REM) sleep were significantly decreased compared with
placebo (P < .005). Two of the 5 subjective sleep-related variables were significantly
different from placebo: morning alertness (improved by 18% with sodium oxybate, compared
with 2% for placebo; P = .0033) and quality of sleep (improved by 33% and 10%,
respectively; P = .0003).
The investigators conclude that sodium oxybate effectively reduced the symptoms of pain
and fatigue in patients with FM, dramatically reduced the sleep abnormalities of alpha
intrusion, and decreased slow-wave sleep associated with the characteristic nonrestorative
sleep. This study is important for rheumatologists, because fatigue and fibromyalgia are
common problems in our patients and a new effective class of drugs may improve functional
outcome in FM patients.
FM is associated with alpha intrusion during sleep and low growth hormone secretion.
Moldofsky and coworkers have demonstrated that alpha intrusion on the electroencephalogram
(EEG) is a normal part of wakefulness; however, when it occurs too frequently in sleep, it
is accompanied by daytime complaints of musculoskeletal pain, fatigue, and altered
Although the mechanisms of sleep induction maintenance in normal individuals are poorly
understood, they are even more complex and multifactorial in patients with FM and in
patients with inflammatory processes associated with proinflammatory cytokines such as
tumor necrosis factor. In normal subjects, patients with FM or inflammatory conditions,
and animal models, evidence for an increasingly important role for GHB has been
accumulating.[6,7] GHB is a naturally occurring metabolite of the human nervous system,
with the highest concentration in the hypothalamus and basal ganglia. A commercial form of
GHB has been developed as sodium oxybate. In healthy human volunteers, sodium oxybate has
been shown to promote a normal sequence of non-REM and REM sleep for 2 to 3 hours.
However, it is also important to recognize that
GHB has gained wide recognition in the popular press as a "recreational drug"
used for date rape[8,9] as it is tasteless and creates a sense of amnesia when taken with
Thus, GHB is both a therapeutic agent and a recreational drug. It has sedative,
anxiolytic, and euphoric effects. These effects are believed to be due to GHB-induced
potentiation of cerebral gamma-aminobutyric acid-ergic and dopaminergic activities, and
recent studies suggest the serotonergic system might also be involved. As the
serotonergic system may be involved in the regulation of sleep, mood, and anxiety, the
stimulation of this system may be involved in certain neuropharmacologic events induced by
The biology of GHB may shed light on the important abnormality in sleep and the associated
hypothalamic diurnal variations found in FM.[2,11] The potential importance of the study
by Sharf and coworkers is that no medication has previously been shown to improve the EEG
sleep arousal disorders that include phasic (alpha-delta), tonic alpha non-REM sleep
disorders, or the periodic alpha cycling alternating pattern disorder.
Traditional hypnotic agents, while helpful in initiating and maintaining sleep and
reducing daytime tiredness, do not provide restorative sleep or reduce pain. Tricyclic
drugs, such as amitriptyline and cyclobenzaprine, may provide long-term benefit for
improving sleep but may not have a continuing benefit beyond 1 month for reducing pain.
The basic balance between sleep and wakefulness has been an area of active interest in
neurochemistry in recent years. There have been significant advances in understanding the
molecular biology involved, largely based on studies of patients with narcolepsy and
One emerging area of importance is the neuro-hormone hypocretin
(orexin), whose deficiency (< 40 pg/mL) is highly associated with narcolepsy and
cataplexy (89.5%). In animal models of narcolepsy, the absence of hypothalamic orexin
(hypocretin) neuropeptides leads to inability to maintain wakefulness and intrusion of REM
sleep into wakefulness. Absence of oxyrexen-2 receptor eliminates orexin-evoked
excitation of histaminergic neurons in the hypothalamus, which gate non-REM sleep onset.
In summary, the article by Scharf and colleagues demonstrates that
sodium oxybate improves functional status in fibromyalgia patients. This benefit may
result from a significant reduction in the sleep abnormalities (alpha intrusion and
diminished slow wave sleep) associated with the nonrestorative sleep that is a critical
feature of FM. According to the authors, no other compound has been reported to reduce the
alpha sleep abnormality. Although this abnormality is not specific to FM and its presence
has not been distinguished as a cause or effect in FM, reducing alpha intrusion appears to
correlate with clinical improvement.
1. Roizenblatt S, Moldofsky H, Benedito-Silva AA, Tufik S. Alpha sleep characteristics in
fibromyalgia. Arthritis Rheum. 2001;44:222-230.
2. Moldofsky HK. Disordered sleep in fibromyalgia and related myofascial facial pain
conditions. Dent Clin North Am. 2001;45:701-713.
3. Moldofsky H, Lue FA, Shahal B, Jiang CG, Gorczynski RM. Diurnal sleep/wake-related
immune functions during the menstrual cycle of healthy young women. J Sleep Res.
4. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the
regulation of feeding and wakefulness. Annu Rev Neurosci. 2001;24:429-458.
5. Dickstein JB, Moldofsky H, Hay JB. Brain-blood permeability: TNF-alpha promotes escape
of protein tracer from CSF to blood. Am J Physiol Regul Integr Comp Physiol.
6. Gamma hydroxybutyrate (Xyrem) for narcolepsy. Med Lett Drugs Ther. 2002;44:103-105.
7. Xyrem approved for muscle problems in narcolepsy. FDA Consum. 2002;36:7.
8. Tellier PP. Club drugs: is it all ecstasy? Pediatr Ann. 2002;31:550-556.
9. Smalley S. The perfect crime. Newsweek. February 3, 2003:141:52.
10. Gobaille S, Schleef C, Hechler V, Viry S, Aunis D, Maitre M. Gamma-hydroxybutyrate
increases tryptophan availability and potentiates serotonin turnover in rat brain. Life
11. Scharf MB, Hauck M, Stover R, McDannold M, Berkowitz D. Effect of
gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with
fibromyalgia. Preliminary report. J Rheumatol. 1998;25:1986-1990.
12. Brooks S, Black J. Novel therapies for narcolepsy. Expert Opin Investig Drugs.
13. Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH. Hypocretin (orexin) levels in
cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA
DQB1*0602 status. Sleep. 2002;25:733-736.
14. Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in Orexin
receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep
regulatory processes. Neuron. 2003;38:715-730.
Return to Table of Topics.
The contribution of pain, reported sleep quality, and depressive symptoms to
fatigue in fibromyalgia. By Mark Moran
Poor sleep quality appears to account for the positive relationship between pain and
fatigue in patients with fibromyalgia, suggesting a cyclical pattern of heightened pain
and non-restful sleep.
Researchers at the California School of Psychology, in San Diego, California, United
States, evaluated the predictors of fatigue in patients with fibromyalgia, using
cross-sectional and daily assessment methods.
In a sample of 105 fibromyalgia patients, greater depression and lower sleep quality were
found to be concurrently associated with higher fatigue. But, while pain was correlated
with fatigue, regression analysis revealed that it did not independently contribute to
However, for a subset of patients (n=63) who participated in a week of prospective daily
assessment of their pain, sleep quality, and fatigue, multiple regression analysis
revealed that previous day's pain and sleep quality predicted next day's fatigue.
An analytic model in which between-subject variability was removed and in which pain was
predicted to contribute to lower sleep quality and greater fatigue revealed that poor
sleep quality fully accounted for the positive relationship between pain and fatigue.
This substantiates the role of sleep quality in mediating pain and fatigue, the researches
say. "The findings are indicative of a dysfunctional, cyclical pattern of heightened
pain and non-restful sleep underlying the experience of fatigue in fibromyalgia,"
Pain 2002 Dec;100(3):271-9.
Return to Table of Topics.
Fibromyalgia in men: comparison of clinical features with women.
Yunus MB, Inanici F, Aldag JC, Mangold RF. Department of Medicine, University of Illinois,
College of Medicine at Peoria, 61656, USA. firstname.lastname@example.org
OBJECTIVE: To describe possible differences between male and female patients with
fibromyalgia syndrome (FM) in their clinical manifestations. METHODS: Five hundred
thirty-six consecutive patients with FM (469 women, 67 men) seen in a university
rheumatology clinic and 36 healthy men without significant pain seen in the same clinic
were included in the study. Data on demographic and clinical features were gathered by a
standard protocol. Tender point examination was performed by the same physician. Level of
significance was set at p < or = 0.01. RESULTS: Several features were significantly (p
< or = 0.01) milder or less common among men than women, including number of tender
points (TP), TP score, "hurt all over," fatigue, morning fatigue, and irritable
bowel syndrome (IBS). The total number of symptoms was also fewer among men and approached
significance (p = 0.02) by parametric test, but reached significance (p = 0.001) by
nonparametric analysis. All clinical and psychological symptoms as well as TP were
significantly (p < 0.01) more common or greater in male patients with FM than healthy
male controls, with the exception of IBS (p = 0.03). Patient assessed global severity of
illness, Health Assessment Questionnaire disability score, and pain severity were similar
in both sexes. CONCLUSION: Male patients with FM had fever symptoms and fewer TP, and less
common "hurt all over," fatigue, morning fatigue, and IBS, compared with female
patients. Stepwise logistic regression showed significant differences between men and
women in number of TP (p < 0.001).
Return to Table of Topics.
Relationship between fibromyalgia features and smoking. Scand
J Rheumatol 2002;31(5):301-5
Yunus MB, Arslan S, Aldag JC. Section of Rheumatology, University of Illinois College of
Peoria, IL 61656, USA. email@example.com
OBJECTIVE: The objective of this study was to examine a possible
relationship between smoking and fibromyalgia features among 233 female
patients with fibromyalgia syndrome. METHODS: Data on clinical and
psychological features were collected by a protocol. Smoking status was
evaluated by a question inquiring about the packs of cigarettes smoked
per day. Differences between the smokers and non-smokers were tested by
Mann Whitney U test. To adjust data for age and education, a partial
correlation test was used. A p value of < or = 0.01 was accepted as the
level of significance. RESULTS: Fifty-one patients (21.9%) smoked. After
adjustment for age and education, significantly positive relationship
was found between smoking and pain, patient global severity,
functional disability, and numbness. There was no difference between
smokers and non-smokers for fatigue, morning fatigue, sleep
difficulties, tender points (TP), depression, anxiety and stress.
CONCLUSIONS: Smokers reported significantly more pain, numbness, patient
global severity, and functional difficulties than non-smokers. There was
no significant difference between smokers and non-smokers for fatigue
and TP. PMID: 12455822
Return to Table of Topics.
Fibrositis/fibromyalgia: a form of myofascial trigger points?
Simons DG. Am J Med 1986 Sep 29;81(3A):93-8
The diagnostic criteria for fibrositis and primary fibromyalgia are similar to those for
myofascial pain syndromes due to trigger points. Tender points in muscles are likely to be
myofascial trigger points;
nonmuscular tender points clearly are not myofascial trigger points, but may be areas of
tenderness referred from such trigger points.
Myofascial trigger points refer pain to a distance and restrict range
of motion of
the muscle. They are associated with a palpable taut band that exhibits a local twitch
response of the muscle, and they are responsive to treatment.
Persistence of myofascial trigger points is due to perpetuating factors
that can usually be corrected. Although their number is unknown, it is likely that some
patients who are
diagnosed as having fibrositis/fibromyalgia have multiple myofascial trigger points
aggravated by a powerful perpetuating factor and also have a systemic disease process
independent of the myofascial trigger points.
Since myofascial pain syndromes are treatable, these patients would
benefit greatly by identification and relief of the myofascial component of their pain.
Return to Table of Topics.
USE OF P-31 MAGNETIC RESONANCE SPECTROSCOPY TO
ABNORMALITIES IN MUSCLES OF PATIENTS WITH FIBROMYALGIA.
Jane H. Park, Phomma Phothimat, Carolyn T. Oates, Marta Hernanz-Schulman, Nancy J. Olsen.
A Possible new way to test for FM!
