ARTICOLI INGLESI SULLA FIBROMIALGIA

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sadrakan4/9/2008, 15:57
Fibromialgia: Mostrami come procura dolore"

Traduzione e articolo attinti dai messaggi di Donatella – gennaio 2007

Fibromialgia: Mostrami come procura dolore"
Un nuovo studio collega la FM alla riduzione di dopamina nel
cervello

ORANGE, California---- 4 January 2007---- La National Fibromyalgia
Association ha annunciato oggi che un nuovo studio pubblicato nel
numero di Gennaio della rivista The Journal of Pain (Il Giornale del Dolore)
fornisce una nuova
evidenza scientifica che dimostra, per la prima volta, l'esistenza
di una fondamentale differenza tra il cervello dei pazienti affetti
da FM e soggetti sani.

L'autore dello studio, Dr. Patrick Wood, Ë un ricercatore
conosciuto a livello nazionale ed una autorità nel trattamento
della FM. Questo studio è correlato alla "Teoria della dopamina
nella FM" dello stesso Dr Wood che interpreta come fenomeno
specifico il fatto che le persone con FM fibromialgia produrrebbero
meno dopamina — sostanza chimica naturale presente nel corpo umano
con la funzione di neurotrasmettitore— in quelle zone specifiche del
cervello dove la dopamina. E’ necessaria per elaborare le sensazioni
dolorose provenienti dal corpo.

La riduzione di attività dei neuroni della dopamina (che si crede
derivi dalla combinazione di fattori ambientali tra cui stress
cronico così come fattori genetici) sembrerebbe in grado di fornire
una forte evidenza del fatto che manifestazioni connesse con la
dopamina possano essere la radice della causa della FM.

Il dr. Wood afferma: "Questo studio fornisce un'intera nuova
prospettiva sulla patologia della FM".

Lo Studio

La ricerca ha utilizzato la PET (positron emission tomography) per
confrontare la capacità dei pazienti affetti da FM di sintetizzare la
dopamina rispetto ad un gruppo di controllo. Un totale di sette
donne affette da FM e otto soggetti sani (gruppo di controllo) sono
stati esaminati nel Centro di Scienze della salute dell'Università
statale della Louisiana dove insegna il Dr. Wood mentre dirige sia
il Programma di Ricerca sulla FM sia la Clinica per la cura della
FM. I risultati dello studio dimostrerebbero che i pazienti di FM
hanno una significativa riduzione della capacità di sintetizzare la
dopamina in diverse regioni cerebrali.

"E' tutto della vostra testa!"

Per anni alle persone affette da FM è stato detto che la loro
malattia ed i relativi sintomi erano immaginari o "tutto nella loro
testa!". In effetti la FM ha diviso la comunità medica sulla
questione della sua legittimità dovuta in larga parte al ritardo di
conoscenza relativa ai marcatori genetici.

Secondo l'Associazione Nazionale di FM si stima che circa 10 milioni
di americani siano affetti da questa patologia. Fattori genetici ed
esposizione a stress cronici sono stato con sempre maggior frequenza
Identificati come I fattori associati con la FM. Il trattamento si
orienta tipicamente sui sintomi della FM: dolore diffuso,
affaticamento e disturbi del sonno.

"Una delle ragioni per cui la FM è materia così controversa risiede
nel fatto che molto semplicemente non se ne conosce la causa" spiega
il Dr. Wood. "Il trattamento dei sintomi è una specie
di 'sparo nel buio' in quanto non sappiamo con precisione che
cosa stiamo trattando. Comunque, sulla base di questi studi vi è
motivo per portare maggior enfasi su quei trattamenti che possano
avere effetto sull'attività della dopamina cerebrale. In effetti",
afferma Wood, "possiamo iniziare a trattare la sorgente della
patologia e non soltanto i suoi sintomi."

---------------------------------------------------------------------------------------------------

FOR IMMEDIATE RELEASE

4 January 2007

“Fibromyalgia: Show Me Where It Hurts”
New Study Links Fibromyalgia to Reduced Brain Dopamine

ORANGE, Calif---- 4 January 2007---- The National Fibromyalgia Association today announced that a new study published in the January issue of The Journal of Pain provides new scientific evidence demonstrating for the first time that there is a fundamental difference between the brains of fibromyalgia patients and healthy individuals not afflicted with the disorder.


The study’s lead author, Dr. Patrick Wood, is a nationally recognized researcher and authority on the cause and treatment of fibromyalgia. This groundbreaking study supports Dr Wood’s “Dopamine Theory of Fibromyalgia,” which proposes that people with fibromyalgia produce less dopamine—a natural chemical in the body that functions as a neurotransmitter—in the very areas of the brain where dopamine is needed to process painful bodily sensations.

The reduction in the activity of dopamine neurons, believed to result from a combination of environmental factors, including chronic stress, as well as genetic factors, serves as the strongest evidence yet that dopamine-related issues may be the root cause of fibromyalgia.

“This study provides a whole new perspective on the pathology of fibromyalgia symptoms,” says Wood.

STUDY


The research study used positron emission tomography (PET) to compare the capacity of fibromyalgia patients to synthesize brain dopamine in comparison with healthy controls. A total of seven female fibromyalgia patients and eight healthy controls were recruited for the study at Louisiana State University Health Sciences Center, where Dr. Wood serves as assistant professor and directs both the Fibromyalgia Research Program and the Fibromyalgia Care Clinic. The results of the study demonstrate that patients with fibromyalgia have significantly reduced dopamine synthesis in multiple brain regions.

“It’s all in your head!”

For years, people with fibromyalgia have been told that their illness and symptoms were imaginary, or “all in their heads!” Indeed, fibromyalgia has divided the medical community on the subject of its legitimacy due in large part to the lack of a known cause or genetic markers,.

According to the National Fibromyalgia Association, an estimated 10 million Americans are affected by the disorder. Genetic factors and exposure to chronic stress have been increasingly suspected as key factors associated with fibromyalgia. Treatment typically focuses on addressing fibromyalgia symptoms, which include widespread pain, fatigue and sleep disturbance.

“One of the reasons fibromyalgia is considered so controversial is because we simply don’t know the cause,” explained Dr. Wood. “Our treatment of the symptoms has been sort of a ‘shot in the dark’ because we don’t really understand what it is we are treating.” However, based in the results of this study, there is reason to bring more emphasis on those treatments that may affect brain dopamine activity. “In effect,” Wood said, “we may begin to treat the source of the disorder, and not just its symptoms.”


---------------------------------------------------------------------------


“Fibromyalgia: Show Me Where It Hurts”


Dr. Wood’s research involving the Dopamine Theory of Fibromyalgia is featured in a recently released film entitled “Fibromyalgia: Show Me Where It Hurts,” which premiered at the National Fibromyalgia Association's 2006 National Patient Conference in March.


A trailer of the film can be viewed on the National Fibromyalgia Association’s website: http://www.FMaware.org.


In light of the latest results and the small initial sample size, Dr. Wood and the National Fibromyalgia Association (NFA) are urging further studies to determine the extent to which the lack of dopamine might be associated with the pain and other symptoms that characterize fibromyalgia.


"Further research on Dr. Wood’s Dopamine Theory could help answer questions that could directly benefit people with fibromyalgia,” said Lynne Matallana, founder and president of the National Fibromyalgia Association, the largest nonprofit association serving people with fibromyalgia and other chronic pain illnesses. Matallana, who was diagnosed with fibromyalgia in 1995, appears in “Fibromyalgia: Show Me Where It Hurts.”


For the complete text of the study, visit: http://journals.elsevierhealth.com/peri ... ai/current

ABOUT THE NFA:

The National Fibromyalgia Association is a non-profit 501(c)(3) organization whose mission is to develop and execute programs dedicated to improving the quality of life for people with fibromyalgia by increasing the awareness of the public, media, government and medical communities. The NFA publishes a quarterly magazine, Fibromyalgia AWARE and hosts an award-winning website at http://www.FMaware.org.


sadrakan4/9/2008, 17:06
Research on Fibromyalgia

Increased 24-hour urinary cortisol excretion in patients with post- traumatic stress disorder and patients with major depression, but not in patients with fibromyalgia.

AUTHORS: Maes M; Lin A; Bonaccorso S; van Hunsel F; Van Gastel A; Delmeire L; Biondi M; Bosmans E; Kenis G; Scharpe S
AUTHOR AFFILIATION: Clinical Research Center for Mental Health, Antwerp, Belgium.
SOURCE: Acta Psychiatr Scand 1998 Oct;98(4):328-35
CITATION IDS: PMID: 9821456 UI: 99038897
ABSTRACT: There is now firm evidence that major depression is accompanied by increased baseline activity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of 24-h urinary cortisol (UC) excretion. Recently, there were some reports that fibromyalgia and post-traumatic stress disorder (PTSD), two disorders which show a significant amplitude of depressive symptoms, are associated with changes in the baseline activity of the HPA axis, such as low 24-h UC excretion. The aim of the present study was to examine 24-h UC excretion in fibromyalgia and PTSD patients compared to normal controls and patients with major depression. In the three patient groups, severity of depressive symptoms was measured by means of the Hamilton Depression Rating Scale (HDRS) score. Severity of fibromyalgia was measured using a dolorimetrically obtained myalgic score, and severity of PTSD was assessed by means of factor analytical scores computed on the items of the Composite International Diagnostic Interview (CIDI), PTSD Module. Patients with PTSD and major depression had significantly higher 24-h UC excretion than normal controls and fibromyalgia patients. At a threshold value of > or = 240 micrograms/24 h, 80% of PTSD patients and 80% of depressed patients had increased 24 h UC excretion with a specificity of 100%. There were no significant differences in 24-h UC excretion either between fibromyalgia patients and normal controls, or between patients with major depression and PTSD patients. In the three patient groups, no significant correlations were found between 24-h UC excretion and the HDRS score. In fibromyalgia, no significant correlations were found between 24-h UC excretion and the myalgic score. In PTSD, no significant correlations were found between 24-h UC excretion and severity of either depression-avoidance or anxiety- arousal symptoms. In conclusion, this study found increased 24-h UC excretion in patients with PTSD comparable to that in patients with major depression, whereas in fibromyalgia no significant changes in 24- h UC were found.

http://www.fibrodoc.org/



recenti scoperte
Understanding Chronic Pain and Fibromyalgia:

A Review of Recent Discoveries



by Robert M. Bennett MD, FRCP


Professor of Medicine, Oregon Health Sciences University



I have seen over 5,000 fibromyalgia patients over the past 20 years; most want to be reassured that their symptoms are the product of a "real disease" rather than figments of a fertile imagination--commonly ascribed to the psychological diagnosis such as somatization, hypochondriasis, or depression. The good news is that contemporary research is hot on the track of unraveling the changes that occur within the nervous system of fibromyalgia patients. The basic message is that fibromyalgia cannot be considered a primarily psychological disorder, but as in many chronic conditions, psychological factors may play a role in who becomes disabled and may even up-regulate the central nervous system changes that are the root cause of the problem.



What is the problem?

