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Latest Update: May 16, 2009

Articles

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 seriously," Novel Treatments for Fibromyalgia Syndrome.
Yes,Virginia, there is Fibromyalgia. Suzi Prokell, Targeted Gene Therapy Provides Relief For Chronic Pain
The Fibromyalgia Spectrum - Understanding Fibromyalgia Fibromyalgia Pain Is Real
Fibromyalgia is not an imagined illness! Is Fibromyalgia Really a Rheumatologic Diagnosis?
Improving Sleep Quality - Fibromyalgia or Chronic Fatigue Neurobiology of fibromyalgia syndrome
Treating Fibromyalgia with Testosterone Fibromyalgia Takes Different Tolls on Different People
Is fibromyalgia an organic disease? Fibromyalgia: an oxidative stress disorder?
Fibromyalgia: Treatment Update -- Kim Jones, PhD, RN, FNP Fibromyalgia syndrome in patients with hepatitis C infection.
Remodeling ideas about stress and the brain Exercise for Patients with Fibromyalgia: Risks versus Benefits.
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 Fibromyalgia The contribution of pain, reported sleep quality, and depressive symptoms to fatigue in fibromyalgia.
Neurobiological Alterations That Result From Early Life Trauma Update on Mechanisms and Management Clauw, Daniel J. MD


Studies and Trials

Treatment of Fibromyalgia Syndrome With Antidepressants Muscle Performance in Fibromyalgia Patients Tested
Comparison of viral antibodies in 2 groups of patients with fibromyalgia. Prevalence of fibromyalgia, anxiety and depression in chronic hepatitis C virus infection:
Childhood adversities in patients with fibromyalgia and somatoform pain disorder Attentional functioning in fibromyalgia, and musculoskeletal pain
Sexual dysfunction in female subjects with fibromyalgia Fibromyalgia in men: comparison of clinical features with women.
The Effects of Sodium Oxybate on Clinical Symptoms and Sleep Patterns in Patients with Fibromyalgia High rates of autoimmune and endocrine disorders, FM, CFS among women with endometriosis
Peripheral blood mononuclear cell beta-endorphin concentration is decreased in CFS,FM but not in depression Fluoxetine Effective In Women With Fibromyalgia
Plasma oxytocin levels in female fibromyalgia syndrome patients. EMG activity and pain development in fibromyalgia patients exposed to mental stress of long duration.
Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. A study of standard care in fibromyalgia syndrome: a favorable outcome.
Fibrositis/fibromyalgia: a form of myofascial trigger points? Fibromyalgia And Myofascial Pain Syndrome Share Nervous Peptidergic Hyperactivity
Oral symptoms associated with fibromyalgia syndrome Relationship between fibromyalgia features and smoking.
Person-centered approach to care, teaching, and research in fibromyalgia syndrome Does psychological vulnerability determine health-care utilization in fibromyalgia?
Use of P-31Magnetic Resonance Spectroscopy to Detect Metabolic Abnormalities in Muscles. Supplemental Dextromethorphan in the Treatment of FM
A Reduced Functionality of Gi Proteins as a Possible Cause of Fibromyalgia Detection of Interleukin 1beta (IL-1beta), IL-6, and Tumor Necrosis Factor-alpha in Skin of Fm'ers.
Lesions of rat skeletal muscle following local block of acetylcholinesterase and neuromuscular stimulation. Lipid profile in patients with fibromyalgia and myofascial pain syndromes.
Visceral Hypersensitivity Is Not a Feature of Fibromyalgia Syndrome Concomitant Environmental Chemical Intolerance Modifies the Neurobehavioral Presentation of Women withFM
Sleep Disturbance Does Not Correlate With Cognitive Dysfunction in Fibromyalgia.  



Links to More Articles.

Fibromyalgia Study: It's a Real Disease

Kamiah A. Walker
Medical Writer
SpineUniverse
Wheaton, IL

We 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 brain.

Dr. 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.

"Past 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."

Translation: 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.