Objective: To investigate the metabolic and functional status of muscles of
fibromyalgia (FM) patients, using P-31 magnetic resonance spectroscopy
(MRS). Methods: Twelve patients with FM and 11 healthy subjects were
studied. Clinical status was assessed by questionnaire. Biochemical status
of muscle was evaluated with P-31 MRS by determining concentrations of
inorganic phosphate (Pi), phosphocreatine (Pcr), ATP, and phosphodiesters
during rest and exercise. Functional status was evaulated from the Pcr/Pi
ratio, phosphorylation potential (PP), and total oxidative capacity (Vmax).
Results: Patients with FM reported greater difficulty in performing
activities of daily living as well as pain, fatigue and weakness compared
with controls. MRS measurements showed that patients had significantly lower
than normal Pcr and ATP levels (P<0.004) and PCR/Pi ratios (P<0.04) in the
quadriceps muscles during rest. Values for PP and Vmax also were
significantly reduced during rest and exercise.
Conclusion: P-31 MRS provides objective evidence for metabolic abnormalities
consistent with weakness and fatigue in patients with FM. Non-invasive P-31
MRS may be useful in assessing clinical status and evaluating the
effectiveness of treatment regimens in FM.
Reference: Arthritis and Rheumatism, Vol. 41, No. 3, March 1998, pp 406-413,
©, American College of Rheumatology.
Return to Table of Topics.
Office management of fibromyalgia.
Rheum Dis Clin North Am 2002 May;28(2):437-46, xi
Goldenberg DL. Division of Rheumatology, Newton-Wellesley Hospital, Department of
Medicine, Tufts University School of Medicine, Newton, MA 02462, USA. firstname.lastname@example.org
The office management of fibromyalgia (FM) is best determined by two variables: (1) the
severity and complexity of each patient's symptoms,and (2) the specialization and interest
of the treating physician.
Because there are 6 to 10 million Americans with FM, most patient
visits will be to the primary
care physician. Rheumatologists, physiatrists, and other musculoskeletal specialists must
work with primary care physicians to foster the early diagnosis and appropriate treatment
Primary care physicians are faced with enormous challenges in caring
for patients with chronic pain disorders like FM. Our managed health care system insists
that patient encounters be brief. Specialty referrals are often discouraged. There is
little if any reimbursement for patient education. FM treatment is
Therefore, optimal planning and use of precious office time and
resources are most important. Rheumatologists should train our primary care colleagues to
recognize FM. Many patients still go months
or years before this common syndrome is diagnosed. Rheumatologists should also spearhead
teaching primary care physicians the basic treatment principles of FM.
If the diagnosis is made early, patients with FM in community practice
do very well with simple management
techniques. As consultants, rheumatologists should confirm the diagnosis of FM and suggest
basic FM management. Some primary care providers or other specialists will be fully
capable of bypassing this consultation, especially if the patient responds to simple
Manpower surveys have not studied the cost-effectiveness of
specialty care in FM. Rheumatologists should also assume the responsibility for the
management of FM patients who have not responded to basic FM management.
Additionally, some rheumatologists may wish to subspecialize in
FM, a major career commitment to this perplexing disorder. These situations constitute
advanced FM management.
Return to Table of Topics.
Fibromyalgia Pain Isn't All in Patients' Heads
Source: University of Michigan
ANN ARBOR, MI - A new brain-scan study confirms scientifically what fibromyalgia patients
have been telling a skeptical medical community for years: They're really in pain.
In fact, the study finds, people with fibromyalgia say they feel severe pain, and have
measurable pain signals in their brains, from a gentle finger squeeze that barely feels
unpleasant to people without the disease. The squeeze's force must be doubled to cause
healthy people to feel the same
level of pain - and their pain signals show up in different brain areas.
The results, published in the current issue of Arthritis & Rheumatism, the journal of
the American College of Rheumatology, may offer the proof of fibromyalgia's physical roots
that many doubtful physicians have sought. It may also open doors for further research on
the still-unknown causes of the disease, which affects more than 2 percent of Americans,
Lead authors Richard Gracely, Ph.D., and Daniel Clauw, M.D., did the study at Georgetown
University Medical Center and the National Institutes of Health, but are now continuing
the work at the University of Michigan Health System. In an editorial in the same issue,
Clauw and U-M rheumatologist Leslie Crofford, M.D., stress the importance of fibromyalgia
To correlate subjective pain sensation with objective views of brain signals, the
researchers used a super-fast form of MRI brain imaging, called functional MRI or fMRI, on
16 fibromyalgia patients and 16 people without the disease. As a result, they say, the
study offers the first objective
method for corroborating what fibromyalgia patients report they feel, and what's going on
in their brains at the precise moment they feel it. And, it gives researchers a road map
of the areas of the brain that are most - and least - active when patients feel pain.
"The fMRI technology gave us a unique opportunity to look at the neurobiology
underlying tenderness, which is a hallmark of fibromyalgia," says Clauw. "These
results, combined with other work done by our group and others, have convinced us that
some pathologic process is making these
patients more sensitive. For some reason, still unknown, there's a neurobiological
amplification of their pain signals."
Further results from the study were presented last year at the ACR annual meeting. The
project will continue later this year at UMHS, joining other fMRI fibromyalgia research
now under way.
For decades, patients and physicians have built a case that fibromyalgia is a specific,
diagnosable chronic disease, characterized by tenderness and stiffness all over the body
as well as fatigue, headaches, gastrointestinal problems and depression. Many patients
with the disease find it interferes with their work, family and personal life. Statistics
show that far more women than men are affected, and that it occurs mostly during the
The ACR released classification criteria for fibromyalgia in 1990, to help doctors
diagnose it and rule out other chronic pain conditions. Clauw and Crofford's editorial
looks at the current state of research, and calls for rheumatologists to take the lead in
fibromyalgia care and science.
But many skeptics have debated the very existence of fibromyalgia as a clearly distinct
disorder, saying it seemed to be rooted more in psychological and social factors than in
physical, biological causes. Their argument has been bolstered by the failure of research
to find a clear
cause, an effective treatment, or a non-subjective way of assessing patients.
While the debate has raged, neuroscientists have begun to use brain scan technology to
identify the areas of the normal human brain that become most active during pain. A few
studies have even assessed the blood flow in those areas in fibromyalgia patients during
baseline brain scans. The new study is the first to use both high-speed scanning and a
In the study, fibromyalgia patients and healthy control subjects had their brains scanned
for more than 10 minutes while a small, piston-controlled device applied precisely
calibrated, rapidly pulsing pressure to the base of their left thumbnail. The pressures
were varied over time, using painful and
non-painful levels that had been set for each patient prior to the scan.
The study's design gave two opportunities to compare patients and controls: the pressure
levels at which the pain rating given by patients and control subjects was the same, and
the rating that the two different types of participants gave when the same level of
pressure was applied.
The researchers found that it only took a mild pressure to produce self-reported feelings
of pain in the fibromyalgia patients, while the control subjects tolerated the same
pressure with little pain.
"In the patients, that same mild pressure also produced measurable brain responses in
areas that process the sensation of pain," says Clauw. "But the same kind of
brain responses weren't seen in control subjects until the pressure on their thumb was
more than doubled."
Though brain activity increased in many of the same areas in both patients and control
subjects, there were striking differences too. Patients feeling pain from mild pressure
had increased activity in 12 areas of their brains, while the control subjects feeling the
same pressure had activation in only
two areas. When the pressure on the control subjects' thumbs was increased, so did their
pain rating and the number of brain areas activated. But only eight of the areas were the
same as those in patients' brains.
In all, the fibromyalgia patients' brains had both some areas that were activated in them
but not in controls, and some areas that stayed "quiet" in them but became
active in the brains of controls feeling the same level of pain. This response suggests
that patients have enhanced response to pain in some brain regions, and a diminished
response in others, Clauw says.
The study was supported in part by the National Fibromyalgia Research Association, the
U.S. Army and the NIH. In addition to Clauw and Gracely, the research team included Frank
Petzke, M.D.; and Julie M. Wolf, BA. For more information on fibromyalgia research at
Return to Table of Topics.
Fluoxetine Effective In Women With Fibromyalgia
The American Journal of Medicine 2002;112(3):191-197 "A randomized,
placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of
women with fibromyalgia" 03/28/2002 09:33:18 AM
By Robert Short
The SSRI fluoxetine is effective and generally well tolerated in women with fibromyalgia.
A randomized, placebo-controlled, double-blind flexible-dose study of
fluoxetine in 60 women with fibromyalgia was carried out by Dr Lesley Arnold and
colleagues. Dr Arnold is based at the Women's Health Research program, Department of
Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio, United States.
The intent-to-treat analysis in women who had received fluoxetine showed significant
improvement in the Fibromyalgia Impact Questionnaire (FIQ) total score, compared with
women who received placebo (difference of -12). The FIQ pain score was also 2.2 points
lower in fluoxetine-treated women compared with the control group. Similarly, the FIQ
fatigue and depression scores were lower in the treated group compared with women who
received placebo. Fluoxetine-treated women also showed significant improvement in the
McGill Pain Questionnaire, relative to the placebo group of women.
The effects of fluoxetine on tender points and myalgic scores were not
so clear-cut. Said Dr Arnold, "Although counts for the number of tender points and
total myalgic scores improved more in the fluoxetine group than in the placebo group,
these differences were not statistically significant."
Dr Arnold concluded, "Fluoxetine was found to be effective on most outcome measures
and generally well tolerated in women with fibromyalgia."
Return to Table of Topics.
SUPPLEMENTAL DEXTROMETHORPHAN IN THE TREATMENT OF FIBROMYALGIA: A DOUBLE
BLIND,PLACEBO CONTROLLED STUDY OF EFFICICACY AND SIDE-EFFECTS.
Sharon R Clark, Robert M Bennett Portland OR November 01, 2000
Dexromethorphan (DM) is a cough suppressant that is also an NMDA receptor antagonist. NMDA
receptor activation is involved in the perpetuation of chronic pain states and
dextromethorphan has been successfully used in the treatment of post herpetic neuralgia
(Nelson, Neurology 48:1212,1997). In the current study we investigated the efficacy of DM
in the treatment of fibromyalgia pain.
Patients and Methods: Forty eight female fibromyalgia patients (age 49.716.1) who were
taking a stable dose of tramadol (~ 200 mg/d) were given an escalating dose of DM (50 mg
to 200 mg/d) at a rate increase of 50 mg every 3 days. They were instructed to stabilize
the dose either when they achieved a worthwhile improvement in pain or if they experienced
Subjects reporting a 25% improvement on a pain VAS were then randomized into a double
blind protocol in which they either continued on the same number of DM capsules or took
and active placebo (PL)(diphenhydramine 2mg / capsule). They were instructed to return in
30 days or when their pain level returned to the pre-study level. The primary outcome
measure was time to drop out.
Results: Forty six patients entered the study, 2 failed to follow-up. Twenty (45%)
experienced a 25% improvement in pain without significant side effects and entered the
double blind phase (DB). Reasons for not proceeding to DB were lack of efficacy
([pound]10) and adverse events ([pound]10). The most common AEs were dizziness, mental
fog, nausea and fatigue.
Eleven subjects entered the DM arm (final dose 173168 mg/d) and 9 the PL arm of the DB
(final dose 156173 mg/d). One subject in the placebo arm (placebo responder) and 6
subjects in the dextromethorphan arm completed the study (Fischer exact test P=0.07). The
6 DM responders reduced their pain VAS by 43% (P<0.001) and had a global improvement of
51%. The 5DM non-responders increased their pain VAS by 4% (P=0.7) and reported a global
worsening of 8%.
Conclusion: Dextromethorphan added to tramadol either does not benefit or is not tolerated
by the majority of FM patients. However some 14% of those starting this study experienced
an impressive improvement in pain and most have continued to use supplemental DM.
Supplemental dextromethorphan may have a therapeutic role in a small subset of
Return to Table of Topics.