The problem is: disordered sensory processing.
I will try to convey to you what we mean by "disordered sensory processing." Even a superficial understanding of this topic will change the way you think about the fibromyalgia problem. Furthermore, recent advances that have been made at the molecular level hold out the promise of more effective treatment for fibromyalgia pain.



What is Fibromyalgia?

Fibromyalgia is a chronic pain state in which the nerve stimuli causing pain originates mainly in the muscle. Hence the increased pain on movement and the aggravation of fibromyalgia by strenuous exertion.



Pain is a universal experience that serves the vital function of triggering avoidance. A few unfortunate individuals have a congenital absence of pain sensation; they do not fare well due to repeated bodily insults that go unnoticed. As a physician I see patients with an acquired deficiency in the pain sensation (e.g. diabetic neuropathy or neurosyphilis) who develop a severe destructive arthritis--a result of repeated minor joint injuries that are overlooked. Thus pain sensation is a necessary part of being human. Pain sensation is a fact of life. Even the primitive amoeba takes avoiding action in the face of adverse events. In such primitive life forms, pain avoidance is purely reflex action, as they do not have the complexity of a highly developed brain to feel pain in the sense that humans do: (1)The unconscious reflex avoidance reaction that is so rapid that it occurs before the actual awareness of the pain sensation (as in all life forms), (2) the actual experience of the pain sensation (that can only occur in highly complex organisms). This is an important point, as it implies that different parts of the brain are involved in these two consequences of the pain reaction.



Over the last few years a number of important research discoveries have started to clarify the enigma of chronic pain. Many of these new findings have a special relevance to the chronic pain of fibromyalgia. The cardinal symptom of FM is widespread body pain. The cardinal finding is the presence of focal areas of hyperalgesia, the tender points. Tender points imply that the patient has a local area of reduced pain threshold, suggesting a peripheral pathology. In general, tender points occur at muscle tendon junctions, a site where mechanical forces are most likely to cause micro-injuries. Many--but not all--FM patients have tender skin and an overall reduction in pain threshold. These latter observations suggest that some FM patients have a generalized pain amplification state. There has been a recent plethora of experimental studies apposite to the pathophysiological basis of both the peripheral and central aspects of pain.



The Pathophysiological Basis for Chronic Pain


The International Association For the Study of Pain (ASP) defines pain as follows: "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." This definition explicitly affirms that pain has both a sensory and an affective-evaluative component, and furthermore acknowledges that it may occur in the absence of obvious visceral or peripheral pathology. To fully understand chronic pain, one must integrate the sensory and affective/evaluative elements of the pain experience. It is equally misguided to focus on the psychological aspects of pain, as it is to address only the sensory component and ignore the affective dimensions. However, for the sake of clarity, each of these two constitutive elements will be considered separately.



The Sensory Component

Pain is generally envisaged as a cascade of impulses that originates from nocioceptors in somatic or visceral tissues. The impulses travel in peripheral nerves with a first synapse in the dorsal horn and a second synapse in the thalamus, and end up in the cerebral cortex and other supraspinal structures.




This results in an experience of pain and the activation of reflex and later reflective behaviors. These reflex and reflective behaviors are aimed at eliminating further pain. The expectation is that this nocioceptor driven pain will be successfully abolished, allowing healing and a return to a pain-free state. The problem with chronic pain is that the linear relationship between nocioception and pain experience is inappropriate or even absent, and the expected recovery does not occur.



It is a common misconception to view the nervous system as being "hard-wired"; that is, stimulation of a nerve ending (say a needle prick) always produces the same behavioral and affective response. This concept implies that the same intensity of pain stimulus will always elicit the same degree of nerve stimulation and hence the same subjective experience of pain. It is now understood that the concept is wrong. Some 30 years ago, Melzeck and Wall proposed that pain is a complex integration of noxious stimuli, affective traits, and cognitive factors. In other words, the emotional aspects of having a chronic pain state and one's rationalization of the problem may both influence the final experience of pain. Mendell and Wall provided the first experimental evidence that the nervous system was not hard-wired in 1965. They noted that a repetitive stimulation of a peripheral nerve, at sufficient intensity to activate C-fibers, resulted a progressive build-up of the amplitude of the electrical response recorded in the second order dorsal horn neurons. If the system had been hard-wired, each stimulus would have elicited the same response in the second order neuron. They termed this phenomenon "wind-up." It is now appreciated that the phenomenon of wind-up is crucial to understanding the problem of chronic pain via the mechanism of "central sensitization."



Central sensitization refers to an increased activation of second order neurons in the spinal cord, resulting from injury or inflammation-induced activation of peripheral nocioceptors. Sensory input from muscle, as opposed to skin, is a much more potent effector of central sensitization. This may be the clue to the role of muscle pain in the total spectrum of fibromyalgia. A common example of central sensitization is post-herpetic neuralgia. Previous injury to a peripheral nerve leads to an amplification of both nocioceptive and non-nocioceptive impulses. The mechanism responsible for the abnormal perception of non-nocioceptive impulses in post-herpetic neuralgia is an increased excitation of second order nocioceptive neurons in the dorsal horn of the spinal cord. A special example of central pain occurs when there is pathology within the central nervous system. This occurs in a thalamic stroke--severe unilateral pain, often accompanied by strong emotions, that occurs in the absence of any nocioceptive input.



There are two forms of second order spinal neurons involved in central sensitization. (1) Nocioceptive--specific neurons--respond only to nocioceptive stimuli, and (2) Wide dynamic range neurons--respond to both nocioceptive and non-nocioceptive afferent stimuli. Both may be sensitized by nocioceptive stimuli leading to central senitization but wide-dynamic range neurons are generally more intensely sensitized than nocioceptive-specific neurons. Nocioceptive and non-nocioceptive peripheral nerves often converge onto the same wide dynamic range neuron (see figure). Once sensitized by ongoing nocioceptive impulses from peripheral nerves, wide-dynamic range neurons will respond to non-nocioceptive stimuli just as intensely as they did prior to sensitization. This results in sensitizations like a light touch to be experienced as pain (i.e. allodynia). Sensitization of wide-dynamic range neurons by prior pain stimuli provides the pathophysiological foundation for nonnocioceptive pain.



There is emerging evidence that afferent activity from Golgi tendon organs and muscle spindles can be converted into pain signals under the influence of central sensitization. For instance, some patients with strokes and spinal cord injuries develop severe pain on movement. Benc has proposed the term "proprioceptive allodynia" to describe this phenomenon. He describes such individuals as "while not experiencing pain at rest, they develop excruciating burning and tingling, often difficult to describe, that appear only when trying to hold an object, move a limb, stand or walk." Thus everyday muscle activity may cause pain and impair function in some individuals with central sensitization. At a physiological level, pain on movement implies that proprioceptive afferents are projecting onto second order wide-dynamic-range spinal neurons that have been sensitized by previous nocioceptive activity. Thus the central nervous system of subjects who have ongoing pain (e.g. arthritis) or have had previous pain experiences (e.g. post injury pain) may be permanently altered due to changes that can now be understood at the physiological molecular and structural levels. At a clinical level this is seen as persistent pain in survivors of serious illness who experienced high levels of pain during hospitalization, persistent pain after breast surgery, or the occurrence of fibromyalgia after automobile accidents. The reason why the phenomenon of central sensitization only occurs in a minority of individuals is not currently known. At a molecular level, there are many studies demonstrating the important role of excitatory amino acids such as glutamate and neuropeptides such as substance P in the generation of central sensitization. Substance P and CRGP are important neurotransmitters in lowering the threshold of synaptic excitability, which permits the unmasking of normally silent interspinal synapses and the sensitization of second order spinal neurons. Substance P, unlike the excitatory amino acids, can diffuse long distances in the spinal cord and sensitize dorsal horn neurons in spinal segments both above and below the input segment--with resulting pain signal generation from non-nocioceptive afferent activity. Clinically this will lead to an expansion of receptive fields; e.g. the spread of pain from to uninjured areas after an automobile accident.



The Psychological Component


It was seen in the preceding section that chronic pain could occur in the absence of ongoing tissue damage--this is an example of the sensory component of pain. It was also noted that one component of pain is a reflex avoidance behavior that can occur before the conscious appreciation of pain. In terms of brain physiology this implies that more primitive parts of the brain contain several discrete nuclei (e.g. the thalamus, cingulate gyrus, hippocampus, amygdyala, and locus ceruleus) that interact to form a functional unit called the limbic system. This is the part of the brain that subserves many reflex phenomena, including the association of sensory input with specific mood states (e.g. pleasure, fear, aversion etc.). These facts form the physiological basis for considering the emotional aspect of pain. Interestingly, the electrical stimulation of the brain during neurosurgical procedure does not induce pain sensations in pain-free subjects. However, in past pain patients it often reawakens previous pain experiences. It is surmised that such stimulation re-activates cortical and subcortical pain circuits that were previously dormant. It is not known whether there is a single cortical structure that subserves pain memory. Currently it appears that different cortical and subcortical structures are involved in the pain experience. For instance, removal of the somatosensory cortex does not abolish chronic pain, but excision of lesions of the anterior cingulated cortex reduces the unpleasantness of pain. The anterior cingulated cortex is involved in the integration of affect cognition and motor response aspects of pain and exhibit increased activity on PET studies of pain patients. Other structures involved in cortical pain processing include the prefrontal cortex (activation of avoidance strategies, diversion of attention and motor inhibition); the amygdala (emotional significance and activation of hypervigilance); and the locus ceruleus (activation of the "fight or flight" response).



All these structures are linked to the medial thalamus, whereas the lateral thalamus is linked to the somatosensory cortex (pain localization). One example of limbic system activation is the hypervigilance that accompanies many chronic pain states, including fibromyalgia.



The emotional component of pain is multifactorial and includes past experiences, genetic factors, generals state of health, the presence of depression and other psychological diagnosis, coping mechanisms, and beliefs and fears surrounding the pain diagnosis. Importantly, thoughts as well as other sensations can influence the sensory pain input to consciousness as well as the emotional coloring of the pain sensation. The term given for this modulation of pain impulses is the "gate control theory of pain." Thus thoughts (beliefs, fears, depression, anxiety, anger, helplessness, etc.), as well as peripherally generated sensations, can both dampen or amplify pain. Indeed, in many chronic pain conditions (that lack any effective therapy for the sensory/pain component), a reduction of pain and the resulting suffering can only be affected by modulating the psychological aspects of pain. As the psychological contribution to pain varies enormously from patient to patient, this approach has to be individualized. However, there are some general principles that are worth noting. There are important consequences of having pain that will not go away (as is the expected experience for most pain in most people). The unsettling realization that the problem may well be life-long generates a varied mix of emotions and behaviors that are often counterproductive to coping with a chronic problem. Many of these changes (which are partly reflex in origin) would be appropriate for dealing with acute self-healing pain events, but become a liability when dealing with chronic pain. The end result of chronic pain is often depressive illness, marital discord, vocational difficulties, chemical dependency, social withdrawal, sleep disorders, increasing fatigue, inappropriate beliefs, and a radical alteration in their previous personality. Varying degrees of functional disability are a common accompaniment of chronic pain states. The reasons for dysfunction are multiple and vary from individual to individual. Pain often monopolizes attention (causing lack of focus on the task at hand). It is usually associated with poor sleep (causing emotional fatigue). Movements may aggravate pain (causing a reluctance to engage in activity). Fear of activity often leads to deconditioning (which predisposes to muscle and tendon injuries and reduced stamina). Pain causes stress, which may result in anxiety, depression, and inappropriate behavior (causing disability due to secondary psychological distress). The modern era of psychological imaging is providing an important new framework for understanding these "emotional" responses.

http://www.fmaware.org/site/PageServer? ... ia_science

Fibromyalgia tends to be treated rather dismissively, sometimes with cynical overtones. When I trained in London some 30 years ago, this diagnosis was never mentioned, even though I trained with one of the foremost rheumatologists in the world at the time. In the United States fibromyalgia has become a semi-respectable diagnosis within the last 10 years, but even so it has some critics. The problem for doctors is that fibromyalgia is not a problem that can be understood according to the classic medical model. This is the model that is used in all medical training. It is based on the correlation of specific tissue pathology with distinctive symptoms (e.g. tuberculosis of the lung causing a chronic cough). Elimination of the causative agent (e.g. the tubercule bacillus) cures the disease. This model has led to the most major advances in medicine that we benefit from today.