Then the women underwent single photon emission computed tomography (SPECT)—a special kind of brain scan.

The researchers analyzed the women's answers to the questionnaires in conjunction with analyzing their brain scans.

So 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.

Additionally, 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.

Interestingly, 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.

So 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'."

In 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.

The study could help the medical community better understand fibromyalgia and how to effectively treat it.

Fibromyalgia is a complex condition affecting 3 million to 7 million American—most 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: 11/04/2008

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Yes, Virginia, there is Fibromyalgia, Suzi Prokell, 817-598-1556

Some still believe disease is a myth; sufferers say it’s 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.

“I 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.

Given the research and information provided by physicians, researchers, drug companies and every expert under the sun, we can clearly see the disease does exist.”

Fibromyalgia 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 article.

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Treatment of Fibromyalgia Syndrome With Antidepressants JAMA. 2009

A Meta-analysis Winfried Häuser, MD; Kathrin Bernardy, PhD; Nurcan Üçeyler, MD; Claudia Sommer, MD ;301(2):198-209.

Context   Fibromyalgia syndrome (FMS) is a chronic pain disorder associated with multiple debilitating symptoms and high disease-related costs. Effective treatment options are needed.

Objectives   To determine the efficacy of antidepressants in the treatment of FMS by performing a meta-analysis of randomized controlled clinical trials.

Data 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.

Study 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 analyzed.

Data Extraction and Data Synthesis  Two authors independently extracted data. Effects were summarized using standardized mean differences (SMDs) by a random-effects model.

Results   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 –0.25).

Conclusion   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).

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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 person’s 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 skin.

Complications can occur in some individuals, though. You shouldn’t use electrotherapy if you:

  • are pregnant

  • have a pacemaker

  • have an implanted defibrillator

  • have high or low blood pressure

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 treatments.

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.

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Nonpharmacological method in fibromyalgia: the use of wool

J Altern Complement Med. 2009 Apr;15(4):399-405. Kiyak EK. Atat=FCrk University, School of Nursing, Erzurum, Turkey. frtemine@hotmail.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 0.001).

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.

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Fibromyalgia Pain Is Real

Brain Scan Proves What Sufferers Have Always Known By Daniel DeNoon
WebMD Medical News. Reviewed By Gary Vogin, MD

People 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.

It's 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.

In 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.

Healthy 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.

"What 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 injured."

I. 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 center.

"This 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."

Russell 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.

Also impressed by the new research is Terence W. Starz, MD, an FM expert at the University of Pittsburgh Medical Center.

"These 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 information."

Doctors have been slow to accept FM as a real disease -- but that quickly is changing.

"I've 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."

Gracely, 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.

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Targeted Gene Therapy Provides Relief For Chronic Pain, Study Shows

ScienceDaily (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.

"Fifty 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.

Mount 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.

"Our 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."

The 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).

Adapted 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 sensitization mechanisms.

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 control subjects.

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

From 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.

THE 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 discrete illness.

In 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.

Even 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.

These 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.

Since 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.

So 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.

I 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.

This 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.

Robert 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.

MECHANISMS 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.

So 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.

The 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.

One 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.

There 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.

Four 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.

We 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.

The 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.

Everyone 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.

This 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.

One 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

These 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.

There 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.

In 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 us.

DIAGNOSIS 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.

PHARMACOLOGICAL 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.

NONPHARMACOLOGICAL 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.

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Is Fibromyalgia Really a Rheumatologic Diagnosis? A Controversial View

The 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 rheumatologic illness.

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 disease."

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.

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Brain-derived Neurotrophic Factor Elevated in Fibromyalgia Patients

In 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 pilot study.

Fibromyalgia (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.

This 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."

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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, Tuzun C.

  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.

  PMID: 16006924

  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
  (p >0.05).

  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.

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Does psychological vulnerability determine health-care utilization in fibromyalgia?
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.

PMID: 12810928

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Person-centered approach to care, teaching, and research in fibromyalgia
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 61605, USA.

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 distress.