Plasma oxytocin levels in female fibromyalgia syndrome patients.
Z Rheumatol 2000 Dec;59(6):373-9 Anderberg UM, Uvnas-Moberg K Department of Neuroscience,
Psychiatry University Hospital, 75185 Uppsala, Sweden. UllaMaria.Anderberg@UASPsyk.uu.se
OBJECTIVES: Fibromyalgia syndrome (FMS) is a chronic pain disorder, where 90% of
the patients struck by the disorder are women. The neuropeptide oxytocin is known to have
antinociceptive and analgesic, as well as anxiolytic and antidepressant effects, which
makes this neuropeptide of interest in fibromyalgia research. The aim of this study was to
assess oxytocin concentrations in female FMS patients with different hormonal status and
in depressed and non depressed patients and relate oxytocin concentrations to adverse
symptoms as pain, stress, depression, anxiety and to the positive item happiness.
METHODS: Thirty-nine patients and 30 controls registered these symptoms daily during 28
days and blood samples for the assessment of oxytocin were drawn twice in all patients and
controls. Besides the daily ratings, depression was also estimated with the self-rating
instrument Beck Depression Inventory (BDI).
RESULTS: Depressed patients according to the BDI differed significantly with low levels of
oxytocin compared to the non-depressed patients and the controls. Low levels of oxytocin
were also seen in high scoring pain, stress and depression patients according to the daily
ratings; however, these subgroups were small. A negative correlation was found between the
scored symptoms depression and anxiety and oxytocin concentration, and a positive
correlation between the item happiness and oxytocin. The oxytocin concentration did not
differ between the hormonally different subgroups of patients or controls.
CONCLUSION: The results suggest that the neuropeptide oxytocin may, together with other
neuropeptides and neurotransmitters, play a role in the integration of the stress axes,
monoaminergic systems and the pain processing peptides in the pathophysiologic mechanisms
responsible for the symptoms in the FMS.
Return to Table of Topics.
Exercise for Patients with Fibromyalgia: Risks versus
Clark SR, Jones KD, Burckhardt CS, Bennett R. 1: Curr Rheumatol Rep
2001 Apr;3(2):135-40 Oregon Health Sciences University, 3181 SW Sam Jackson, L323,
Portland, OR 97201, USA. email@example.com
Although exercise in the form of stretching, strength maintenance, and aerobic
conditioning is generally considered beneficial to patients with fibromyalgia (FM), there
is no reliable evidence to explain why exercise should help alleviate the primary symptom
of FM, namely pain. Study results are varied and do not provide a uniform consensus that
exercise is beneficial or what type, intensity, or duration of exercise is best. Patients
who suffer from exercise-induced pain often do not follow through with recommendations.
Evidence-based prescriptions are usually inadequate because most are based on methods
designed for persons without FM and, therefore, lack individual-ization. A mismatch
between exercise intensity and level of conditioning may trigger a classic neuroendocrine
stress reaction. This review considers the adverse and beneficial effects of exercise. It
also provides a patient guide to exercise that takes into account the risks and benefits
of exercise for persons with FM. PMID: 11286670
Return to Table of Topics.
EMG activity and pain development in fibromyalgia patients
exposed to mental stress of long duration. Scand J Rheumatol
2001;30(2):92-8 Bansevicius D, Westgaard RH, Stiles T.
Norwegian University of Science and Technology, Division of Organization and Work Science,
Trondheim. PMID: 11324796
OBJECTIVE: To examine the distribution of stress-induced upper-body pain in fibromyalgia
patients, and the possible association of pain with electromyographic activity in muscles
near the sites of pain development.
METHODS: Fifteen fibromyalgia patients and 15 pain-free subjects were exposed to low-level
mental strain over a one-hour period. EMG was recorded from frontalis, temporalis,
trapezius, and splenius capitis. Pain in the corresponding locations was recorded before
the test, every 10 minutes during the test, and the 30-minute posttest period.
RESULTS: The fibromyalgia patients developed pain during the test in all the above body
locations. Pain development in all locations associated with trapezius EMG activity, but
not with EMG activity in underlying muscles for forehead, temples, and neck.
CONCLUSION: Stress-induced pain in fibromyalgia patients is not generally caused by muscle
activity. The trapezius EMG response may be part of a general stress response that cause
pain independently of motor activity in muscles.
Return to Table of Topics.
A Reduced Functionality of Gi Proteins as a Possible Cause of Fibromyalgia
NICOLETTA GALEOTTI, CARLA GHELARDINI, MASSIMO ZOPPI, ENRICO DEL BENE, LAURA
RAIMONDI, ELISABETTA BENEFORTI, and ALESSANDRO BARTOLINI
Objective. The etiopathogenesis of fibromyalgia (FM), a syndrome characterized by
widespread pain and hyperalgesia, is still unknown. Since the involvement of Gi
proteins in the modulation of pain perception has been widely established, the aim of the
present study was to determine whether
an altered functionality of the Gi proteins occurred in patients with FM.
Methods. Patients with FM and other painful diseases such as neuropathic pain, rheumatoid
arthritis (RA), and osteoarthritis, used as reference painful pathologies, were
included in the study. The functionality, evaluated as capability to inhibit
forskolin-stimulated adenylyl cyclase
activity, and the level of expression of Gi proteins were investigated in
peripheral blood lymphocytes.
Results. Patients with FM showed a hypofunctionality of the Gi protein system. In
contrast, unaltered Gi protein functionality was observed in patients with
neuropathic pain, RA, and osteoarthritis. Patients with FM also showed basal cAMP
levels higher than controls. The reduced activity of Gi proteins seems to be unrelated to
a reduction of protein levels since
only a slight reduction (about 20-30%) of the Gi3a subunit was observed.
Conclusions: Gi protein hypofunctionality is the first biochemical alteration observed in
FM that could be involved in the pathogenesis of this syndrome. In the complete
absence of laboratory diagnostic tests, the determination of an increase in cAMP
basal levels in lymphocytes, together
with the assessment of a Gi protein hypofunctionality after adenylyl cyclase
stimulation, may lead to the biochemical identification of patients with FM. (J Rheumatol
Return to Table of Topics.
Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of
second pain in normal males but not in normal females or fibromyalgia patients.
Pain 2003 Jan;101(1-2):167-74 Staud R, Robinson ME, Vierck CJ, Price DD. Department of
Medicine, University of Florida, P.O. Box 100221, 32610-0221, Gainesville, FL, USA PMID:
Diffuse noxious inhibitory control (DNIC) is part of a central pain
modulatory system that relies on spinal and supraspinal mechanisms. Previous studies have
shown that fibromyalgia (FMS) patients are lacking DNIC effects on experimental pain,
compared to normal control (NC) subjects.
Because DNIC has a greater effect on second pain than on first pain,
we hypothesized that wind-up (WU) of second pain should be attenuated by a strong
conditioning stimulus. Thus, we compared DNIC's effect on WU in three groups of subjects:
11 NC males, 22 NC females, and 11 FMS females.
To separately assess the contributions of distraction related
mechanisms to inhibition of second pain, we designed the experiment in such a way that
directed the subjects' attention to either the test or conditioning stimulus. Repeated
heat taps to the thenar surface of the right hand were used as test stimuli to generate WU
of second pain. Immersion of the left hand into a hot water bath was the conditioning
As previous experiments have shown, DNIC requires a strong
conditioning stimulus for pain attenuation, which may be at least partly dependent on a
distraction effect. DNIC significantly inhibited thermal WU pain in normal male subjects,
but adding distraction to the DNIC effect did not increase the extent of this inhibition.
In contrast, neither DNIC nor DNIC plus distraction attenuated thermal
WU pain in female NCs. DNIC plus distraction but not DNIC alone produced significant
inhibition of thermal WU pain in female FMS patients.
Our results indicate that DNIC effects on experimental WU of second
pain are gender specific, with women generally lacking this pain-inhibitory mechanism.
Return to Table of Topics.
A study of standard care in fibromyalgia syndrome: a favorable outcome.
J Rheumatol 2003 Jan;30(1):154-9 Fitzcharles MA, Costa DD, Poyhia R. Division of
Rheumatology, Montreal General Hospital, Montreal, Quebec, Canada.
OBJECTIVE: A longitudinal prospective study was undertaken to examine the outcome of
fibromyalgia (FM) with standard medical care, as well as factors that might either predict
or influence this outcome.
Eighty-two women with clinical FM were evaluated at baseline and 70 were
followed for a mean of 40 months. Patients continued their usual management for FM as
prescribed by their own physicians. The primary outcome variable was patient's overall
status compared to baseline on a 7 point Likert scale (range 1 = much worse, 7 = much
outcome measures included measurements for pain, fatigue, and patient and physician global
assessment on a visual analog scale. Additional functional measures were the
disease-specific Fibromyalgia Impact Questionnaire (FIQ), and the generic Health
RESULTS: Of 70 (85%) patients who were followed up at 3 years,33 (47%) reported overall
moderate to marked improvement, and the remaining 53% reported either slight improvement,
no change, or deterioration. The improved group (n = 33) compared to those that remained
the same or worsened (n = 37) showed significant differences for change of score from
baseline for tender point count, patient global assessment, sleep disturbance, fatigue,
pain, FIQ and HAQ, and were
younger, 46 versus 51 years. No other baseline demographic or disease variables
discriminated between the 2 groups. The only baseline predictors for a favorable outcome
were younger age and less sleep disturbance.
CONCLUSION: The overall outcome in this group was favorable, with almost half the sample
reporting clinically meaningful improvement in overall FM status. These findings are
discussed in terms of their implications regarding current theory on the pathogenesis of
Return to Table of Topics.
Detection of Interleukin 1beta (IL-1beta), IL-6, and Tumor Necrosis
Factor-alpha in Skin of Patients with Fibromyalgia.
J Rheumatol 2003 Jan;30(1):146-50 Salemi S, Rethage J, Wollina U, Michel BA, Gay RE, Gay
S, Sprott H. Center of Experimental Rheumatology, Department of Rheumatology and
Institute of Physical Medicine, University Hospital, Zurich, Switzerland and the
Department of Dermatology Allergology, Friedrich-Schiller University, Jena, Germany.
OBJECTIVE: To determine if abnormal collagen metabolism is correlated with neurogenic
inflammation, a potential activator of collagen metabolism, in patients with fibromyalgia
(FM). METHODS: The presence of inflammatory cytokines, interleukin (IL)-1beta, IL-6, and
factor (TNF)-a was investigated in skin tissues by using reverse transcription-polymerase
chain reaction (RT-PCR) and immunohistochemistry. Fifty-three skin biopsies from female
with FM (30-65 years of age) were examined and compared to skin biopsies of 10 age and sex
matched healthy controls. Biopsies were obtained from the left deltoid region. Rheumatoid
arthritis synovial fibroblasts and tissues were used as positive
controls for the expression of
cytokines. Total RNA isolated from the tissue samples were reverse transcribed (RT) by
random hexamers as the primer for RT followed by PCR amplification using specific primers
for IL-1beta, IL-6 or TNF-a. Expression of IL-1beta, and TNF-a protein was investigated in
the skin by immunohistochemistry using specific antibodies (avidin-biotin method).
RESULTS: Positive signals (RT-PCR) were detected in skin tissues of 19/50 (38%) FM
patients for IL-1beta, in 14/51 FM patients (27%) for IL-6, and in 17/53 patients (32%)
for TNF-a. None of the
cytokines could be detected in healthy control skin. Immunoreactivity for IL-1beta
and TNF-a was demonstrated in certain skin tissues of our FM patients.
CONCLUSION: The detection of cytokines in FM skin indicates the presence of inflammatory
foci (neurogenic inflammation) in the skin of certain patients (about 30% of FM patients),
inflammatory component in the induction of pain. This may explain the response to
nonsteroidal antiinflammatory therapy in a subset of FM patients. PMID: 12508404
Return to Table of Topics.