QUARTA PARTE ARTICOLO IN INGLESE
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.

REFERENCES
1. Wolfe F, Symthe HA, Yunus MB, et al. The American college of
rheumatology 1990 criteria for the classification of fibromyalgia. Report
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10. Clauw DJ. The health consequences of the first Gulf War. Br Med J.
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11. Giesecke T, Williams DA, Harris RE, et al. Subgrouping of fibromyalgia
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12. Kosek E, Hansson P. Modulatory influence on somatosensory perception
from vibration and heterotopic noxious conditioning stimulation (HNCS) in
fibromyalgia patients and healthy subjects. Pain 1997;70:41-51.
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15. Giesecke T, Gracely RH, Williams DA, et al. The relationship between
depression, clinical pain, and experimental pain in a chronic pain cohort.
Arthritis Rheum. 2005;52:1577-1584.
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16. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial
comparing duloxetine with placebo in the treatment of fibromyalgia patients
with or without major depressive disorder. Arthritis Rheum. 2004;50:2974-2984.
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17. Gracely RH, Geisser ME, Giesecke T, et al. Pain catastrophizing and
neural responses to pain among persons with fibromyalgia. Brain.
2004;127:835-843.
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18. Giesecke T, Gracely RH, Grant MA, et al. Evidence of augmented central
pain processing in idiopathic chronic low back pain. Arthritis Rheum.
2004;50:613-623.
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19. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia
syndrome. JAMA. 2004;292:2388-2395.
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20. White KP, Nielson WR, Harth M, et al. Does the label fibromyalgia alter
health status, function, and health service utilization? A prospective,
within-group comparison in a community cohort of adults with chronic
widespread pain. Arthritis Rheum. 2002;47:260-265.
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fibromyalgia. A meta-analysis and review. Psychosomatics. 2000;41:104-113.
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Ann Med. 2000;32:305-316.
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23. Gendreau RM, Thorn MD, Gendreau JF, et al. The efficacy of milnacipran
in fibromyalgia. J Rheumatol. 2005;10:1975-1985.
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24. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the
treatment of fibromyalgia syndrome: results of a randomized, double-blind,
placebo-controlled trial. Arthritis Rheum. 2005;52:1264-1273.
[Medline Link] [CrossRef] [Context Link]
25. Scharf MB, Baumann M, Berkowitz DV. The effects of sodium oxybate on
clinical symptoms and sleep patterns in patients with fibromyalgia. J.
Rheumatol. 2003:30:1070-1074.
[Medline Link] [Context Link]
26. Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled
trial of pramipexole, a dopamine agonist, in patients with fibromyalgia
receiving concomitant medications. Arthritis Rheum. 2005;52:2495-2505.
[Medline Link] [CrossRef] [Context Link]
27. Russell J, Michalek JE, Xiao Y, et al. Therapy with a central alpha-2
adrenergic agonist [tizanidine] decreases cerebrospinal fluid substance p,
and may reduce serum hyaluronic acid as it improves the clinical symptoms
of the fibromyalgia syndrome. Arthritis Rheum. 2002;46(9 suppl):S614.
[Context Link]
28. Bennett RM, Kamin M, Karim R, et al. Tramadol and acetaminophen
combination tablets in the treatment of fibromyalgia pain: a double-blind,
randomized, placebo-controlled study. Am. J. Med. 2003;114:537-545.
[Medline Link] [CrossRef] [Context Link]
29. Williams DA, Cary MA, Gronerr KH, et al. Improving physical functional
status in patients with fibromyalgia: a brief cognitive behavioral
intervention. J. Rheumatol. 2002;29:1280-1286.
[Medline Link] [Context Link]
30. Harris RE, Tian X, Williams DA, et al. The treatment of fibromyalgia
with acupuncture: effects of needle placement, needle stimulation, and
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[Context Link]
31. Assefi NP, Sherman KJ, Jacobsen C, et al. A randomized clinical trial
of acupuncture compared with sham acupuncture in fibromyalgia. Ann Intern
Med. 2005;143:10-19.



TERZA PARTE ARTICOLO IN INGLESE
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.





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Messaggio N°36 29-02-2008 - 22:42
Tags: MATERIALE IN INGLESE
SECONDA PARTE ARTICOLO IN INGLESE
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.





ARTICOLO SULLA FIBROMIALGIA IN INGLESE
Fibromyalgia: Update on Mechanisms and Management
[Rheumatology Grand Rounds at Rush]

JCR: Journal of Clinical Rheumatology:Volume 13(2)April 2007pp 102-109

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.
E-mail: [log in to unmask]

PMID: 17414543


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.




REIKI E FIBROMIALGIA

Reiki Therapy and Fibromyalgia
Thursday, June 21, 2007
By: Anthony Schifano

.



Reiki (pronounced ray-key) means "universal life energy." Reiki is a gentle healing modality that enhances the body’s well-being. Reiki accelerates the body’s natural ability to heal itself; it can relieve pain, reduce stress, induce relaxation, and promote well-being by bringing harmony to body, mind and spirit.



How?



Reiki is a natural form of hands-on energy transfer. The trained Reiki Practitioner channels this universal life energy as a spiritual means of enhancing the recipient’s own bodily energies and natural response to disease and illness.



Reiki energy flows in and though the practitioner; therefore the practitioner’s own energy level is increased, never reduced or depleted, during treatments. It is transmitted by soothing touch.



The practitioner’s hands are placed over the seven chakras of the body. This is followed by the balancing of the entire body. A chakra is a spinning vortex of activity created by the presence of consciousness within the physical body. These vortices exist within what is called the subtle body, a hidden field of energy that carries your urges, emotions, and habits, as well as the imprints of all that has happened to you. As vital portals between mind and body, the chakras can be thought of as chambers in the temple of the body that organize various elements of your life force as it travels through you. Chakras are centers of organization for the reception, assimilation, and expression of life force energy. They are:

In my practice, I perform Reiki on all my FM clients, and the results are amazing. This form of therapeutic touch treatment is ideal for all those who suffer from FM, because it is non-invasive and gentle. Many felt they had tried everything and expect Reiki will give them the same results—nothing. But the results they receive are outstanding. Clients have experienced feelings of floating out and above their body. Some are so relaxed that when they try to get up, they fall right back down on the massage table. No matter what the client experiences during the treatment, all feel the same end result—total relaxation, less tense muscles, and improvement in their range of motion.



"During the treatments, I feel as though there is a small ball within me," one of my clients, Kathy Daley of Brooklyn, NY, told me. "With every move of Reiki, I feel this ball move, bringing a balancing feeling to every area.



"I have suffered many years with FM. Since started over a year ago with Reiki treatments, I feel the connection between mind, body and spirit. I’m off all medications … and pain levels continue to stay very low."



Another form of therapy that I widely use on my FM clients is hot stone massage. Like Reiki, it provides a feeling of deep relaxation. Hot stones are placed directly on all seven chakras; the stones are then used for soft tissue massage. Penetrating heat radiates into the muscles to provide stress reduction and relief from all physical pain. "I have FMS and this therapy is very affective on my condition," said one of my clients, Rose LoGuirat of Staten Island, NY. "It’s more than just a massage!"



As a concerned practitioner and the president of H.U. Counseling FMS Support Group of Staten Island, I do understand the discomfort of everyone who suffers with this Dis-ease. I myself do not suffer from FM but am very involved in finding the answers for relief and one day saying good-bye to FM.



Anthony Schifano, RP, is a member of the International Association of Reiki Practitioners. You can contact him at

Asreiki@aol.com
·

First Chakra - Coccygeal Plexus (base of spine)
·

Second Chakra - Sacral Plexus (abdomen, genitals)
·

Third Chakra - Solar Plexus
·

Fourth Chakra - Cardiac Plexus (heart)
·

Fifth Chakra - Pharyngeal Plexus (throat)
·

Sixth Chakra - Carotid Plexus (brow)
·

Seventh Chakra - Cerebral Cortex (top of head)


sadrakan11/9/2008, 11:46
Siti generali sulla FIBROMIALGIA

http://www.afsafund.org/default.htm

http://www.fibrohugs.com/

http://www.fibromialgia.com.br/novosite/

http://www.fibromialgia.cc/web/

http://www.fmnetnews.com/



STUDI SULLA FIBROMIALGIA E SPERIMENTAZIONI

http://www.fmnetnews.com/basics-studies.php

http://www.current-reports.com/article. ... &KeyWords=

http://www.rheumatology.org/public/fact ... sp?aud=pat

http://www.fibroandfatigue.com/clinical.php

REIKI E FIBROMIALGIA

http://www.annieappleseedproject.org/reikforfibst.html

http://www.fmaware.org/site/News2?page= ... le&id=5287

http://clinicaltrials.gov/show/NCT00051428

http://ezinearticles.com/?The-Benefits- ... &id=574615

http://www.eliminatefibromyalgia.com

CURE NATURALI / OLISTICHE PER LA FIBROMIALGIA / MEDITAZIONE

http://www.webmd.com/fibromyalgia/natur ... RSS_PUBLIC

http://www.sciencedaily.com/releases/20 ... 134742.htm

http://www.theraj.com/fibromyalgia/

http://www.back-fibromyalgia-pain.com/e ... emedy.html

http://www.wildmind.org/applied/health

http://www.offerutah.org/localresearch.htm





LAURA BUSH, WHITE HOUSE
1600 Pennsylvania Avenue, NW
Washington, DC 20500
U.S.A



FM/CFIDS SUFFERERS UNITE
MAY 1, 2005
MILLION LETTER CAMPAIGN


YOUR NAME NOME /COGNOME ……………………………………………..

LOCATION (città, nazione) …………………………………………………..

OCCUPATION or achievements prior to FMS/CFIDS
IMPIEGO attuale o successi professionali ottenuti prima dell’esordio della FMS /Sindrome Stanchezza Cronica:

…………………………………………………………………………………………………………………….