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)

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High rates of autoimmune and endocrine disorders, fibromyalgia, chronic
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. sinaiin@mail.nih.gov

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
population.

PMID: 12351553

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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, Sacerdote P.
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 <0.01).

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.

PMID: 12131069

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Attentional functioning in fibromyalgia, rheumatoid arthritis, and
musculoskeletal pain patients.
Arthritis Rheum. 2002 Dec 15;47(6):639-44.
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
patient groups.

CONCLUSION: All 3 groups of chronic pain patients, regardless of diagnosis, had impaired cognitive functioning on an ecologically sensitive neuropsychological test of everyday attention.

PMID: 12522838

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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, IL, USA.

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 psychosomatic. 

Studies 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 for FM.

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]

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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, ekozanoglu@yahoo.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.

Ninety-five 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.

Mean tender point count, pain intensity scored on a visual analog scale (VAS), sleep disturbance,
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.

All of the symptoms except stiffness were not statistically significant between the HCV and control groups with FS.

Our results demonstrate a tendency toward higher prevalence of FS in patients with HCV infection. Besides
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

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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
mystery.

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 common cause.
COPYRIGHT 2003 Lippincott/Williams & Wilkins

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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.

OBJECTIVE: 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. PMID: 12913944

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Fibromyalgia: Treatment Update -- Kim Jones, PhD, RN, FNP

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.
Click here to read the transcript of the chat, it is very informative.

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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
humans.

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 situation."
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 Rockefeller University,
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, and stress
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 been investigating
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 hours
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 depression.

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 in
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, post-traumatic
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 imbalances in
neurotransmitters that we've been thinking about for decades," he told BioMedNet News.

"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
hormones."

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.

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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[1] and low growth hormone secretion.[2] 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 mood.[2,3]

Although the mechanisms of sleep induction maintenance in normal individuals are poorly understood,[4] they are even more complex and multifactorial in patients with FM[2] and in patients with inflammatory processes associated with proinflammatory cytokines such as tumor necrosis factor.[5] 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 alcohol.

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.[10] 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 GHB administration.[10]

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.[12]

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 cataplexy.

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%).[13] 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.[14] 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.

References
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. 1995;4:150-159.
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. 2000;279:R148-R151.
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 Sci. 2002;70:2101-2112.
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. 2002;11:1821-1827.
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.

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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 fatigue.

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," they conclude.
Pain 2002 Dec;100(3):271-9.

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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. yunus@uic.edu

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).

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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 Medicine at
Peoria, IL 61656, USA. yunus@uic.edu

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

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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.

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USE OF P-31 MAGNETIC RESONANCE SPECTROSCOPY TO DETECT METABOLIC
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.

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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. dgoldenb@massmed.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 of FM.
    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
labor-intensive.
    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 management suggestions.
     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.

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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, mainly women.

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 research and
care.

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 childbearing years.

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 painful stimulus.

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 UMHS, visit
www.med.umich.edu/intmed/rheumatology/fmweb.

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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."

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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 unacceptable side-effects.

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 fibromyalgia patients.

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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.

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Exercise for Patients with Fibromyalgia: Risks versus Benefits.

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. robben@msn.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

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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.

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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

ABSTRACT.

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    2001;28:2298-304)

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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: 12507711

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 stimulus.

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.

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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.
METHODS:
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 better). Secondary
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 Assessment Questionnaire
(HAQ).
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 FM.
PMID: 12508406

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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 tumor necrosis
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 patients
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), suggesting an
inflammatory component in the induction of pain. This may explain the response to nonsteroidal antiinflammatory therapy in a subset of FM patients.  PMID: 12508404

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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 trigger points.

To test this hypothesis, in rats, small amounts of an acetylcholinesterase inhibitor (diisopropylfluorophosphate, DFP) were injected into the proximal half of the gastrocnemius muscle,
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 regional abnormal
contractions which are thought to be essential for the formation of myofascial trigger points.
PMID: 12576409

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Fibromyalgia And Myofascial Pain Syndrome Share Nervous Peptidergic Hyperactivity
A DGReview of :"Image Analysis Quantification of Substance P Immunoreactivity in the Trapezius Muscle of Patients with Fibromyalgia and Myofascial Pain Syndrome" y Veronica Rose

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 (MPS).