Lesions of rat skeletal muscle following local block of acetylcholinesterase and
neuromuscular stimulation. J Appl Physiol 2003 Feb 7;
Mense S, Simons DG, Hoheisel U, Quenzer B.Department of Anatomy and Cell Biology III,
Heidelberg University, Heidelberg, Germany.
In skeletal muscle, a local increase of acetylcholine (ACh) in a few endplates has been
hypothesized to cause the formation of contraction knots that can be found in myofascial
To test this hypothesis, in rats, small amounts of an acetylcholinesterase inhibitor
(diisopropylfluorophosphate, DFP) were injected into the proximal half of the
and the muscle nerve was electrically stimulated for 30-60 min for induction of muscle
twitches. The distal half of the muscle, served as a control to assess the effects of the
twitches without DFP. Sections of the muscle were evaluated for morphological changes in
relation to the
location of blocked endplates. In comparison to the distal half of the muscle, the
DFP-injected proximal half exhibited significantly higher numbers of abnormally contracted
fibers (local contractures), torn fibers, and longitudinal stripes. DFP-injected
animals in which the
muscle nerve was not stimulated, and which were allowed to survive for 24 h, exhibited the
same lesions but in smaller numbers. The results support the assumption that a
dysfunctional endplate exhibiting increased release of ACh may be the starting point for
contractions which are thought to be essential for the formation of myofascial trigger
Return to Table of Topics.
Fibromyalgia And Myofascial Pain Syndrome Share Nervous Peptidergic
A DGReview of :"Image Analysis Quantification of Substance P Immunoreactivity in the
Trapezius Muscle of Patients with Fibromyalgia and Myofascial Pain Syndrome" y
Peripheral hyperactivity has been found in the peptidergic nervous system of patients with
fibromyalgia or with myofascial pain syndrome.
This supports the notion of pathogenic involvement of the afferent nervous system in the
development and perception of myofascial pain.
A neurotransmitter known as substance P (SP) and stored within the afferent nociceptive
fibres is possibly involved in the pathogenesis of musculoskeletal pain.
Researchers used immunochemistry to investigate SP immunoreactive (SP-ir) in nerve fibres
in the upper trapezius of patients with fibromyalgia (FM) and myofascial pain syndrome
Participants included 27 women subdivided into three categories. Trapezius muscle was
obtained from the tender points of nine women with primary fibromyalgia, from the trigger
points of nine patients with regional myofascial pain and from nine female controls.
The muscle was immunostained with anti-SP sera, and quantitative evaluation was undertaken
by computerised image analysis.
There were no significant differences detected between groups, in the number of SP-ir
areas. Contrastingly, mean optical density of SP-ir exhibited a significant difference
comparing the groups. Mean optical density (OD) of the immunostaining for SP was
statistically higher in the
trapezius muscle of patients with MPS by comparison with specimens from patients with
fibromyalgia and controls.
The mean optical density of immunostaining for SP was also greater in FM specimens than in
The Journal of Rheumatology. 2000 Vol 27 pp 2906-2910. "Image Analysis Quantification
of Substance P Immunoreactivity in the Trapezius Muscle of Patients with Fibromyalgia and
Myofascial Pain Syndrome"
Return to Table of Topics.
Lipid profile in patients with fibromyalgia and myofascial pain syndromes.
Yonsei Med J 2000 Oct;41(5):541-5 Ozgocmen S, Ardicoglu O Department of Physical Medicine
& Rehabilitation, Ankara State Hospital,Turkey. mailto:firstname.lastname@example.org
PMID: 11079612, UI: 20529996
In this study serum lipid profile of patients with fibromyalgia
syndrome (FMS) and myofascial pain syndrome (MPS) were investigated and compared with
Thirty women who had FMS and 32 women who had MPS with the characteristic trigger points
(TrP), especially on the periscapular region were included in this study. Thirty one age
matched healthy women were assigned as a control group. All of the subjects were sedentary
Total cholesterol, triglyceride and high-density lipoprotein
cholesterol (HDL-c) levels were not significantly different between the FMS and control
groups. On the other hand the MPS group had total cholesterol (198.7 vs 172.9 mg/dL,
p=0.003), triglyceride (124.7 vs 87.6 mg/dL, p=0.01), low-density lipoprotein cholesterol
(LDL-c) (127.5 vs 108.4 mg/dL, p=0.02) and very low-density lipoprotein cholesterol
(VLDL-c) (24.9 vs 17.3 mg/dL, p=0.008) levels, which were significantly higher than the
controls. There was no significant difference between the
lipid profiles in the FMS and MPS groups.
Tissue compliance, which was measured from trigger points in the MPS group, correlated
significantly with total cholesterol and LDL-c levels.
In conclusion, a significant difference was found between the lipid levels of patients
with MPS and the controls. More extensive investigation of lipid and lipoprotein levels is
required to determine whether high lipid levels are the cause or result of MPS.
Return to Table of Topics.
Fibromyalgia: The Controversy Continues New disagreements over pain syndrome
By Janice Billingsley
SATURDAY, March 3 (HealthScout) -- Shirley Mynatt's debilitating neck,
shoulder, hip and leg pains were diagnosed five years ago as fibromyalgia. She's grateful
for that, surprisingly. "It was another way of saying, 'Yes, this isn't in your
head,' " says the 56-year-old Kansas City, Mo., grandmother. For years, though, that
was the response to sufferers because doubters dismissed their complaints as little more
"Twenty years ago the perception was that ... [fibromyalgia sufferers'] pain wasn't
real," says Dr. I. Jon Russell, associate professor of medicine at the University of
Texas in San Antonio and co-author of The Fibromyalgia Help Book. "Now we have
biochemical evidence to support their claims of what they feel." Indeed, many doctors
and researchers are encouraged by the attention now being paid to fibromyalgia, a syndrome
that didn't even have a name until 1990 yet afflicts an estimated 3.7 million Americans
older than 18. It also strikes women seven times more often than men, according to a 1998
National Institutes of Health report.
There is no known cause for fibromyalgia, which includes symptoms ranging from chronic and
diffuse pain throughout the body, fatigue and depression. And there is no cure. But the
scientific community has responded to the challenges posed by the syndrome with a growing
body of research. At the recent annual meeting of the American College of Rheumatology,
"90 abstracts were presented on fibromyalgia," says Russell, comparing the
situation to before 1990, when no one believed there was such a thing as fibromyalgia.
"It's quite a change." Role of nervous system studied Much of the new research
has focused on the central nervous system, Russell says, and the biochemical pain
processes of brain and spinal nerves. For instance, in one new study researchers found
that people diagnosed with fibromyalgia had more intense and longer-lasting pain than
people without the syndrome when touched with a hot instrument for a brief moment.
"[Fibromyalgia patients] still had pain after two minutes, compared to 15 seconds
[for those without the disorder] ... a significant difference," says Dr. Roland
Staud, a University of Florida rheumatologist who presented his findings at the annual
Staud says his study suggests that people with fibromyalgia have a lower pain threshold
than people without the disorder, and that the nerve cells responsible for firing in
response to pain -- part of the body's warning system -- stay activated for too long in
However, not everyone is encouraged by the research, including one of the doctors who
spearheaded the identification of fibromyalgia.
Dr. Frederick Wolfe, director of the Arthritis Research Center Foundation in Wichita,
Kan., was among a group of rheumatologists who established in 1990 the criteria for
According to the guidelines approved by the American College of
Rheumatology, fibromyalgia can be diagnosed based on a patient's description of her pain,
and finding the pain in at least 11 of 18 specific pressure points in the body, including
the neck, shoulders, hips and knees. But Wolfe now worries that the research he'd hoped
would result from the naming of the condition hasn't yet focused on finding a cure.
"The breakthroughs are discovering [characteristics of fibromyalgia] rather than the
causes," he says.
'An honest label of what it is' But another doctor who worked with Wolfe on the
fibromyalgia guidelines couldn't disagree more.
"If illness is attached to an honest label of what it is and isn't, people will
respond well," says Dr. Don Goldenberg, a Tufts University rheumatologist who works
extensively with fibromyalgia patients. "Also, we need to tell people what they don't
have, like multiple sclerosis or lupus."
Goldenberg also says that to talk about a cure for fibromyalgia is unrealistic because it
is a chronic illness, like migraine headaches or hypertension.
"We don't cure almost any chronic illness," he says, but rather identify its
contributing factors, whether genetic, physiological, psychological or environmental, and
So, while doctors disagree over the progress of the fight against
fibromyalgia, patients like Mynatt cope as best they can.
Mynatt had been a migraine sufferer all her life but it never
interfered with her work. In 1992, however, after a bad case of the flu, she had to quit
her secretarial job because she began to suffer from fatigue, discomfort and a memory loss
so extensive that she couldn't remember the shorthand symbols she'd used her entire
professional life. She was then diagnosed with chronic fatigue syndrome. In 1995, she
suddenly found herself experiencing a tremendous increase in pain throughout her body and
went to a rheumatologist, who diagnosed fibromyalgia.
"[Fibromyalgia] affects everything. There is no part of my life that it has not
seeped into," she says. Now under a rheumatologist's care, Mynatt takes a muscle
relaxant to ease her shoulder and neck pain and 10 milligrams of an anti-depressant to
help her sleep. She also keeps as active as possible by walking, doing stretching
exercises, and receiving physical therapy and massages.
Dr. Nabih Abdou of Kansas City, Mo., has been treating fibromyalgia
patients for more than a decade and sees approximately a dozen a week. He says about half
the patients he sees, almost all of them women, improve after six months of treatment
similar to the type prescribed for Mynatt. Another 30 percent improve after about two
years, while 15 percent are "very tough -- just really resistant."
He's optimistic about the future of fibromyalgia research -- "The
acceptance and knowledge and information is improving" -- but acknowledges that the
illness is hard on his patients.
"It's not life-threatening but it's a disability, and a tragic
situation for these women," he says.
What To Do To find out more about fibromyalgia, visit the American College of
Rheumatology. Or you can take a look at current clinical trials under way for
fibromyalgia by going to the National
Institutes of Health. SOURCES: Interviews with I. Jon Russell, M.D., Ph.D., associate
professor of medicine, director, University Clinical Research Center, University of Texas,
San Antonio; Roland Staud, M.D., associate professor of medicine, division of rheumatology
and immunology, University of Florida College of Medicine, Gainesville; Frederick Wolfe,
M.D., director, Arthritis Research Center Foundation, Wichita, Kan.; Don Goldenberg, M.D.,
professor of medicine, Tufts University School of Medicine, Boston; Nabih Abdou, M.D.,
Ph.D., professor of medicine, University of Missouri Medical School, Kansas City; Shirley
Mynatt, fibromyalgia patient, Kansas City, Mo.
Return to Table of Topics.
Novel Treatments for Fibromyalgia Syndrome.
SAN DIEGO--(BW HealthWire)--April 2, 2001--Cypress Bioscience, Inc.
(Nasdaq:CYPB - news) and Georgetown University Medical School
('Georgetown') today announced the establishment of a research agreement to
identify and develop novel therapies to treat fibromyalgia syndrome ('FMS').
This relationship is a part of the Company's strategic initiative into the
treatment of FMS, begun in January 2001.
Under the direction of Dr. Daniel
Clauw, Chief of the Division of Rheumatology, the Chronic Pain and FatigueResearch Center
at Georgetown is currently the largest recipient of government-funded FMS and
chronic fatigue research in the U.S., and is world renowned for the study of these
illnesses. The Center brings together expertise in rheumatology, pain assessment,
psychology and psychiatry, and
is dedicated to a multidisciplinary approach to FMS diagnosis and treatment.
'We believe that by working closely with Dr. Clauw's team, we will be uniquely well
positioned in our efforts to identify, develop and market products for the treatment of
FMS. By establishing this relationship with the world-class investigators at Georgetown,
we are taking the first step toward
our goal of becoming the innovator and commercial leader in the field,' said
Jay D. Kranzler, M.D., Ph.D., CEO and Chairman of the Board of Cypress. 'We intend to
establish additional collaborative arrangements to obtain access to specific development
candidates or products.'