DATE OF ONSET of your FMS/CFIDS
DATA esordio FMS/Sindrome Stanchezza Cronica
……………………

SYMPTOMS SINTOMI …………………



This illness has affected my career, finances, relationships, family, etc. Questa malattia ha influenzato la mia attività lavorativa, la mia situazione economica, i rapporti interpersonali, le relazioni familiari


WHAT I’m asking for: recognition of this illness, for doctors and lawyers to take FMS/CFIDS seriously for disability cases, for understanding from family and friends, for money to be spent on research for a cure, for media coverage.
CHE COSA chiedo:riconoscimento della malattia; investimenti nella ricerca; sensibilizzazione da parte dei mass-media, comprensione di famigliari e amici ecc.


Fibromyalgia

The Food Allergy Component

By Dr. Edward J. Conley, D.O.

Founder and Director of The Fatigue & Fibromyalgia Clinic of Michigan

Author of "America Exhausted: Breakthrough Treatments of Fatigue and Fibromyalgia"


*Reprinted from ARTHRITIS AND RHEUMATISM Journal, copyright 1990.



At The Fatigue and Fibromyalgia Clinic of Michigan, we take a functional , multifaceted approach to the treatment of Fibromyalgia. This consists of using appropriate medications such as anti-inflammatories, pain medications, anti-depressants and sleep medications. In my experience, however, only a small percentage of patients with Fibromyalgia (PWF) are adequately controlled using this medication approach. Over the course of the last 12 years we have worked to develop a functional approach, where we go above and beyond treatment of symptoms and try to address underlying pathophysiology of the disease. This article will discuss one aspect of that treatment, the importance of food allergies in the development and ongoing process of fibromyalgia.

One of the things that I have found from the treatment of hundreds of patients with Fibromyalgia is that by removal of offending food allergies we are able to get significant improvement in the patient's pain level. Not everyone improves 100%, however, we have had our share of cases where a patient has had dramatic improvement once the offending food allergens were removed. When this happens, it is like hitting a home run in the World Series and obviously everyone feels marvelous. Most of the time patients who eliminate food allergies are able to achieve a reduction of 25% in their pain levels. This allows them to go from a pain level, for example, of 7-8 out of 10 on the pain scale, down to perhaps a 5-6 out of 10, and this allows for two things. First, obviously it improves their quality of life and allows them a greater activity level. Second, if we are able to reduce the underlying components to the disease process, often traditional medications will begin to work better and the patient will have some significant improvement in control of their pain.

Why are food allergens important in Fibromyalgia? Our goal is always to eliminate anything which overstimulates the immune system. In 90 % of the PWF's I have seen at the FFCM we are able to document IgG food allergy. It is now becoming increasingly recognized in the treatment of auto-immune diseases such as Rheumatoid Arthritis and Lupus that food allergies play an important part in the development of an auto-immune disease and, therefore, its treatment and control. I have noticed through clinical observation that anytime a PWF is exposed to significant allergens they worsen. An example of this: Routinely we have patients who become worse in August or September if they are allergic to Ragweed. The additional stress on their system, along with the underlying disease process, worsens their condition. I must state that I originally started treating food allergies in PWF's to control their upper respiratory symptoms. Many patients with fibromyalgia had chronic sinus drainage, asthma, and irritable bowel syndrome. It has been recognized for many years that controlling allergic exposure is helpful in controlling these symptoms. As we began working with PWF's on controlling their upper respiratory drainage (and other symptoms), identified their food allergies and eliminated them from their diets, people began reporting to us that they noticed improvement in their muscle pain. Over the course of the last decade we have made evaluation of food allergies a standard part of our diagnostic work up for patients with Fibromyalgia. It is that important! It has been recognized by many researchers that there may be an underlying auto-immune basis to Fibromyalgia. This is not overt and overwhelming as noted in Rheumatoid Arthritis or Lupus but we often see patients with Fibromyalgia have an elevated C Reactive Protein, Interleukin levels, Natural Killer Cell activities and an elevated CD4 to CD8 ratio. Many patients that I see also have elevated circulating histamine and elevated IgE levels in their blood work, all of which points to an underlying auto-immune process.

How do food allergies increase these auto-immune reacting substances and why do people with Fibromyalgia (PWF) have food allergies? Briefly, one current hypothesis on the development of food allergies involves developing leaky gut. What this means is that through damage to the good bacteria of the bowel by antibiotics or other reasons, eventually the lining of the bowel becomes damaged. Through the years, as this damage becomes more severe, the bowel begins to allow larger molecules into the underlying tissue. Since the bowel is our major immune organ, the body begins to build up immune globulins, IgE or IgG. to these large molecules which are being presented to the underlying bowel structures. As we continue to eat the foods to which we are allergic , we slowly build up immune globulins and eventually start to trigger our immune inflammatory cascade. The reacting food is eaten and triggers increased histamine release from ,mast cells in the gut and activation of inflammatory substances called leukotrienes. Leukotrienes then activate macrophages, monocytes and neutrophils to release oxidants. With the release of these oxidants, pain ,swelling and tissue destruction all manifest themselves. People usually develop allergies to the foods eaten most commonly: eggs, wheat, dairy, corn, oats, rye, citrus and coffee. When you continue to eat these foods, day in and day out, your immune system continues to trigger the inflammatory cascade which results in more severe pain, inflammation, swelling and free radical release. Eventually, it may start to wear down your adrenal glands which are responsible for producing cortisone which helps to control this imflammatory process. Because these are foods you eat everyday it usually does not come into your consciousness that your pain and inflammation is increasing because of the foods that you eat. Most people do not say "Ah ha! My muscles are screaming today because I had wheat this morning for breakfast." Indeed you may have had wheat every day for the last 20 years! Therefore, it is very difficult to differentiate that this is a food which is actually contributing to your pain.

How do you know if you have food allergies? All of the patients seen at the FFCM for a complaint of Fibromyalgia have food allergy blood work completed. This includes looking at over 90 foods and spices both with the immune globulin E and also immune globulin G. It is important to state that the allergy testing only gives you suspects. There is not a perfect allergy test. It is also important to state that if you had skin testing and had been told you do not have any food allergies this is not sufficient. Skin testing only picks up IgE food allergies and many times it is the delayed hypersensitivity or IgG immune globulin that is involved in food allergies. When we have patients with positive IgG food allergies, we eliminate the food from the diet and determine whether of not they feel improvement. We then bring the food back in, as specified below, to determine whether or not they notice worsening of their condition. We always let their body be the final judge on whether or not they are having problems with a certain food. There is an inexpensive, basically free, way for you to evaluate this at home. It is called The Elimination Diet. By avoiding milk, eggs, gluten, citrus, corn, sugar, coffee and tea completely from your diet for one month (remember to read labels!) you then evaluate your symptoms for the one month you are off of these foods and determine if your fibromyalgia pain improves. If it does, almost certainly you have some component of food allergy. If it does not improve, you either do not have a food allergy, which in my experience, is rare, or you are allergic to some foods that your still eating. People often ask, "well then, what in the world do I eat for a month?" We allow people to eat lean proteins: chicken, fish, turkey, lean meats, soy products and most vegetables (excluding corn and possibly potatoes) and we allow them rice as a carbohydrate and rice products which are freely available in health food stores. (This includes rice crackers, rice cakes, rice pasta, and rice flour) The next step, after one month is to then add back one food group every 4-7 days to see how you react. Pay attention to your pain levels, especially after you eat. For example, if you awake and your muscle pain is not too bad but then after breakfast or lunch you notice your pain level increases significantly and you have not done anything to warrant this such as increasing your activity, etc. it is a tip off that you have food allergies. Also, as you bring in one food group per week, you evaluate how you feel. For instance: Bringing milk and milk products back into your diet. You bring back the milk products while continuing to avoid gluten , eggs, corn, etc. If you feel worse after that week, then almost certainly you have milk allergy. If you feel worse in bringing back a food group, then you would eliminate it for the long term. If you do not feel worse, then you are allowed to resume that food group and you would then move on to the next food group. Sometimes this becomes a little complicated. For example: if you bring back cheese and suffer increased pain, are you allergic to the milk or the mold? (which is present in cheese and a very common allergen) This can be sorted out in that if you do not react to milk but do react to cheese, then you would be lead to believe perhaps you are reacting to the mold in the cheese and not the milk itself. Each group is re-introduced one at a time to determine what your symptoms are and whether or not you react to that food group. For further information on the Elimination Diet, I refer you to the appendix in the back of the book "America Exhausted: Breakthrough Treatments of Fatigue and Fibromyalgia", addendum three, which will give you a more detailed discussion of both food allergies, the Elimination Diet and bowel abnormalities.

As simple as it may seem, by discovering and eliminating your food allergens you can significantly reduce pro-inflammatory substances circulating in your blood stream and therefore reduce muscle pain and inflammation. This does not require expensive medications. There are virtually no side effects and actually treats one of the possible underlying causes of Fibromyalgia Syndrome.




[Fatigue & Fibromyalgia Clinic] [About Us] [Book Info.] [Events] [CDC/FMS Criteria] [Newsletter]

Fatigue and Fibromyalgia Clinic of Michigan. All rights reserved. This site is intended to be informative and assumes no responsibility for any treatment or activity undertaken by persons visiting this site. Visitors to this site should consult their family physician for guidance. The Fatigue & Fibromyalgia Clinic of Michigan will not be responsible for any errors or information printed herein. The Fatigue & Fibromyalgia Clinic of Michigan will not give out or sell our visitors names, email addresses, billing or personal information.



Fibromyalgia - Medical Research Abstracts

Dr. John Limbert
3096 Cadboro Bay Road, Victoria BC, V8R 5T9 Canada, Canada
mailto:jlimbert@medlit.com


--------------------------------------------------------------------------------

PROGNOSIS

1. AUTHOR Siegel-D-M, Janeway-D, Baum-J.
INSTITUTION Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, Strong Children's Research Center, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
TITLE Fibromyalgia syndrome in children and adolescents: clinical features at presentation and status at follow-up.
SOURCE Pediatrics 1998 Mar, VOL: 101 (3 Pt 1), P: 377-82, ISSN: 0031-4005.
ABSTRACT OBJECTIVES:
To 1) describe the characteristic features of fibromyalgia syndrome (FS) in a pediatric population, 2) note similarities and differences with FS in adults, and 3) determine outcome after treatment.

SETTING AND DESIGN:

The Pediatric Rheumatology Clinic at the University of Rochester Medical Center is staffed by two pediatric rheumatologists and serves as a regional subspecialty referral service with approximately 450 annual patient visits, of which approximately 120 are initial evaluations. A retrospective medical record review from 1989 to 1995 was used to identify and describe the study population, and a structured telephone interview served to determine current status and response to treatment.

RESULTS:

A total of 45 subjects were identified (41 female; 42 white; mean age, 13.3 years), of whom 33 were available for telephone interview at a mean of 2.6 years from initial diagnosis (0.1 to 7.6 years). Of a possible 15 symptoms associated with FS, subjects reported a mean of 8, with >90% experiencing diffuse pain and sleep disturbance. Less frequent were headaches (71%), general fatigue (62%), and morning stiffness (53%). The mean cumulative number of tender points summed over all visits was 9.7 (of 18). Telephone interviews showed improvement in most patients, with a mean positive change of 4.8 on a self-rating scale of 1 to 10 comparing current status to worst-ever condition.