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 controls.

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"

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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:sozgocmen@hotmail.com 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 healthy controls.
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 healthy housewives.
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.

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Fibromyalgia: The Controversy Continues New disagreements over pain syndrome By Janice Billingsley
HealthScout Reporter

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 than malingering.

"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 meeting.

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 fibromyalgia patients.
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 diagnosing fibromyalgia.

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 treat them.

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.

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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&reg; 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 Administrator

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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.

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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:getinfo@haworthpressinc.com Website: http://www.HaworthPress.com ] 2001 by The Haworth Press, Inc. All rights reserved.

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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 parameters.

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 major depressive
disorder.

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

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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 of FM
patients.

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 understood,
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 (6,7).

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 patients
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 general population
(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 higher
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 system of
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.

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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 these patients.
PMID: 11296966

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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, United Kingdom

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 patients.
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 Corporation

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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.

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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
system(corticotropin-releasing
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,[23] 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).[24]

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
muscle atrophy.[24]
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."[29]

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.[30] 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.[31] 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.[39]

Decreased neurogenesis.
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.[47] Neonatally deprived adult monkeys
exhibit hyperactivation of the locus ceruleus, which persists for months
after the early adverse event.[48] 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
deprived monkeys.
There are clear connections between the CRF and the locus ceruleus
systems[50]: 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
administration.[50]

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.[29] 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
disorders

The strong evidence of the interaction between life experience and
disposition in the generation of MD ( Major Depression) led researchers to
posit a
"stress-diathesis model" of mood disorders.[8,51] In this model,
Nemeroff[52] explained that in some individuals, depression might result
from interplay between "vulnerability genes," "resistance genes," and early
adverse life events. However, he acknowledged the limitations of this model
in explaining all cases of depression.[51] Not all depressed patients report
early life trauma. Also, not all depressed patients exhibit genetic
predisposition, but this may be difficult to assess.

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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 conditions.

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 Center
(310) 375-2705

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Childhood adversities in patients with fibromyalgia and somatoform pain disorder.
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 nervous pain
processing. The study aims to discuss vulnerability for fibromyalgia from a developmental psychopathological perspective.
  We investigated the presence of psychosocial adversities affecting the childhood of adult fibromyalgia patients (FM) and compared them to those of patients with somatoform pain disorders
(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 CG
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 disorders. The
potential role of these factors as increasing the vulnerability for fibromyalgia is discussed.
PMID: 12600792

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"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
www.docguide.com.

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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 feeling.

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 muscle."

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 a patent.

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
October 2000.

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 treat fibromyalgia.

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 story."

-Goldie Blumenstyk.  The website of the Dartmouth Medical School is http://www.dartmouth.edu/dms/index.shtml.

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Fibromyalgia Takes Different Tolls on Different People

04-19-2004

Doctors discover three distinct patient clusters, a finding that could help tailor treatment for the chronic disorder. By Kathleen Doheny
HealthDay Reporter

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 [2003] 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," Giesecke says.

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 sufferers experience.

"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: HealthDay News.

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Links To More Articles.

Alpha sleep characteristics in fibromyalgia. Arthritis Rheum. 2001 Jan;44(1):222-30.PMID: 11212164

Do predictors exist for the therapeutic effect of 5-HT3 receptor antagonists in fibromyalgia? Scand J Rheumatol Suppl 2000;113:63-5

Present state of medication therapy in fibromyalgia syndrome. Scand J Rheumatol Suppl 2000;113:32-6.

Physical therapy in the treatment of fibromyalgia. Scand J Rheumatol Suppl 2000;113:78-85.

EFNS: Cabergoline May Be Effective In Reducing Symptoms Of Restless Legs Syndrome 

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