'Cypress is one of the first companies that has made a significant commitment
to addressing the needs of patients with FMS,' said Dr. Clauw. 'We are
delighted to be working together to help these patients. The goal of the
alliance is to better understand the nature of this syndrome and to develop
products that will help millions of people who are currently suffering and
have few treatment options available to them.' Dr. Clauw and his group have
received numerous government grants for the study of other disorders
including illnesses associated with Gulf War Syndrome.
FMS is the second most commonly diagnosed rheumatologic disorder after
osteoarthritis, and is estimated to affect 2-4% of the population. The symptoms of FMS are
severely debilitating and are characterized by chronic and widespread pain and stiffness
throughout the body accompanied by severe fatigue, poor sleep and headache. Patients with
FMS have at least comparable disability, more pain, and lower quality of life than
patients with rheumatoid
arthritis (RA) or osteoarthritis.
The American College of Rheumatology diagnostic criteria for FMS include a history
of widespread pain and pain in 11 of 18 tender point sites when pressure is applied.
Treatment options are
limited as there are no drugs specifically approved by the U.S. Food and Drug
Administration for the treatment of FMS.
About Cypress Bioscience, Inc.
Cypress is engaged in the development of novel therapeutic agents for the
treatment of rheumatologic and blood platelet disorders. In addition, to its
FMS program, Cypress is the developer of the PROSORBA® column, an
approved therapeutic medical device which is used for treatment of RA and idiopathic
thrombocytopenic purpura ('ITP'). Fresenius HemoCare, Inc. is solely
responsible for on-going clinical trials, regulatory support, sales and
marketing of the PROSORBA column. Cypress is also developing Cyplex(TM) as a
potential alternative to traditional platelet transfusions, in collaboration
with the Sanquin Blood Supply Foundation, CLB Division, formerly known as
the Dutch Red Cross Blood Transfusion Service. For more information about
Cypress, please visit the company's Web site at www.cypressbio.com.
This press release, as well as Cypress' SEC filings and web site at
http://www.cypressbio.com, contain forward-looking
statements within the
meaning of the Private Securities Litigation Reform Act of 1995. Actual
results could vary materially from those described as a result of a number
of factors, including those set forth in Cypress Annual Report on Form 10-K and
any subsequent SEC filings. In addition, there is the risk that Cypress may
not be able to successfully develop or market any products for the treatment
for FMS; or be successful in establishing collaborative arrangements to
obtain access to specific development candidates or products for FMS; or that
Cypress and the CLB will not be able to successfully develop, improve the
manufacturing of, or receive regulatory clearance for Cyplex on a timely
basis, or at all; or that even if approved, that Cyplex will become a
significant product within the blood products market. Cypress undertakes no
obligation to revise or update these forward-looking statements to reflect
events or circumstances after the date of this press release, except as
required by law. Contact: Cypress Bioscience, Inc. Jay D.
Kranzler, M.D., Ph.D., 858/452-2323 CEO, Chairman of the Board
R. Michael Gendreau, M.D., Ph.D., 858/452-2323
Executive Vice President Manda Hall, 858/452-2323 Investor Relations
Return to Table of Topics.
Prevalence of fibromyalgia, anxiety and depression in chronic hepatitis C virus
infection: relationship to RT-PCR status and mode of
acquisition. Eur J Gastroenterol Hepatol 2001 May;13(5):507-11 Goulding C,
O'Connell P, Murray FE. Department of Gastroenterology and Rheumatology, Beaumont
Hospital,Dublin, Ireland. PMID: 11396529
BACKGROUND: Musculoskeletal complaints, dry eyes, fatigue and anxiety
are common symptoms in patients with hepatitis C virus (HCV) infection, but there are few
controlled data evaluating this.
AIM: To assess the prevalence of rheumatological disease, fatigue and anxiety in different
groups of patients with chronic HCV infection.
PATIENTS AND METHODS: Seventy-seven patients with HCV were evaluated. Of these, 49 (64%)
had been infected via contaminated anti-D immunoglobulin, 25 (33%) were intravenous drug
users (IVDUs), and three were transfusion related; 78% were female. Twenty-five age- and
sex-matched controls were also evaluated. Assessment was performed by history, physical
examination, the Fibromyalgia Impact Questionnaire (FIQ) and the Hospital Anxiety and
Depression Score (HADS).
RESULTS: Four (5%) patients fulfilled the criteria for fibromyalgia. All were infected via
anti-D immunoglobulin, and three were PCR positive. The mean number of tender points in
anti-D patients was 5.0 (+/- 4.07) compared with 2.8 (+/- 2.7) in controls (P= 0.028) and
2.5 (+/- 2.2) in
IVDUs (P< 0.004). There was no significant difference in the number of tender points
between PCR-positive and PCR-negative patients (P= 0.23). Anxiety and depression scores
were significantly higher in anti-D patients (P= 0.0001) and IVDUs (P= 0.005) compared
with controls. Forty per cent of the HCV patients had a positive Schirmer test. Forty-two
per cent of PCR-positive patients had a positive rheumatoid factor (RF, > 1/80).
CONCLUSION: This study reveals a moderate increase in prevalence of
fibromyalgia in HCV patients. The number of tender points was related to mode of
acquisition but not to PCR status. Anxiety and depression levels are also increased in HCV
patients compared with controls. Prevalence of RF was higher in PCR-positive patients
compared with controls and those who had cleared the virus.
Return to Table of Topics.
Visceral Hypersensitivity Is Not a Feature of Fibromyalgia Syndrome
Journal: Journal of Musculoskeletal Pain, Vol. 9(1) 2001, pp. 47-55 Authors: Fabio Pace,
Piercarlo Sarzi-Puttini, Guendalina Manzionna, Paola Molteni, Maurizio Turiel, Benedetta
Panni, Gabriele Bianchi-Porro
Affiliations: Fabio Pace, MD, Guendalina Manzionna, MD, Paola
Molteni, MD, and Gabriele Bianchi-Porro, MD, are affiliated with the
Gastroenterology Unit, University Hospital L. Sacco, v. G. B. Grassi 74, 20157 Milan,
Italy. Piercarlo Sarzi-Puttini, MD, and Benedetta Panni, MD, are affiliated with the
Rheumatology Unit, University Hospital L. Sacco, Milan, Italy. Maurizio Turiel, MD, is
affiliated with the Internal Medicine Division II, University Hospital L. Sacco, Milan,
Italy. Address correspondence to: Dr. Piercarlo Sarzi-Puttini, University Hospital L.
Sacco, Rheumatology Unit, Via G. B. Grassi 74, 20157 Milan, Italy [E-mail address: Sarzi@tiscalinet.it ]. Submitted: August 23, 1999.
Revision accepted: May 9, 2000.
ABSTRACT. Objective: Visceral hyperalgesia is commonly observed in
irritable bowel syndrome [IBS], a common cause of comorbidity with fibromyalgia syndrome
[FMS]. The aim of this study was to evaluate in patients affected by FMS the presence of
IBS-like symptoms and of visceral hyperalgesia.
Methods: Twenty-seven FMS patients were studied and compared with 32
IBS patients for visceral hyperalgesia by the anorectal balloon distension test.
Results: Eighteen [66%] of FMS patients fitted the Rome criteria for
IBS. Patients with IBS presented lower than normal thresholds for the sensation of urgency
and pain [P < 0.05], whereas the sensation of gas present in the rectum and of desire
of defecation were not statistically different from normals. On the contrary, patients
with FMS, either with or without IBS-like symptoms, presented values similar to normals
for all the examined thresholds [P > 0.05].
Conclusions: Our study confirms that IBS symptoms are present in a
relevant proportion of FMS patients, and that the majority of IBS patients present a
condition of visceral hypersensitivity, as induced by a rectal balloon distension test.
Patients with FMS, however, do not present this feature. The reason why FMS patients
frequently have IBS-like symptoms with a normal visceral hypersensitivity remains elusive.
KEYWORDS. Fibromyalgia syndrome, irritable bowel syndrome, visceral
hypersensitivity INTRODUCTION In recent years, it has become increasingly
clear that visceral hyperalgesia (1) is a distinctive feature of the irritable bowel
syndrome [IBS]. Fibromyalgia syndrome [FMS] is a chronic painful musculoskeletal syndrome
(2,3), occurring in up to 2% of the general population, characterized by diffuse pain and
tender points which shares many clinical and epidemiological features with IBS, such as,
for example, the age [peak age of both conditions about 30-40 years], the gender [female
are 80 to 90% of the patients] and associated conditions such as sleep disturbances,
depression, and anxiety (4). The two conditions frequently coexist (5), with IBS described
in 34-50% of cases (6-8); in addition, the presence of IBS is a minor criterion that has
been proposed for the diagnosis of FMS (9). It has therefore been suggested that IBS and
FMS may have a common pathogenetic mechanism (10, 11).
The aim of the present study has been to ascertain whether a condition
of visceral hyperalgesia is present in patients with FMS as it is in IBS patients. For
this purpose we have used the rectal balloon distension test, as previously described by
Prior et al. (12).
[Article copies available for a fee from The Haworth Document Delivery Service:
1-800-342-9678. E-mail address: mailto:email@example.com
Website: http://www.HaworthPress.com ] 2001 by
The Haworth Press, Inc. All rights reserved.
Return to Table of Topics.
Neuroimmunologic aspects of sleep and sleep loss.
Journal: Semin Clin Neuropsychiatry 2001 Oct;6(4):295-307
Authors: Rogers NL, Szuba MP, Staab JP, Evans DL, Dinges DF.
Affiliation: Department of Psychiatry, University of Pennsylvania,
School of Medicine, Philadelphia, PA. NLM Citation: PMID: 11607924
The complex and intimate interactions between the sleep and immune systems have been the
focus of study for several years. Immune factors, particularly the interleukins, regulate
sleep and in turn are altered by sleep and sleep deprivation.
The sleep-wake cycle likewise regulates normal functioning of the immune system. Although
a large number of studies have focused on the relationship between the immune system and
sleep, relatively few studies have examined the effects of sleep deprivation on immune
Studies of sleep deprivation's effects are important for several reasons. First, in the
21(st) century, various societal pressures require humans to work longer and sleep less.
Sleep deprivation is
becoming an occupational hazard in many industries. Second, to garner a greater
understanding of the regulatory effects of sleep on the immune system, one must understand
the consequences of sleep deprivation on the immune system.
Significant detrimental effects on immune functioning can be seen after a few days of
total sleep deprivation or even several days of partial sleep deprivation. Interestingly,
not all of the changes in immune physiology that occur as a result of sleep deprivation
appear to be negative.
Numerous medical disorders involving the immune system are associated with changes in the
sleep-wake physiology-either being caused by sleep dysfunction or being exacerbated by
sleep disruption. These disorders include infectious diseases, fibromyalgia, cancers, and
In this article, we will describe the relationships between sleep physiology and the
immune system, in states of health and disease. Interspersed will be proposals for future
research that may illuminate the clinical relevance of the relationships between sleeping,
sleep loss and immune function in humans. Copyright 2001 by W.B. Saunders Company
Return to Table of Topics.
Concomitant Environmental Chemical Intolerance Modifies the
Neurobehavioral Presentation of Women with Fibromyalgia
Journal: J of Chronic Fatigue Syndrome, Vol. 9(1/2) 2001, pp. 3-19
Authors: Iris R. Bell, MD, PhD; Carol M. Baldwin, RN, PhD, HNC; Erin
Stoltz, BA; Bridget T. Walsh, DO; Gary E. R. Schwartz, PhD
Affiliations: Iris R. Bell is affiliated with the Department of
Psychiatry, Department of Psychology, Family and Community Medicine (the
Program in Integrative Medicine), and the Southern Arizona VA Healthcare
System;Address correspondence to: Dr. Iris R. Bell, Program in Integrative
Medicine, University of Arizona Health Science Center, P.O. Box 245153,
Tucson, AZ 85724-5153 (E-mail: IBELL@U.ARIZONA.EDU).