CONCLUSIONS:

FS in patients referred to a pediatric rheumatology clinic is characterized by diffuse pain and sleep disturbance, the latter being more common than that in adults. The mean number of tender points summed over all visits is fewer than the criterion of 11 established for adults at a single visit. The majority of patients improved over 2 to 3 years of follow-up. Author.


2. AUTHOR Wolfe-F, Anderson-J, Harkness-D, Bennett-R-M, Caro-X-J, Goldenberg-D- L, Russell-I-J, Yunus-M-B.
INSTITUTION Arthritis Research Center, and University of Kansas School of Medicine, Wichita 67214, USA.
TITLE Health status and disease severity in fibromyalgia: results of a six- center longitudinal study (see comments).
SOURCE Arthritis-Rheum 1997 Sep, VOL: 40 (9), P: 1571-9, ISSN: 0004-3591. CM Comment in: Arthritis-Rheum 1997 Sep; 40(9):1553-5.
ABSTRACT OBJECTIVE:
To determine the intermediate and long-term outcomes of fibromyalgia in patients seen in rheumatology centers in which there is special interest in the syndrome.

METHODS:

We conducted a longitudinal outcome study by mailed comprehensive Health Assessment Questionnaire administered every 6 months to 538 patients, from 6 rheumatology centers, whose median duration of disease at first assessment was 7.8 years. The final assessment took place after 7 years. In addition, there was study followup on 85 patients who had attended the Wichita center for > 10 years.

RESULTS:

Although functional disability worsened slightly and health satisfaction improved slightly, measures of pain, global severity, fatigue, sleep disturbance, anxiety, depression, and health status were markedly abnormal at study initiation and were essentially unchanged over the study period. Correlations between first and last assessment values were as high as r = 0.82. For some variables, abnormalities were 3 times greater at one center compared with another.

CONCLUSION:

Patients with established fibromyalgia, seen in rheumatology centers in which there a special interest in the disease and followed up for as long as 7 years, have markedly abnormal scores for pain, functional disability, fatigue, sleep disturbance, and psychological status, and these values do not change substantially over time. Half the patients are dissatisfied with their health, and 59% rate their health as fair or poor. There are marked differences in disease severity among the various centers, but < 14% of the variance in outcomes can be explained by demographic or center factors. Values at the first assessment are predictive of final values. Author.



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Low-Dose Naltrexone for the Treatment of Fibromyalgia
Principal Investigators: Jarred Younger, Ph.D., and Sean Mackey, M.D., Ph.D.
Stanford University, Palo Alto, California
Award Amount: $50,000

Relief from chronic pain is difficult to achieve, and this may be partly explained by the fact that there are two targets: the neurons and the nearby glial cells. All drugs to date were designed to work on the neurons, but some of them have the ability to alter the function of the glial cells. Naltrexone is one of them.

Under normal circumstances, the glial cells provide the neurons with nutrients and are silent in the role of pain transmission. However, many glia-activating substances are elevated in the spinal fluid of people with fibromyalgia, such as substance P, nerve growth factor, and even opioids produced by the body. Activated glial cells produce a surge of pro-inflammatory cytokines, including interferon, tumor necrosis factor, and various interleukins, which then sensitize the nerve fibers. The goal of the study is to reduce the sensitization of the pain-transmitting nerve fibers that are believe to be involved in fibromyalgia.

AFSA has funded Younger and Mackey to test a novel treatment option of low-dose naltrexone to relieve the symptoms of fibromyalgia. In normal doses (around 50 mg), the drug blocks pain-relieving chemicals such as endorphins (the body’s own opioids). This would certainly not be desirable for people with fibromyalgia, but the drug also blocks the activation of the glial cells so they do not produce pain-promoting substances. The key is to use a smaller dose of naltrexone (3-4.5 mg), which may still “chill out” the glial cells while not appreciably interfering with the body’s own opioid pain relievers.

The ability of naltrexone to shut down the pain-promoting activities of the glial cells was recently discovered and appears to be safe. It has been tested in small trials for the treatment of Crohn’s disease and multiple sclerosis pain. Now it will be determined if the drug can benefit individuals with fibromyalgia.

Forty people with fibromyalgia will participate in the trial. For part of the study, these individuals will receive low-dose naltrexone every night before bedtime. For another part of the study, they will receive an inactive placebo substance. Neither the participants nor the researchers will know what the participants are receiving until the study is completed. In a research plan called a crossover design, participants will start on either the drug or placebo, and will then switch to the other substance. A two-week period will separate the conditions so the drug can leave the body.

Participants will fill out a short questionnaire every night to chart their pain levels, sleep quality, physical activity, mood, fatigue and other aspects related to fibromyalgia. These symptom values will be collected on hand-held computers (e.g., palm pilots) and will allow the researchers to conduct very powerful tests of the drug’s effectiveness. For example, an analysis of the data may show that daily fatigue and pain are both reduced when a person is taking the drug. The method will also allow the researchers to identify which symptoms improve first. In addition, participants will visit the Stanford Pain Clinic Lab every two weeks to undergo more thorough and objective tests of pain sensitivity.

Finally, it is well-known that not all people will react well to a certain drug. Participants will undergo a variety of tests at the beginning of the study to determine the characteristics of the patients who reap the most relief from the medication. This will help physicians determine which individuals should receive the medication.


Establishing a Fibromyalgia Tissue Donation Program for Studying Human Chronic Pain States
Principal Investigator: Dianne Lorton, Ph.D.
Sun Health Research Institute, Sun City, AZ
Award Amount: $58,750

Effective treatments for FMS are needed, but this requires knowledge of what is happening in the cells of the central nervous system and other body tissues that are contributing to the symptoms. The purpose of this study is to enroll FMS patients into a post-mortem tissue donation program at Sun Health Research Institute (SHRI, a nonprofit research foundation), in which brain, spinal cord and other tissues/fluids will be collected.

“The SHRI tissue bank is world-renown for its quality of post-mortem tissue,” says Lorton. “Post-mortem times average 2.5 hours, making it possible to use the collected tissue for research that is not possible with tissue from other banks (e.g., the quick collection time produces tissues that closely resemble how the cells functioned when the person was alive). Tissue collected from Alzheimer’s and Parkinson’s patients at SHRI are sent to researchers all over the world. Now it will be possible to extend this tissue bank to facilitate research on FMS.”

These valuable tissues will be made available to scientists who submit top quality proposals to study FMS, which will rapidly expand our knowledge about this condition. Tissues will also be used to complete an already approved and funded project by AFSA (Translation from Animals to Humans: Are Chronic Pain States in Humans Associated with Glial Activation in Spinal Cord and/or Brain?).

The principal investigators of the above study are Linda Watkins, Ph.D., of the University of Colorado at Boulder, and Dianne Lorton, Ph.D., of SHRI. A full description of this project was provided in the May 2005 AFSA Update and can also be read in the May 2005 Update. Glial cells amplify pain by releasing pro-inflammatory cytokines. Recent studies indicate that glia within pain-processing areas of the brain and spinal cord are critical to the maintenance of pathological pain, and animal studies show total pain remission with suppressed glial activity. It is unknown whether the glia are activated in FMS, but it is a strong likelihood given the studies showing elevated levels of pro-inflammatory cytokines in the blood.

This uncertainty about the involvement of glia in FMS sets it apart from low back pain, nerve damage pain, and other pain syndromes in which a rat model with glia activation has been demonstrated. In fact, for all of these pain syndromes, the rat models prove glial activation is key ... but FMS does not even have a rat model. While it is rather easy to interest pharmaceutical companies in targeting glia for pain syndromes where the glia are known to be involved, it has proven impossible to interest them in such clinical trials for FMS.

The purpose of this related study by Watkins and Lorton is to look for evidence of glial activation in the brain and spinal cord tissues of FMS patients collected shortly after death (e.g., from this tissue donor program). Comparisons will be made with other chronic pain syndromes and healthy control subjects. If glial activation is found, it would provide a strong argument for testing drugs that target glial activation as a solution for FMS pain.

The FMS tissue donation program is expected to recruit 70 FMS patients during its first year and 20-30 more each year thereafter. “SHRI has already enrolled 20 FMS patients thus far,” says Lorton, “and are working through community education talks, local newspaper articles, SHRI facility tours, and outreach to physicians to increase enrollment.” To ensure that all patients enrolled clearly have FMS and not a condition that may mimic it, their diagnoses must be independently confirmed by two experienced physicians. Also, enrolled patients will continue to be followed by SHRI’s physicians on an annual basis to document any changes in their health status.

The establishment of a tissue donor program for FMS will accelerate knowledge about this condition and streamline the speed at which effective therapies can be developed. Lorton and SHRI are using their experience and resources to work with AFSA to develop an FMS registry to expedite research in this field. The project award is for a two-year period and was essential for demonstrating to the NIH that such a tissue bank for FMS could be successfully established.

Lorton submitted a grant application to the NIH’s National Institute of Arthritis and Muculoskeletal and Skin Disease for the continuance and, hopefully, the expansion of this tissue donor bank. “Just recently,” says Lorton, “SHRI’s application was approved and awarded approximately $1.4 million over a four year period to further support the costly endeavor of developing an FMS tissue bank and to provide additional funding for Dr. Watkins’ ground-breaking pain research.”


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Alterations in COMT Gene Contribute to Pain Susceptibility in FMS. Part 2- Comparison of large patient/control population in Mexico Versus Spain
Principal Investigator: Manuel Martinez-Lavin, M.D.
National Institute of Cardiology in Mexico City
Award Amount: $16,800
Catechol-O-methyl-transferase (COMT) is an enzyme that breaks down catecholamines (a class of neurotransmitters): dopamine, norepinephrine and epinephrine. These transmitters are involved in the regulation of the sympathetic nervous system. Many studies have shown that the sympathetic system is dominant (hyperactive) in people with FMS, while the parasympathetic branch is not as active as it needs to be to aid with sleep and digestion.

Substitution of one amino acid for another, and other structural glitches on the COMT gene, can alter the speed at which the enzyme breaks down catecholamines. For example, if the amino acid valine is substituted for methionine in a specific region, then the COMT enzyme becomes “lazy” and degrades the catecholamines three to four times slower than normal (causing the catecholamines to accumulate). This sluggishness in the enzyme’s action not only alters the way the sympathetic system works, it also leads to a lower pain threshold (i.e., greater pain sensitivity because excessive catecholamines interferes with the body’s production of pain-relieving opioids). However, there are many other potential anomalies in the gene that controls the COMT enzyme, making the genetic evaluations more complex.

In the initial study conducted by Martinez-Lavin (Part 1), he evaluated 40 FMS patients and compared them to 40 age-matched controls (all women to minimize variations). He found that FMS patients tend to have a COMT gene variation associated with increased pain susceptibility.

“These preliminary results suggest that an altered COMT gene predetermines the autonomic dysfunction in a subgroup of FMS patients,” says Martinez-Lavin. “It also provides gene-related support for the concept that FMS is a sympathetically maintained pain syndrome.” In other words, the malfunctioning sympathetic system could be responsible for the symptoms in a subgroup of patients with the COMT gene alterations.

In order to uncover more genetic variations and differences between FMS patients and healthy controls, one must look at a larger group of people. In Part 2 of the project, Martinez-Lavin will be evaluating an additional 120 FMS patients and 120 healthy controls to add to his existing genetic data. In the end, he plans to have 80 patients and 80 controls from Mexico, and a parallel patient/control group residing in Spain. He is joining forces with another investigator, Ferran García-Fructuoso, M.D., of Spain, who has collected DNA from a well-selected Spanish population. Looking at the genetic background of two different populations will undoubtedly strengthen the study. It will determine if the purported COMT gene abnormalities are similar in two different geographic areas.

“We want to add an important piece to the fibromyalgia jigsaw puzzle,” say Martinez-Lavin. “The most consistent abnormalities found so far in fibromyalgia are the electrocardiographic changes of ongoing sympathetic dominance (the chart recording should show repeating fluctuations between sympathetic and parasympathetic control, but a sympathetic dominant signal has been reported by multiple researchers). If we find that a subgroup of patients have a genetic predisposition for this sympathetic dominance, it may explain why fibromyalgia runs in some families. The genetic alteration may possibly identify people at risk of developing the illness. If we identify early on people that do not degrade catecholamines properly, and at the same time are hypersensitive to pain perception, it would be possible to take preventive interventions.”

According to Martinez-Lavin, Part 2 of his project is expected to be finished by mid-2007.


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CFS - Role of Sleep Disturbance and Exercise on Symptoms and Cytokine Production
Principal Investigator: Benjamin Natelson, M.D.
University of Medicine and Dentistry of New Jersey, Newark
Award Amount: $35,100
(AFSA Awarded a Tag-on Project to this NIH-funded Study)
Natelson’s ambitious NIH-funded project involves studying the sleep of patients during three nights in a sleep lab. The goal is to measure the impact of disturbed sleep and an exercise regimen on the next-day symptoms for CFS patients and their production of cytokines. Roughly 20% of CFS patients have measurable signs of obvious disturbed sleep (such as sleep apnea and restless legs syndrome), which means that the majority do not have a well-defined sleep disorder. Natelson excludes patients with these sleep disorders, leaving him with patients having sleep complaints that have no medical explanation. Then he divides his study group of CFS patients (many of whom overlap with FMS) into two different groups based on the results of their formal sleep study: those with disturbed sleep and many awakenings and those without disturbed sleep. For comparison, he will use an age-matched control group of women who do not have any symptoms of CFS (all CFS patients will be female because cytokine levels are higher in women and it is important to minimize variability in the data).

One hypothesis about the cause of CFS (and FMS) is that immune dysfunction leads to poor sleep, and that this immunological malfunction is linked to abnormal production of cytokines. Although cytokines have been studied in both CFS and FMS patients, no firm data exists to support the immunological ties between cytokines and sleep disruption or daytime fatigue in these patients. Cytokines are produced by the immune system and are suspected to be the neuro-immune link in CFS/FMS because the glial cells that secrete these substances reside within the central nervous system. Natelson suspects that cytokines are responsible for causing the sleep disorder in some CFS patients, and not the other way around. Due to the fact that he will be evaluating CFS patients with and without disturbed sleep, he hopes to be able to confirm this theory.

Why would cytokines cause sleep disturbances in patients? Natelson’s research team hypothesizes that this is due to abnormalities in the pattern of sleep-disrupting and sleep-promoting cytokines in patients with objective measures of disturbed sleep. For example, cytokines that disrupt sleep include interleukin-4 and interleukin-10 (i.e., IL-4 and IL-10). Those that enhance sleep onset include interleukin-1beta and tumor necrosis factor-alpha (i.e., IL-1beta and TNF-alpha). Natelson proposes to look at these cytokines periodically throughout the sleep/wake cycle to not only determine their level of production, but also their nocturnal rhythms. Then, he will try to correlate the cytokine levels with sleep study findings and symptoms.

How might cytokine production fit in with the symptoms of pain that most patients have? This is a complicated matter. TNF-alpha is a pro-inflammatory cytokine that produces pain, and IL-10 is supposed to block it (but if IL-10 levels are elevated, this could contribute to disturbed sleep). Ironically, the two cytokines that disrupt sleep were recently reported to be significantly low in the blood of patients with FMS (see box on next page for study details).

The AFSA-funded portion of this project is a tag-on to the NIH study and involves the assessment of two other important cytokines: interleukin-6 (IL-6) and interleukin-8 (IL-8). These two cytokines have been shown in more than one study to be elevated in patients with FMS.1,2,3 Elevated IL-8 was found to correlate with pain intensity and duration of FMS symptoms. IL-8 is also believed to be an indicator of sympathetically-maintained pain (i.e., pain generated by a hyperactive sympathetic nervous system). IL-6 is thought to produce not only pain, but also fatigue and depressed mood. The table on page 6 provides a brief description of the role each cytokine plays in the body. In addition, a report that was just published on the low levels of IL-4 and IL-10 in people with pain (e.g., FMS) demonstrates the dual roles that some of these cytokines play in generating the symptoms of pain and fatigue. This could complicate the picture!

Functional brain imaging studies by Natelson and others also confirm that a dysfunction occurs in the central nervous system of both CFS and FMS patients, and this may likely be a result of abnormal cytokine production.4 For example, brain blood flow evaluations in both FMS and CFS patients have shown a significant decrease in the brainstem area (which includes the pons) in both patient groups. In addition, a study by Ali Gur, M.D., of Turkey, found that a greater drop in blood flow to the pons in people with FMS meant a higher level of interleukin-8 (IL-8) in the blood.5 However, looking at the impact of depression, those patients without depressed mood exhibited even higher IL-8 levels than those who were depressed. Also, the presence of elevated IL-8 correlated with increased morning stiffness and sleep disturbance (based on questionnaires that asked about perceived sleep quality, rather than a sleep study).

After the second night in the sleep lab, the CFS patients in Natelson’s study will be guided through an exercise test. The purpose of this test is to identify the effect that exercise has on nighttime sleep. In 2002, Natelson and coworkers published a report showing that exercise in CFS patients disrupts the body’s normal 24-hour rhythm, which may help explain the common patient complaint that symptoms worsen following exertion.6 The physiological reason for this phenomenon is not known, but evaluation of the patient’s next night of sleep (the third night in the lab), including cytokine testing, may be key in understanding symptom flares.

Cytokines and Sleep

Studies in patients with obstructive sleep apnea syndrome or fatigued patients who complained of insomnia show substantial elevations in daytime secretions of TNF-alpha and IL-6, implying that a disruption of sleep causes a shift in cytokine production (less at bedtime and more during the day). With regards to IL-6, it is suspected to be associated with cognitive dysfunction, fatigue, feelings of exhaustion, and the symptom of pain. Thus, IL-6 may play a crucial role in generating the daytime symptoms of CFS, as well as those of FMS (one third of Natelson’s subjects meet the criteria for FMS).

The above findings in people with sleep disorders, along with those in FMS that persistently show elevations in IL-8 (and oftentimes IL-6), are the main reasons for AFSA’s tag-on study to Natelson’s NIH project. In order to get a full picture of the cytokine mechanisms occurring in CFS patients, both IL-6 and IL-8 also needed to be assessed.

UARS will be Evaluated!
One of the greatest drawbacks of published studies involving sleep disorders is the common belief that apnea is a pulmonary-related sleep disorder and all other sleeping difficulties (such as insomnia caused by upper airway resistance syndrome, UARS) are mental health problems. This dichotomous view is partly to blame for the lack of thorough sleep testing when apnea is not suspected (which is rarely entertained in young to middle-aged women who develop CFS or FMS). The result has produced a full body of medical literature that shows a disruption of cytokine production in patients with apnea, but none that pertains to people with UARS.7

Natelson’s project is the first study funded by NIH to evaluate patients with subtle symptoms of sleep-related breathing to determine just how much of a problem they are in CFS. In other words, he will be evaluating the often overlooked condition of upper airway resistance syndrome (UARS). He is teaming up with pulmonary/sleep researcher David Rapoport, M.D., at New York University, to determine if any of the sleep disruptions are occurring as a result of breathing impairments during the night, consistent with the diagnosis of UARS. A 2004 report by Avram Gold, M.D., of Stony Brook University in New York reported that UARS may be the source of sleep disruption in almost all patients with FMS, many of whom also have CFS.8 So, evaluating the breathing-related sleep disruptions in patients, as well as the changes in key cytokines, is an essential part of the project design.

Given that the majority of women attending a sleep clinic for evaluation of their insomnia complaints were found to have UARS in a previously published study, it is essential that this condition be assessed in order to fully understand the sleep disorder in CFS/FMS patients.9 In addition, if UARS is found to be present in most of the CFS patients who have a sleep disorder, then future studies looking at the treatment of UARS and its impact on cytokines would be warranted.

Impact of Exercise
After the second night in the sleep lab, subjects will be put through an exercise test so that its effects on cytokines and the third night of sleep can be determined. The third night in the sleep lab will be the last night for the CFS patients. The healthy control subjects will also be tested, but their total sleep time will be restricted to the average time CFS patients spent in sleep during night two. This way, the cytokine productions for both the CFS patients and the healthy controls will be based on the same amount of sleep.

After the third night of sleep, the healthy controls will undergo the same exercise test that was administered to the CFS patients following the second night in the lab. Published research shows that sleep restriction in healthy subjects (two hours for one week) causes a disruption in cytokine production rhythm.10 However, the added effects of exercise are not known, but its influence on sleep and cytokine production will be determined.

Cytokine Imbalance in FMS: Too many pain promoters & not enough pain relievers
Cytokines represent the link between the central nervous system and the immune system. When looking at their role in pain, these substances can generally be grouped into two main categories: (1) pro-inflammatory cytokines that produce pain (i.e., the bad guys) and (2) anti-inflammatory cytokines that reduce pain (i.e., the good guys). Previous studies in FMS have shown that an abundance of the “bad” cytokines exist in the blood, skin, and most likely, the central nervous system. This group of cytokines includes interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-alpha). The body also produces cytokines that counter the pain-producing effects of the “bad guys,” such as interleukin-4 (IL-4) and interleukin-10 (IL-10), but a recent study by a German team shows that they are both low in people with FMS.11

Note that while IL-4 and IL-10 are considered the “good guys” when it comes to fighting pain, they are viewed as the “bad guys” when it comes to disturbing sleep. So, for conditions in which both pain and sleep disruption exist (i.e., most patients with FMS and CFS), clear-cut groupings of these substances into “good” or “bad” is not possible, at least not for IL-4 and IL-10.