The study was supported by a grant from the American Fibromyalgia
Syndrome Association, Inc.
These findings were presented in part at the 20th Annual Scientific
Sessions of the Society of Behavioral Medicine, San Diego, CA, March
3-6, 1999. The authors thank Susanne Haugebak, Renee Wolff, Mercedes Fernandez,
PhD, and Elizabeth Hardin for their assistance in collecting and/or
analyzing the data for this project.
ABSTRACT. Background: This study compared personality, dietary, and psychophysiological
characteristics of 3 groups of women: fibromyalgia (FM) with illness from low levels of
environmental chemicals (chemical intolerance, CI), FM alone without CI, and normal
controls. CI may be a
marker for enhanced central nervous system response amplification (sensitization) in
limbic and mesolimbic pathways, which play a role in hedonic responses to food and drugs
and in pain.
Method: Fibromyalgia women with (FM/CI, n = 11) and without CI (FM, n =10) and normals
(NORM, n = 10) participated in the study. Measures included psychological trait
questionnaires, a food frequency questionnaire, a taste test for hedonic and sweetness
ratings of different sucrose concentrations, pain self-ratings, and resting spectral
electroencephalographic alpha over midline sites, averaged over four separate days.
Results: FM with CI had the highest scores on the Harm Avoidance dimension of the
Tridimensional Personality Questionnaire, Carbohydrate Addicts Test, Limbic Symptom
sensory and behavior subscales, and SCL-90-R somatization and obsessiveness subscales. FM
groups both had
the highest mean pain ratings for 21 tender point sites. Groups did not differ for
macronutrient intake or for sweetness and hedonic ratings for sucrose. The combined FM
groups had greater EEG alpha activity towards posterior midline sites than did normals.
Conclusion: The pattern of findings may reflect impaired serotonergic function and/or
elevated dopaminergic receptor activation by endogenous and/or exogenous agents. The data
could have implications for pharmacological and dietary interventions in different subsets
Introduction: Fibromyalgia (FM) is a debilitating medical condition associated with
chronic musculoskeletal pain and extreme fatigue as well as increased rates of comorbid
irritable bowel, migraine headache, and major depression (1,2). FM overlaps other poorly
controversial conditions such as chronic fatigue syndrome (CFS),multiple chemical
sensitivity (MCS), and Persian Gulf War Syndrome in terms of chronic multi-system,
polysymptomatic complaints with few objective abnormalities on routine clinical laboratory
tests (3-5). Women are more vulnerable to FM and related syndromes than are men (l,3).
Some studies have shown that histories of early life abuse may be increased in FM and MCS
A symptom common to many cases of FM and related conditions is chemical intolerance (CI),
i.e., perceived illness such as difficulty concentrating, headache, dizziness, and/or
nausea from low levels of environmental chemicals. Buchwald and Garrity (3) noted that FM
report some degree of CI to four common environmental substances (pollution/exhaust,
cigarette smoke, gas/paint/solvent fumes, perfumes) at high rates, e.g., 46-67%. By
comparison, the approximate prevalence of mild CI is 15-30% and of severe CI, 4-6%, in the
(8). Slotkoff et al. (4) reported that 33/60 (55%) FM patients also met criteria for MCS.
In addition, several investigators have found that many persons with CI report concomitant
difficulties with multiple severe food and drug intolerances, including a high prevalence
of adverse reactions to sugar (i.e., 25-60%) (9-11).
CI may provide a link between dietary patterns and possible physiological mechanisms in FM
and other chronic conditions. Bell et al. (8,12) have previously proposed that CI is a
marker for heightened central nervous system sensitizability and sensitization. Neural
sensitization is the progressive amplification of a given response (e.g., behavioral,
neurochemical, endocrine) by the passage of time between the initial and later, repeated,
intermittent exposures to a given endogenous or exogenous stimulus. Stimuli that can
initiate and/or elicit sensitized responses include substance P analogs, opioids,
cytokines, volatile organic compounds, pesticides, stimulant drugs, and physical or
psychological stress (12,13). Notably, increased spontaneous
ingestion of sucrose is a predictor of subsequent sensitization to stimulant drugs (14).
Stimuli from completely different classes, e.g., stress and endogenous opioids (15) or
formaldehyde and cocaine (16), can cross-sensitize with one another. Sensitization is a
model for a range of clinical problems potentially relevant to FM, such as post-traumatic
stress disorder, recurrent depression,somatization disorder, bulimia, and drug cravings in
addiction (17, 18).
Moreover, in FM per se, Ursin (19) postulated that the chronic hyperalgesia may represent
CNS sensitization to painful stimuli. Experimental models of chronic pain suggest that
limbic nervous system sensitization may be necessary for establishment of the subsequent
hyperalgesia following acute local injury (20). Researchers have found elevated levels of
the peptide hormone substance P (SP) (21) and reduced levels of biogenic amine metabolites
(5-HIAA from serotonin; MHPG from
norepinephrine; HVA from dopamine) in the cerebrospinal fluid (CSF) of FM patients (22).
It is plausible that one or more of these biochemical deviations from normal contributes
to and/or reflects an increased vulnerability to sensitization in FM.
Despite the sugar intolerance histories, persons with CI also often report increased
levels of food cravings, especially for sweet foods (9,10,23). Consequently, we
hypothesized that FM might involve (a) sensitization to endogenous substance P or other
mediators and perhaps
(b) cross-sensitization to exogenous substances, including sweet foods and/or
environmental chemicals, and/or to nonpharmacological stress. If so, the manifestations of
this proposed sensitization might include a higher degree of self-rated pain and greater
sugar cravings in FM than
in normals, especially in the subset of FM with CI.
Furthermore, we have found that increased resting electroencephalographic (EEG) alpha,
especially towards posterior midline, is a replicable marker for CI. Women with CI exhibit
baseline EEG alpha activity than do controls with depression (24) or with sexual abuse
histories but no CI (25). Previous studies suggest that increased EEG alpha in sensitized
animals may reflect enhanced dopaminergic receptor responsivity in the mesolimbic reward
the brain (26). The mesolimbic pathway plays an important role in neurobehavioral
responses to natural reinforcers such as foods and sex, as well as to exogenous addictive
substances such as stimulant drugs (27). Thus, an additional hypothesis for the present
study was that FM
patients, especially the FM with CI, would exhibit such increased resting midline EEG
alpha activity as a reflection of previously established sensitization.
Return to Table of Topics.
Comparison of viral antibodies in 2 groups of patients with fibromyalgia.
Wittrup IH, Jensen B, Bliddal H, Danneskiold-Samsoe B, Wiik A.
Parker Research Institute, Department of Rheumatology, Frederiksberg
University Hospital, Copenhagen, Denmark.J Rheumatol 2001 Mar;28(3):601-3
OBJECTIVE: The etiologies of fibromyalgia (FM) are unknown. In some cases an acute onset
following a flu-like episode is described; in other cases patients report slowly
developing disease. We previously found increased prevalence of enterovirus IgM antibodies
in patients with
acute onset of FM compared to healthy controls. We looked for differences in antimicrobial
IgM antibodies in acute versus nonacute onset FM.
METHODS: Two well defined, comparable groups of patients with FM (acute 19, nonacute 20)
were studied for antibodies in serum to an array of viruses including IgM antibodies.
RESULTS: In most viruses no IgM antibodies were found. However, about 50% of the patients
with acute FM onset had IgM antibodies against enterovirus compared to only 15% of the
slow onset patients.
CONCLUSION: The higher prevalence of IgM antibodies against enterovirus in patients with
acute onset of FM may indicate a difference in the etiology or the immune response in
Return to Table of Topics.
Sleep Disturbance Does Not Correlate With Cognitive Dysfunction in Fibromyalgia.
Jennifer M Glass, Denise C Park, Ania Korszun, Leslie J Crofford Ann Arbor, MI; Cardiff,
Introduction: Sleep disturbance is a common symptom in FM and is often hypothesized as the
cause of other FM symptoms. We previously demonstrated cognitive abnormalities in FM
In this study, we tested the hypothesis that FM patients would exhibit less sleep
efficiency than controls, and that poor sleep efficiency would be related to cognitive
function and other symptoms of FM including
depression, fatigue, anxiety and pain.
Methods: Subject groups included FM patients (n = 23) and age-and
education-matched healthy controls (n =
19). We used a wrist-mounted actigraph, an accelerometer designed to measure activity
(Ambulatory Monitoring, Inc, NY). Subjects marked sleep and wake time using an event
marker button. Data were analyzed using Action-W software. Nighttime and daytime activity
levels were determined. Sleep efficiency was defined as the % time asleep during the sleep
period. Group differences were assessed using ANOVA. Cognitive
function was assessed with a battery to test memory, mental speed,verbal fluency and
vocabulary. FM symptoms were assessed using the McGill Pain Questionnaire, the Beck
Depression Inventory, the Geriatric
Depression Scale, the Mental Health Inventory anxiety subscale, and a fatigue scale
designed to measure fatigue throughout the day.Correlations with cognitive function,
depression, anxiety, fatigue and pain were calculated within each group.
Results: FM patients had higher activity levels during the night
(F(1,40)=8.04, p=.007), lower sleep
efficiency (F(1,40)=3.446, p=.071), and had shorter sleep episodes (F(1,40)=6.97, p=.012)
than controls. Daytime activity and daytime sleep were not different. Among the FM group,
there was a negative correlation
between time spent sleeping in a twenty-four hour period and pain (r=-.719), but no
correlation with cognitive measures, fatigue,depression or anxiety. Among the controls,
measures of quality sleep were positively correlated with vocabulary and pain, and
negatively correlated with fatigue.
Conclusions: As expected, FM patients had less efficient sleep than
controls, possibly related to pain. However, these data suggest that cognitive
abnormalities and fatigue in FM patients cannot be explained by a simple sleep
abnormality. Keywords: Fibromyalgia; Sleep Disorders/Disturbance; Cognition (c) 2001 WebMD
Return to Table of Topics.
Muscle Performance in Fibromyalgia Patients Tested
Your muscles ache with a pain that never seems to end what's worse, they're so
fatigued that even the simplest tasks loom before you larger than life. But is there
really a relationship between muscle strength and pain and fibromyalgia (FM)? Many studies
have been conducted on this level one such study examines muscle performance,
endurance, aerobic performance and isokinetic strength and how they relate to muscle
performance, pain severity, physical activity level, and clinical findings in FM patients.
These results were then compared to those of a healthy control group.
Data on 24 FM patients and 15 healthy control group subjects was
gathered symptoms, location and onset of pain, treatment, and associated symptoms.
Patient's isokinetic muscle strength and aerobic performance were tested. Muscle strength
in FM patients was significantly lower than that of the control group; however, muscle
endurance levels were not measurably different between the two groups. Where the control
group excelled over the FM patients was in aerobic performance. Interestingly, there was
no relation between decreased muscle performance and the FM patient's pain severity,
number of tender points, or duration of their symptoms. Abstract Borman P,
Celiker R, Hascelik Z Hacettepe University Department of Physical Medicine &
Rehabilitation, Ankara, Turkey
The objective of the study was to examine the muscle performance,
isokinetic muscle strength, muscle endurance ratio, and submaximal aerobic performance in
fibromyalgia syndrome (FMS) patients, to evaluate the relation between muscle performance,
pain severity, clinical findings, and physical activity level, and to compare the results
with healthy control subjects. Twenty-four FMS patients and 15 control subjects
participated in this study. Data were obtained about the symptoms, location and onset of
pain, treatment, and associated symptoms. Patients and controls underwent an examination
of isokinetic muscle strength of right quadriceps on a Cybex dynamometer, and submaximal
aerobic performance tests (PWC-170) were done for all subjects. Maximal voluntary muscle
strength of the quadriceps was significantly lower in patients compared with the control
group. Endurance ratios showing the work capacity were not statistically different between
two groups. Submaximal aerobic performance scores were higher in the control group. There
was not a relation between the decreased muscle performance and clinical findings,
including pain severity, number of tender points, and duration of the symptoms of FMS
patients. We found a reduced quadriceps muscle strength and submaximal aerobic performance
in patients with FMS, indicating that patients have impaired muscle function.