The German study consisted of 40 patients with chronic widespread pain who did not respond to standard therapies (26 of whom had FMS) and 40 healthy controls. The amount of messenger RNA for IL-4 and IL-10 in the blood was substantially lower in the pain group than in the pain-free controls (but the blood levels of these cytokines were not directly measured). If this pattern of cytokine production can be duplicated, the authors believe that it will be useful for supporting the diagnosis of FMS and guiding the development of more effective therapies. (In recent years, commercially available kits for assaying cytokines have been developed, and their cost continues to drop, so they may soon be used for diagnostic purposes.)

This study’s findings prompt an important question: What role do low IL-4 and IL-10 levels play in the development of FMS pain? Both IL-4 and IL-10 have been shown to greatly reduce pain in rats with injured nerves. In addition, IL-4 increases the number of opioid receptors on the nerves so that the body’s natural opioids can lead to enhanced pain relief. If IL-4 is low, this could mean that fewer opioid receptors are present to “tame your pain.” Prescription opioids may work well for some patients with FMS, while they may be inadequate for others. Fortunately, many therapies that target cytokine production are in the FDA-testing phase for the treatment of painful conditions. Yet, until the pharmaceutical industry is convinced that FMS pain is caused by a disruption of cytokines (due to the glial cells that produce them), these drugs will not be tested in FMS (for more details, see the discussion of Dr. Lorton’s project above).

References
Wallace DJ, et al. Rheumatol 40:743-49, 2001.

Gur A, et al. J Rheumatol 29(2):358-61, 2002.

Salemi S, et al. J Rheumatol 30(1):146-50, 2003.

Cook DB, et al. J Rheumatol 31(2):364-70, 2004.

Gur A, et al. Clin Exp Rheumatology 20(6):752-60, 2002.

Ohashi K, et al. Physiology Behavior 77:39-44, 2002.

Yokoe T, et al. Circulation 107:1129-34, 2003.

Gold A, et al. SLEEP 27(3):459-66, 2004.

Guilleminault C, et al. J Psychosomatic Res 53(1):611-5, 2002.

Vgontzas AN, et al. J Clin Metab 89(5):2119-26, 2004.

Uceyler N, et al. Arthritis Rheum 54(8):2656-64, 2006.



The Role of Inflammation for Pain in Patients with Fibromyalgia Syndrome
Principal Investigator: Roland Staud, M.D.
University of Florida in Gainesville
Award Amount: $75,000
If one could identify a chemical change in the blood of patients with fibromyalgia syndrome (FMS) during painful symptom flare-ups, it might serve as the basis for a disease severity marker and more effective therapies. This is the general premise of Staud's award, and it involves the tracking of cytokines, as well as other immunologically related substances. Elevated serum levels of specific cytokines were first identified by Daniel Wallace, M.D., of UCLA, in a previous AFSA-funded project and similar findings have been found by other investigative teams. These studies involved measuring cytokine levels at a single point in time when patients were at rest and presumably not in a horrible flare-up (this is often referred to as the baseline value). In addition, Wallace found that the elevation of certain cytokines correlated with two factors: pain levels and duration of symptoms.


"One of the questions I am very interested in," says Staud, "is the cause for exacerbations or ‘flares' of FMS pain. Much of this change is not easily detectable because of adaptive coping behaviors that most patients use." Staud comments that over time, these adaptations result in decreased function. The chemical processes that increase pain, and eventually lead to a loss of function, need to be identified and intercepted. Staud's project represents an essential step in identifying chemical changes that may be occurring in FMS patients. He will be analyzing the baseline levels of cytokines (and related substances) in patients and then follow them over time, particularly before, during and after painful symptom flare-ups. In addition to analyzing over ten substances in the blood, Staud will be using objective pain measures, such as windup, to assess the pain levels and the degree to which a person's pain may be amplified by the central nervous system (CNS)—a process referred to as central sensitization.


"My main hypothesis," says Staud, "is that repetitive injury and/or inflammation is responsible for increasing the peripheral and central sensitization processes in FMS, and thus, the subsequent worsening of pain" (and other common symptoms). These injuries or inflammatory (as well as infectious) processes do not have to be dramatic to produce subtle "erosions" in the way the central and peripheral nervous systems operate. According to Staud, cytokines and related substances are used as a common chemical language for communication between the immune, brain and hormonal systems. He adds that if these cytokine chemicals are activated in FMS, it could influence the systems that regulate stress and make patients hypersensitive to stressful stimuli, such as infection and trauma.

Alterations in cytokines have the capacity to cause "downstream" changes in a person's pain sensitivity. The longitudinal study proposed by Staud will span two years, so the work on it will continue through to the end of this year. The goal of the project will be to determine if cytokines increase with symptom flares, and if so, which cytokine-related substances produce the most dramatic changes. Identifying which substances strongly correlate with symptom flares will provide valuable insight for the development of effective therapies and potentially produce markers for disease severity, which would be a tremendous asset for use in treatment trials.

Translation from Animals to Humans: Are Chronic Pain States in Humans Associated with Glial Activation in Spinal Cord and/or Brain?
Principal Investigator: Linda Watkins, Ph.D.
University of Colorado in Boulder
With co-investigator: Dianne Lorton, Ph.D.
Sun Health Research Institute in Sun City, AZ
Award Amount: $50,000

Fibromyalgia syndrome (FMS) is viewed as a form of pathological pain. Since sensory neurons relay pain to spinal cord neurons, which relay pain to the brain, past research has focused exclusively on neurons because the neurological system was blamed for the production of pathological pain. Indeed, the neurons in the pain pathway are plastic; in other words, they are able to change the way they function. Over the years, a wide variety of such changes have been documented at various levels of the pain pathway, so it made sense for the drug development research to focus on correcting these plastic changes.

After a multitude of clinical drug trials, however, the sad conclusion is that drugs which target neurons do not control pathological pain, including FMS. How can this be? Watkins' extensive work in animals over the past ten years points to a previously unrecognized player in chronic pain.

Just as a seething crowd incites boxers in the ring (getting them all worked up), brain and spinal cord cells called glia can incite neurons in the pain pathway. This drives the creation and maintenance of pathological pain. Unlike neurons, glia do not have axons projecting to distant sites, so they cannot operate like neurons to transmit signals to various regions of the body. Instead, when glia become activated, they operate by influencing the neurons in their neighborhood (i.e., nearby in the spinal cord and brain).

Not long ago, glia were ignored by pain researchers because they were not thought to influence neuronal function. This view is dramatically changing. New research implicates two types of glia in the creation and maintenance of pathological pain: microglia and astrocytes. This newly recognized role of activated glia, which function as powerful modulators of pain, has major implications for developing pain-controlling medications.

The problem is, activated glia have not been documented in humans with FMS. Although many studies have shown that cytokines are elevated in patients with FMS, and they are the primary substances produced by glia for communicating with neurons and other cells in the immune system, the glia have not been confirmed as the source of the cytokines. Definitive proof that activated glia are responsible for other pathological pain states (such as low back pain and various conditions involving nerve damage) is not yet available in humans, either. However, for every chronic pain condition that is easily studied in rats (i.e., a rat model exists), glial activation has been proven to play a key role in the production of the pain state. FMS does not have an animal model, so this correlation in rats cannot be demonstrated with the same degree of certainty that it can in low back pain and nerve damage.

The testing of new drugs begins in rat models and then progresses to the human clinical condition. The pharmaceutical industry has already begun to develop drugs that reduce glial activation (i.e., have a calming effect on these cells) and they are targeting conditions in which animal models exist. In this regard, FMS is at a distinct disadvantage because an animal model that represents the human condition has not yet been developed. The result is that the drug industry is not willing to take an expensive and potentially dangerous leap of faith with bypassing the animal testing phase and including people with FMS in their clinical trials.

With an animal model for FMS nowhere in sight, this study has many goals: (1) look for evidence of glial activation in the brain and spinal cord tissues of humans shortly after they have passed on, (2) compare the results found in deceased FMS patients with that of other donors with known chronic pain conditions in which an animal model has shown glial activation, and (3) also compare the results for all conditions to that of donor tissue of healthy, pain-free controls. If glial activation is found, it would provide a strong argument for testing drugs in FMS that target glial activation.

Due to the fact that human subjects have NEVER been assessed for glial activation (even in painful conditions where animal models involving glial activation are available), it is essential that other chronic pain states be used for comparison to build a bridge between animal models and their respective clinical conditions. How else can the results be interpreted—not just whether glial activation exists but also the degree to which it might exist? If Watkins' hypothesis is correct, then tissue from FMS patients will show activated glial cells, and in a roundabout way, it will aid with developing an FMS animal model. Of course, a successful outcome will also encourage the pharmaceutical companies to include FMS in their clinical trials ... even those that have or are just about to undergo human clinical testing. Shortly after AFSA awarded this grant, Watkins was successful in obtaining the supplemental funding from the NIH that is needed to thoroughly pursue all of the goals of this study.

As Watkins indicates, current medications that target neurons do not perform well for treating chronic pathological pain, such as that of FMS. "We believe that this failure is due to the fact that these drugs do not target glial function," states Watkins. AFSA is fortunate that Watkins has taken a strong interest in FMS so that this condition will not continue to be ignored by the vast majority in the pharmaceutical industry.

Association of Fibromyalgia with the Low Activity Catechol-O-Methyl-Transferase (COMT) Alleles
Principal Investigator: Manuel Martinez-Lavin, M.D.
National Institute of Cardiology in Mexico City
Award Amount: $12,000

Prior research by Martinez-Lavin has demonstrated a prominent alteration in the autonomic nervous system (ANS) of patients with fibromyalgia syndrome (FMS). The ANS is the portion of the nervous system that regulates body temperature, blood pressure, heart rate, bowel and bladder function, and other vital processes. By working closely with the brain, the ANS helps regulate these functions that occur in the periphery (e.g., outside the central nervous system), and it also influences the production of a variety of hormones.

The ANS is divided into two branches: sympathetic and parasympathetic. These two branches have antagonistic (i.e., opposite) effects on most bodily functions. Sympathetic activity puts the whole body in a state of "high alert," whereas parasympathetic activity favors the promotion of sleep and digestive function. Using a technique called heart rate variability analysis, Martinez-Lavin's group has demonstrated that people with FMS have a relentlessly hyperactive sympathetic nervous system. Based on his findings, Martinez-Lavin proposes that the key features of FMS (widespread pain and tender points) are largely produced by a physiological mechanism known as "sympathetically maintained pain."

The sympathetic nervous system communicates through the production of catecholamines, and these substances may be degraded by enzymes that have genetic anomalies that could potentially influence the entire ANS function. The three catecholamines used by the sympathetic branch are: dopamine, norepinephrine and epinephrine.

Catechol-O-methyl-transferase (COMT) is an enzyme that inactivates catecholamines. Martinez-Lavin proposes that a slight alteration in the genes that regulate the COMT enzyme could be the missing link to low pain thresholds in people with FMS. The idea for this AFSA-funded project stemmed partly from research published by Jon-Kar Zubieta, M.D., Ph.D., of the University of Michigan. He showed that a single amino acid substitution in the structure of the COMT gene could alter pain processing and produce low pain thresholds in roughly 20% of the general population. This variant of the gene produces a "lazy" COMT enzyme that is unable to clear catecholamines properly. This in turn affects the functions in the ANS that are controlled by dopamine and norepinephrine, and also interferes with the body's opioid-like analgesic substances.