Return to Table of Topics.
Neurobiological Alterations That Result From Early Life Trauma
The major neurobiological changes caused by early life trauma involve 3
major systems in the brain: (1) the HPA axis and the CRF
factor), thyrotropin-releasing hormone (TRH), somatostatin, (2) the
hippocampus, and (3) the noradrenergic system.
The HPA Axis and CRF System
New discoveries involving the CRF system have revolutionized our
understanding of the stress response, the effect of early life trauma on the
brain, as well as the neurochemistry of depression. CRF, a 41-amino
acid-containing peptide, is found in hypothalamic and extrahypothalamic
regions of the CNS.( Central Nervous System)
Physiology and Anatomy of the HPA Axis.
The structure of CRF was elucidated
about 20 years ago, and this discovery has significantly contributed to
our understanding of the stress response and regulation of the HPA axis. In
the hypothalamus, CRF(corticotropin-releasing
factor), is secreted from neurons in the paraventricular
nucleus and then transported via the hypothalamo-pituitary portal
circulation to the anterior pituitary, where it stimulates corticotrophs to
secrete adrenocorticotropic hormone (ACTH). ACTH then enters the peripheral
circulation and stimulates the adrenal cortex to secrete glucocorticoids:
cortisol in primates and corticosterone in most rodents. Glucocorticoids, in
turn, exert negative feedback on the anterior pituitary, hypothalamus, and
the hippocampus via glucocorticoid receptors, which normally maintains
cortisol levels within the normal range (Figure 1).
Functions of cortisol.
Cortisol has multiple actions, most notably,
enhancing the physiological response to stress Under various
stressful conditions, including exercise, trauma, anxiety, and depression,
cortisol levels rise leading to a chain of events that ultimately provides
immediate energy to the body and keeps the individual alert via stimulation
of the adrenergic system (the typical fight-or-flight response). However,
when cortisol is chronically hypersecreted, deleterious physiological
sequelae can evolve, such as increased blood pressure, diabetes,
atherosclerosis, immune suppression, bone resorption (osteoporosis), and
The extrahypothalamic CRF system. In addition to its localization to the
hypothalamus, CRF and CRF messenger RNA (mRNA) have been found to be
heterogeneously distributed in the CNS.[25,26] These extrahypothalamic sites
primarily include the cerebral cortex, central nucleus of the amygdala
(CeA), and the brain stem. The CRF neurons project, in turn, to different
brain regions. Of importance, the amygdaloid CRF neurons project to the
paraventricular nucleus of the hypothalamus as well as to various nuclei of
the brain stem. This latter group includes the locus ceruleus, the
parabrachial nucleus, and the raphe nuclei. The locus ceruleus and raphe
nuclei constitute the major sites of origin for NE and serotonin neurons,
respectively, which project to the forebrain.
This widespread distribution of CRF neurons in the CNS led researchers to
revisit the neurobiology of the stress response. In animal studies, direct
injection of CRF into the CNS induces the typical physiologic and behavioral
alterations that closely resemble the stress response.[27,28] These
alterations include activation of the autonomic nervous system, endocrine
changes secondary to elevated cortisol, and behavioral disturbances similar
to depressive and anxiety symptoms (Figure 1). Therefore, in response to
acute stress, CRF seems to mediate endocrine response via the HPA axis;
emotional reactions via the amygdaloid neurons; cognitive and behavioral
responses via the cortical CRF neurons; and autonomic response via the
amygdaloid projections to brain stem nuclei, mainly the locus ceruleus.
Thus, "CRF appears to function not only as a releasing factor, but also as a
neurotransmitter that functions as a primary CNS mediator of the endocrine,
autonomic, immune, and behavioral responses to stress."
Alterations in the CNS-CRF system due to early trauma. Several studies have
confirmed the findings that trauma early in life leads to persistent changes
in the CNS-CRF system, namely a supersensitive state. In rodent studies,
early maternal separation caused significant changes in the CRF system,
which persisted into adulthood.[20,22] These included an increase in the
number of the CRF neurons throughout the CNS and hyperactivity of the HPA
axis both at baseline and in response to stress in adult rat.[20,22]
A landmark clinical study was recently conducted to measure the stress
responses of adult women survivors of childhood abuse with and without
current MD against those of healthy control subjects without such a
history. Upon exposure to a standardized psychosocial laboratory stress,
women with a history of childhood abuse, with and without current MD, had
significantly greater ACTH responses than those who had not suffered
childhood abuse. Furthermore, women with a history of childhood abuse
demonstrated higher and more persistent heart rate responses to the stress
test as compared with control subjects. These findings suggest that women
with childhood physical and/or sexual abuse have a persistently
hypersensitive stress response system.
Abused women with current MD also exhibited increased cortisol levels in
response to stress, as compared with control subjects and abused women
without MD. A positive correlation existed between the ACTH and cortisol
responses to stress, the magnitude of abuse, and the severity of MD.
Significantly, women who were abuse victims, but did not have current MD,
demonstrated increased ACTH responses with normal to decreased cortisol
responses when CRF was intravenously administered. In contrast, women who
were abuse victims, with current MD, exhibited blunted ACTH responses that
were probably due to chronic overexposure of the pituitary to CRF, which
likely leads to downregulation of CRF receptors in the pituitary.
Stress-Related Changes in the Hippocampus
The hippocampus is a component of the limbic system located in the medial
temporal lobe, and is thought to be involved in mood disorders. Dysfunction
of the hippocampus likely underlies some of the vegetative symptoms and
cognitive deficits that are commonly observed in depressed patients.
Neurotoxicity. Early trauma has been postulated to produce neurotoxicity in
the hippocampus leading to neuronal loss. Hippocampal neuronal loss has
been reported in rodents and nonhuman primates reared in deprived conditions
as compared with that in normally reared peers [32-34] Also, direct
administration of glucocorticoids at doses that approximated levels induced
by stress resulted in similar neuronal atrophy in the hippocampus,[33,34]
although other investigators found discrepant results.[35,36] Importantly,
clinical studies have suggested a reduction in hippocampal volume in adults
with history of childhood abuse[37,38] and in those with depression.
More interestingly, early stress not only leads to
glucocorticoid-mediated neurotoxicity but also to decreased neuronal
production, or "decreased" neurogenesis."[40,41] Contrary to previous
thought, neurogenesis is a process that has been found to continue
throughout the lifetime of rodents, nonhuman primates, and perhaps of
humans.[42-44] In mice, for instance, hippocampal neurogenesis continued
into adulthood as a result of an enriched environment, which included
increased contact with other mice and inanimate objects.[45,46]
Changes in the Noradrenergic System
Within the CNS, NE-containing nerve cell bodies are mainly located in the
locus ceruleus of the brain stem. These neurons project widely to the
cortex, subcortical areas, and the spinal cord. As noted earlier, amygdaloid
CRF neurons project to the locus ceruleus; consequently, one would expect
the locus ceruleus to be influenced by alterations in the CRF system, such
as the changes produced by early trauma. Indeed, early trauma appears to
render the NE system hypersensitive. Neonatally deprived adult monkeys
exhibit hyperactivation of the locus ceruleus, which persists for months
after the early adverse event. In addition, administration of
yohimbine -- an alpha2-adrenergic receptor antagonist that which acts
presynaptically to increase NE release -- produced behavioral disturbances
similar to anxiety in adult monkeys with early life trauma, but not in
normally reared monkeys.[48,49] This finding suggests that the locus
ceruleus was hypersensitive to the effects of yohimbine in these neonatally
There are clear connections between the CRF and the locus ceruleus
systems: both become hyperactive after early life trauma. They mutually
activate each other because administration of yohimbine increases CSF CRF
concentrations in humans, compared with naloxone or placebo
Summary: The "Stress-Diathesis Model" of Depression
Early life trauma may result in long-term, if not permanent, hyperactivity
of the CNS CRF and NE systems with consequent detrimental neurotoxic effects
on the hippocampus that lead to decreased hippocampal volume. These changes
represent sensitization of the CRF circuits to even mild stress in
adulthood, leading to an exaggerated stress response. Upon exposure to
persistent or repetitive stress in adulthood, these already-sensitive stress
pathways become markedly hyperactive leading to a persistent increase in CRF
and cortisol secretion, which causes alterations in the glucocorticoid
receptors and thus forms the basis for the development of mood and anxiety
The strong evidence of the interaction between life experience and
disposition in the generation of MD ( Major Depression) led researchers to
"stress-diathesis model" of mood disorders.[8,51] In this model,
Nemeroff explained that in some individuals, depression might result
from interplay between "vulnerability genes," "resistance genes," and
adverse life events. However, he acknowledged the limitations of this model
in explaining all cases of depression. Not all depressed patients report
early life trauma. Also, not all depressed patients exhibit genetic
predisposition, but this may be difficult to assess.
Return to Table of Topics.
Effective Treatment of Chronic Fatigue Syndrome and Fibromyalgia
02-19-2003 By Kent Holtorf, M.D.
Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are illnesses that often coexist and
affect millions of Americans. Symptoms vary amongst individuals and commonly include
severe fatigue, sleep disturbances, cognitive problems (commonly called brain
fog), muscle pain and multiple infections. Unfortunately, many individuals and
physicians continue to deny that these syndromes are legitimate diseases.
The medical literature is, however, very clear that these are legitimate diseases and
individuals with these syndromes have measurable hypothalamic, pituitary, immune and
coagulation dysfunction. These abnormalities then result in a cascade of further
abnormalities, in which stress plays a role.
The pituitary and hypothalamic dysfunction results in multiple hormonal deficiencies that
are often not detected with standard blood tests, and autonomic dysfunction, including
neurally mediated hypotension.
The immune dysfunction, which includes natural killer cell dysfunction, results in
opportunistic infections and yeast overgrowth, making the symptoms worse. Recent studies
have shown that the coagulation dysfunction is usually initiated by a viral infection and
has genetic predisposition. This abnormal coagulation results in increased blood viscosity
(slugging) and a deposition of soluble fibrin monomers along the capillary
wall. This results in tissue and cellular hypoxia, resulting in fatigue, and decreased
cognition (brain fog). Neurotransmitter abnormalities and macro and micro nutrient
deficiencies have also been shown to occur with these disorders.
Gulf War Syndrome, which is almost identical to CFS and FM, was found to have a parallel
cause. The cause was determined to be from multiple vaccinations under stressful
conditions in susceptible individuals. These vaccines, which are viral mimics, resulted in
the same coagulation cascade and the deposition of fibrin monomers, resulting in the same
tissue hypoxia that occurs in FM and CFS. As a result, these multiple injections are being
discontinued by the armed forces.
Current research suggests that many triggers can initiate a cascade of events, causing the
hypothalamic, pituitary, immune and coagulation dysfunction. The most common initiating
cause is a viral infection, which is very commonly Epstein-Barr Virus, Cytomegalovirus or
HHV6. These are found in 80% of CFS and FM patients. Many people with these syndromes can
pinpoint the onset of the disease(s) to a viral infection that never got better. Also,
stress seems to be a contributing factor. Effective treatment, with 80 to 90 percent of
individuals achieving significant clinical benefits, can be achieved by simultaneously
treating the above problems that an individual is found to have.
The mix of treatments needed varies from patient to patient. There are some abnormalities
that are common. For instance, close to 100% of individuals with these syndromes have low
thyroid. This is, however, usually not picked up on the standard blood tests because the
TSH is not elevated in these individuals due to pituitary dysfunction. Many of these
individuals will also have high levels of the anti-thyroid reverse T3, which is usually
not measured on standard blood tests. In addition, the majority of individuals can also
have a thyroid receptor resistance that is not detected on the blood tests. Consequently,
thyroid treatment, especially with timed release T3, is effective for many patients. T4
preparations (inactive thyroid) such as Synthroid and Levoxyl do not work well for these
Adrenal insufficiency and growth hormone deficiency are also very common with these
disorders, and supplementation with these hormones can often have profound effects. As
with thyroid testing, these deficiencies are, unfortunately, usually not detected with the
standard screen blood tests and require more specific testing.
When an individual is found to have one of the viruses discussed above, these can be
treated with resulting improvement in symptoms. There are a number of drugs, including
anti-viral medication, that are currently undergoing phase III clinical trials at clinics,
including ours [Hormone and Longevity Medical Center], for FDA approval in the treatment
of FM and CFS.
Although a concept that is sometimes uncomfortable and foreign to traditional medical
styles of thinking, the need for multiple interventions is effective when an illness
affects a critical control center (such as the hypothalamus), which impacts the multiple
systems noted above. Unfortunately, there is not a single treatment that reverses
hypothalamic dysfunction directly. Thus, this situation is different from illnesses that
affect a single target organ and which can be treated with a single intervention.
For example, pituitary dysfunction itself often requires treatment with several hormones.
This effect is multiplied in hypothalamic dysfunction, which affects several critical
systems in addition to the pituitary gland. An integrated treatment approach based on
simultaneously treating the above problems is significantly beneficial in CFS and FMS.
Individuals with these devastating syndromes can get their lives back despite
the fact that they were previously told, There is nothing that can be done, or
It is all in your head. Kent Holtorf, M.D. Hormone and Longevity Medical
Return to Table of Topics.
Childhood adversities in patients with fibromyalgia and somatoform pain
Eur J Pain. 2003;7(2):113-9. Imbierowicz K, Egle UT. Department of Psychotherapy and
Psychosomatics, University Hospital Bonn, Bonn, Germany.
Primary fibromyalgia is regarded as disorder with a complex symptomatology, and no
morphological alterations. Findings increasingly point to a dysfunction of the central
processing. The study aims to discuss vulnerability for fibromyalgia from a developmental
We investigated the presence of psychosocial adversities affecting the childhood of
adult fibromyalgia patients (FM) and compared them to those of patients with somatoform
(SOM) and a control group (CG) with medically explained chronic pain. Using the structured
biographical interview for pain patients (SBI-P), 38 FM patients, 71 SOM patients, and 44
patients were compared on the basis of 14 childhood adversities verified as relevant
regarding longterm effects for adult health by prospective studies.
The FM patients show the highest score of childhood adversities. In addition to
sexual and physical
maltreatment, the FM patients more frequently reported a poor emotional relationship with
both parents, a lack of physical affection, experiences of the parents' physical quarrels,
as well as alcohol
or other problems of addiction in the mother, separation, and a poor financial situation
before the age of 7.
These experiences were found to a similar extent in the SOM patients, but
distinctly less frequently in the CG. The results point to early psychosocial adversities
as holding a similar etiological meaning in fibromyalgia as well as in somatoform pain
potential role of these factors as increasing the vulnerability for fibromyalgia is
Return to Table of Topics.
"Free radicals and antioxidants in primary
fibromyalgia: an oxidative stress disorder?"
Rheumatology International 01/07/2004 By Mary Beth Nierengarten
Fibromyalgia may be an oxidative disorder as indicated by the increased levels of
malondialdehyde (MDA) and decreased levels of superoxide dismutase (SOD) in patients with
this disease, reports a study from Turkey.
Although the aetiology of fibromyalgia remains unknown, recent data suggest that the
oxidant/antioxidant balance may play a role in its development.
Based on the hypothesis that a balance discordance in the oxidant/antioxidant status may
indicate that fibromyalgia is an oxidative disorder, Selda Bagis, MD, Mersin University
Medical School, and colleagues
compared the oxidant/antioxidant status of 85 women with primary fibromyalgia to that of
80 healthy, age-, weight-, and height-matched women. Along with evaluation of sex hormone
profiles and routine blood,
sedimentation, thyroid, C-reactive, liver, and kidney function tests, body mass index
(BMI), smoking, and duration of disease were also documented for all patients. Pain was
evaluated using the visual analog scale (VAS) and the presence and number of tender points
were recorded. Assessment of the
oxidant/antioxidant status was based on measuring MDA, which is a marker of free radical
damage, and SOD, which shows antioxidant capacity.
In patients with fibromyalgia, MDA levels were significantly higher (P =.000) and SOD
levels significantly lower (P = .000) than in the control patients. Number of tender
points and VAS were not significantly associated
with MDA or SOD (P > .05), and no correlation was found between BMI, age, duration of
disease and MDA or SOD (P > .05).
These data suggest, claim the authors, that the "oxidant/antioxidant imbalance
related to the disease process, and the increase in free radical levels may be responsible
for the development of fibromyalgia."
The authors conclude that these data support their hypothesis that fibromyalgia is an
oxidative disorder, and that additional larger studies are needed for validation.
Rheumatol Int 2003 Dec 20;[Epub ahead of print]. "Free radicals and antioxidants in
primary fibromyalgia: an oxidative stress disorder?"
Source: Doctor's Guide (DG) online. (C) Doctor's Guide, online at
Return to Table of Topics.
Treating Fibromyalgia with Testosterone
01-14-2004 Source: The Chronicle of Higher Education, December
12, 2003. Report on fibromyalgia research taking place at Dartmouth College.
What it is: A way to treat the muscle pain, chronic fatigue, and other symptoms of
fibromyalgia syndrome using hormones administered through a gel.
The market: Fibromyalgia, a musculoskeletal pain disorder, affects three million to six
million people in the United States, 95 percent of whom are women. There is no known
[single] treatment for the disease, the cause of which is unknown.
The spark: For Hillary D. White, it was all very personal. An associate professor of
microbiology and immunology at Dartmouth Medical School, Dr. White was dealing with the
stress of applying for a big federal grant when
she began to realize how much her back and legs were hurting, and how tired she was
She soon recognized that her symptoms were those of fibromyalgia. Because of her interest
in reproductive immunology, she knew that hormones like estrogen and testosterone are
thought to limit pain. She also knew that male hormones are anabolic - "they build
Then one day she let her mind wander. The symptoms of fibromyalgia, she realized were
"eerily similar" to those for low testosterone: chronic fatigue, sleeplessness,
and muscle wasting. "I was lying down at home
feeling pain all over and feeling miserable," she says, when a simple thought popped
into her head. "Maybe this is a problem with testosterone."
Developing the invention: A blood test gave strength to her theory. While most healthy
women have low levels of testosterone, Dr. White's were extremely low.
"Undetectable," she says.
Under treatment from a fellow Dartmouth physician, she began investigating testosterone.
The results "were immediate and enormous," she says. Soon after, she applied for
Invention's status: Dartmouth received a patent on Dr. White's idea in August 1999, just
five months after applying for it. The university licensed the invention to a New
Hampshire company, Bentley Pharmaceuticals, in
Dartmouth chose Bentley because the company had already developed a technique for
administering testosterone through the skin by use of a gel, but the company hadn't firmly
settled on the kinds of ailments it hoped to treat. "We had the symptoms; they had
the product," says Dr. White.
Bentley subsequently helped pay for a 12-patient clinical trial to test the testosterone
gel for treating fibromyalgia, with some additional financial support coming from a state
program designed to help promote the development of local companies.
The company is now planning a larger follow-up trial. Bentley and Dartmouth have also
jointly applied for a patent specifically on the use of the gel form of testosterone to
Because the product is not yet on the market, Bentley is not paying royalties to
Dartmouth, but the company has made some initial "milestone" payments as it
moves to develop the product.
Meanwhile, Dr. White continues her research. She suspects that other hormones might work
as well or better in treating fibromyalgia. "I don't think testosterone is the entire
-Goldie Blumenstyk. The website of the Dartmouth Medical School is http://www.dartmouth.edu/dms/index.shtml.
Return to Table of Topics.
Fibromyalgia Takes Different Tolls on Different People
Doctors discover three distinct patient clusters, a finding that could help tailor
treatment for the chronic disorder. By Kathleen Doheny
Fibromyalgia patients, who suffer pain in the muscles, joints,
ligaments and tendons, are not all the same and can be classified into three distinct
subgroups, a recent study suggests.
Researchers from the University of Michigan and other institutions are
hopeful the discovery, published in October's  issue of Arthritis & Rheumatism,
will help to better tailor treatment for the chronic disorder.
"Fibromyalgia patients are such a diverse group of patients, they
cannot all be the same," says study co-author Dr. Thorsten Giesecke, a University of
Michigan research fellow.
For reasons unknown, people with fibromyalgia have increased
sensitivity to pain that occurs in areas called their "tender points." Common
ones are the front of the knees, the elbows, the hip joints, the neck and spine. People
may also experience sleep disturbances, morning stiffness, irritable bowel syndrome,
anxiety and other symptoms.
Fibromyalgia affects an estimated 3 million to 6 million Americans,
primarily women of childbearing age, according to the American College of Rheumatology.
Giesecke and his fellow researchers evaluated 97 fibromyalgia
patients, including 85 women and 12 men. The patients underwent a two-day series of tests,
answering questions about their coping strategies and personality traits -- particularly
their emotional well-being. They were also tested for sensitivity to pressure and pain.
After the evaluations, the researchers found the patients fell into
three subgroups that refute conventional wisdom. "It's generally been thought that
fibromyalgia patients who have higher distress have higher pain sensitivities,"
In other words, it was believed that those with fibromyalgia who were
prone to emotional difficulties such as depression and anxiety were more likely to
experience greater physical pain. But in his study, that didn't bear out.
The first subgroup, with 50 patients, included those who had moderate
levels of anxiety and depression. They also felt they had moderate control over their
pain, and they experienced moderate to low levels of pain.
The second group, with 31 patients, had high levels of anxiety and
depression. They felt they had the least control over their pain, and they suffered high
levels of tenderness.
But the third group, with 16 patients, reported the lowest levels of
anxiety and depression and the highest control over their pain. Yet the testing showed
they experienced the highest levels of physical pain.
Some patients have extreme pain but no psychological problems,
Giesecke says, while others have moderate pain tenderness but fairly positive moods.
Giesecke says a more positive frame of mind may help reduce the levels of pain that
"Just because they do well in cognitive and psychological tests
doesn't mean they don't have increased pain sensitivity," he says. The findings, he
says, may persuade some skeptics that fibromyalgia is a real disease and not "all in
one's head." The findings may also help tailor treatments, he says.
For instance, antidepressants might not work well on group three,
whose members were not depressed. They might benefit from exercise therapy instead,
Giesecke says. About 4 percent of the U.S. population has the condition, Giesecke says.
Bruce Naliboff, a professor of medical psychology at the UCLA David
Geffen School of Medicine and on staff at the VA Greater Los Angeles Healthcare System,
calls the new research "a very good study." "To better understand
fibromyalgia and to have better treatment, it's important to find out, is it a homogeneous
group?" he says.
Clearly, Giesecke found it is not, Naliboff adds. Some patients who
have extreme tenderness don't have many emotional issues, which was not expected.
"It's easy to say it's all in their head," says Naliboff,
who works with patients who have other conditions with psychological components, such as
inflammatory bowel disease. The study will help prove that's not so, he adds. Source:
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Links To More Articles.
sleep characteristics in fibromyalgia. Arthritis Rheum. 2001 Jan;44(1):222-30.PMID:
predictors exist for the therapeutic effect of 5-HT3 receptor antagonists in fibromyalgia?
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state of medication therapy in fibromyalgia syndrome. Scand J Rheumatol Suppl
therapy in the treatment of fibromyalgia. Scand J Rheumatol Suppl 2000;113:78-85.
Cabergoline May Be Effective In Reducing Symptoms Of Restless Legs Syndrome
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