In people with the normal or "effective" gene that codes for the COMT enzyme, their ANS works as it should and they have normal pain thresholds. Martinez-Lavin's project will evaluate the gene that codes for the COMT enzyme to determine if the "lazy" variant is more prevalent in patients with FMS, compared to pain-free healthy controls.

At the October 2004 American College of Rheumatology (ACR) meeting, Martinez-Lavin provided preliminary data from this AFSA-funded study with roughly one fourth of his subjects evaluated. He found that FMS patients were more likely to have the gene that coded for the "lazy" COMT enzyme, while healthy controls tended to possess the version that coded for the "effective" COMT enzyme. Some overlap was present in the data and clear-cut conclusions could not be drawn. However, three months after his ACR presentation, Martinez-Lavin suggested to AFSA that additional genetic testing be done because a January 2005 report by Luda Diatchenko, Ph.D., of the University of North Carolinal, indicated that other genetic variants coding for the COMT enzyme have been found. This latest study demonstrated that the susceptibility to pain in normal people was highly reliant upon the additional variations in the COMT gene. Does this mean that evaluation of the other genetic variants for the COMT enzyme could provide more conclusive data for FMS?

According to Matinez-Lavin, "A combination of variants give rise to a COMT enzyme that is even less effective in clearing catecholamines from the system and has a stronger association with pain perception." Referring to the genetic structures detailed in Diatchenko's report, he adds, "This model further advances our proposal of fibromyalgia as a sympathetically maintained pain syndrome." Searching for the presence of the other genetic variants among the 40 FMS patients and 40 pain-free controls is the basis for the next grant that AFSA has awarded to Martinez-Lavin.

Part 2: Cloning a Pain Neuropeptide Receptor
Principal Investigator: John Stewart, Ph.D.
University of Colorado in Denver
Award Amount: $37,475

In 1998, AFSA initially funded Stewart with a small grant ($24,560) to begin the process of cloning the receptor of the end fragment of substance P, referred to as SP(1-7) or simply SP-N. Click here for details of the project and a 2003 progress report. SP-N is enzymatically cleaved off from substance P and has been shown to have pain-relieving properties. Coming up with medications that "act" like SP-N could generate a new class of effective pain-fighting drugs, particularly for combating the extremely high levels of SP that exist in the spinal fluid of people with FMS. Yet, in order for the drug industry to begin making "SP-N like" medications, the structure of the receptor at which it binds to for communication within the central nervous system must be known. Otherwise, it would be like trying to make a customized key for a lock without first knowing the type and structure of the lock.

Stewart has completed several major hurdles of this arduous task and this AFSA award represents the last phase of the journey (Part 2). When AFSA initially funded the first part of this project, concerns were raised that it would take many years. Now that several years have passed, the end is sight! Stewart's tenacity, along with his experience as a biochemist with a keen understanding of FMS, has proven invaluable.


A Case-Controlled Study of Proton Spectroscopy in Fibromyalgia
Principal Investigator: Patrick Wood, M.D.
Louisiana State University at Shreveport (LSU)
Award Amount: $37,450

Fibromyalgia has long been associated with abnormalities in the body's stress response mechanisms and is believed to be due to problems in brain function. Symptoms often surface for the first time after a stressful insult to the body that may include trauma, infectious agents or a prolonged time of severe duress. Once symptoms have developed, stress also tends to make the symptoms worse. Researchers have shown that those parts of the body responsible for handling stress may be overactive in patients with FMS (e.g., hyperactivity of the corticotropin-releasing hormone neurons, which are believed to blunt growth hormone secretion during exercise, and a sympathetic nervous system that is pushed into hyper-drive so that it can't respond appropriately to common daily stressors). These hormonal and nervous system problems could explain many of the symptoms of FMS, including widespread pain, but the search for the root cause of this situation is essential in order to better understand how to treat FMS.

The hippocampus is part of the limbic system of the brain which is best known for its role in memory and learning—but it has many other functions. The hippocampus is also responsible for "putting the brakes" on the stress response network, to prevent it from running out of control. Ironically, the same chemicals that characterize the stress response (namely cortisol, corticotropin-releasing hormone, and adrenaline) are also known to damage the hippocampus, making it less able to do its job. In addition, the hippocampus also handles pain signals by routing them from the spinal cord to the brain. Exposure of the hippocampus to stress chemicals may therefore be associated with the development of chronic pain, such as that found in FMS and CFS patients.

Magnetic resonance spectroscopy (MRS) is a technique used to characterize the chemical content of living tissue without having to take a sample. Using this technique, researchers Patrick B. Wood, M.D., and James C. Patterson, M.D., Ph.D., at Louisiana State University Health Science Center in Shreveport, will investigate whether or not patients with FMS have a lower concentration of n-acetylaspartate, or NAA, in their hippocampus. NAA is a marker of integrity and function within the brain, and a decrease in its concentration is associated with a variety of illnesses. In fact, a short communication published in The British Journal of Radiology in November of 2000 (volume 73, pages 1206-08) indicated that patients with CFS exhibited a substantial decrease in their hippocampal concentration of NAA. The study only assessed seven CFS patients, but this preliminary report presents a strong case for the measurement of NAA levels in both CFS and FMS patients on a larger scale. Wood and Patterson will also be evaluating the effects of depression and anxiety in FMS patients because they may often coexist in people with chronic illnesses.

Other cerebral metabolites will be measured by MRS to provide more knowledge about FMS. Creatine (Cr) levels are predictive of the rate of cellular metabolism and choline (Cho) levels are thought to be a marker of glial cell function. Glial cells surround the neurons in the brain to assist in regulating transmissions and the transfer of nutrients. Hippocampus volumes will be measured as well because a decreased size has been found in patients suffering from combat-related post-traumatic stress disorder (PTSD). People with PTSD not only have impaired memory functions similar to FMS/CFS; they also have higher than normal levels of stress hormones circulating within their brain.

If patients with FMS (and possibly CFS) are found to have a lower concentration of NAA in their hippocampus compared to those without FMS, this might explain the hyperactive stress response, widespread pain, "fibro fog," and many other symptoms. Medications are available to protect the integrity of the hippocampus, but they are not prescribed for patients with FMS/CFS because there is currently no basis for their use. However, if the NAA concentrations are low in patients, then this study will open up a new avenue of drug therapies that will enable the hippocampus to recover from its stressful environment. In addition, abnormal concentrations of NAA, Cr, or Cho in the hippocampus, as well as a smaller hippocampus size, could prove to be of benefit diagnostically for patients.

Dr. Wood is an Assistant Professor at LSU Health Science Center and also serves as co-director of their Primary Care Pain Management Clinic. He recently completed a research fellowship in Psychopharmacology and was honored as one of the nation's most promising New Investigators by the National Institutes of Mental Health (NIMH) for his work involving a novel treatment for patients with FMS. NIMH is one of the major Institutes involved in brain research. He is eager to use his special training in neuropharmacology to help identify novel drugs or potential new classes of medications that will benefit patients with FMS and CFS. Dr. Patterson is director of the neuroimaging research center at LSU and is working with Dr. Wood to bring MRS technology to the field of FMS.



EBV Transformation for Genetic Studies on FMS
Principal Investigator: Laurence Bradley, Ph.D.
University of Alabama at Birmingham (UAB)
Award: $28,049 - January 2002

In the August 2001 issue of the AFSA Update, we mentioned that AFSA was in the process of approving a research project that would be awarded in memory of Laura Skalla, an FMS patient who died tragically in an automobile accident last year. What follows is a description of the award that we alluded to in that Update. Unlike most projects that are funded in the biomedical field, this particular AFSA study will lay the groundwork for an unlimited number of future genetic studies on FMS. In simple terms, the "EBV transformation" in the title above is a process that takes blood samples and immortalizes the genetic material in the cells to generate a replenishable supply of DNA that can be used for qualified AFSA applicants at anytime well into the future. The usefulness of this project will span many years and, in like fashion, we hope that this facet of the study helps to preserve the memory of Laura for the hundreds who contributed on her behalf.

Evidence for a sex-dependent genetic predisposition for the development of FMS is slowly accumulating. The first published study in the 1980s by Mark Pellegrino, M.D., hinted that the genetic predisposition of FMS may be strong, but that the expression of the condition was more likely to occur in female offspring. Many studies since have implicated a strong genetic role in FMS, including studies showing the high incidence of FMS-like sleep disturbances in school-aged children of mothers with FMS and a genetic abnormality pertaining to the way the nervous system in FMS patients regulates the production of serotonin ... an important transmitter involved in pain and sleep.

Laurence Bradley, Ph.D. and his team of FMS experts at UAB plan to compare several measures of pain sensitivity, blood serum serotonin levels, and the frequency of a specific polymorphism in the promoter region of the serotonin transporter gene (5-HTT) in eight (8) groups of subjects. This will build on recently published genetic findings on polymorphism of 5-HTT in FMS patients (polymorphism means more than one structural abnormality occurring in the gene, and in this case, the gene that regulates serotonin production). The eight groups of subjects are: 80 female FMS probands, 80 sex-matched control subjects, 40 sisters and 40 brothers of the FMS probands, 40 sisters and 40 brothers of the control subjects, 40 male spouses/partners of the probands, and 40 male spouses/partners of the controls. These procedures will be performed over a 5-year period as the core part of a larger genetic study.

Bradley anticipates a rank ordering of pain sensitivity across the eight subject groups with the greatest pain sensitivity among the FMS probands, followed by their sisters, followed by their brothers, and then among the remaining groups (controls, sisters and brothers of the controls, and the two spouse/partner groups). He anticipates similar relationships among these subject groups and serum serotonin levels. It is also believed that serum serotonin levels will be found to make a significant contribution to the group differences in pain sensitivity. Finally, the UAB team suspects that the polymorphism in 5-HTT will be found significantly more frequently in the FMS probands compared to the controls. Exploratory analyses will be performed to determine if the polymorphism is found more frequently in the sisters of the FMS probands compared to all of the other sibling groups.

Support from AFSA will allow UAB to create a replenishable supply of genomic DNA from the flood serum donated by the participants using a procedure called EBV transformation. This will ensure that Bradley's team has a sufficient supply of DNA to test their hypotheses concerning the 5-HTT polymorphism. It will also allow them to perform future genetic studies regarding the causes of abnormal pain sensitivity among women with FMS as other candidate genes are identified by basic science investigators (in other words, as genetic technology expands, so too can the genetic basis of FMS increase). Moreover, genetic DNA material will be kept in frozen storage to be made available to other qualified investigators with promising research ideas concerning the causes of FMS. Long delays to recruit 400 samples and the corresponding massive amount of clinical data on each sample will be circumvented by the AFSA project. As Bradley explains in his grant proposal, it will take five years to collect the samples and data, but once the project is completed, future investigators can swiftly obtain the genetic material at a very minimal cost of shipping and handling!

"This project will contribute to more rapid advances in our understanding of the causes of abnormal pain sensitivity in women with FMS, and thus lead to significant advances in treatment," says Laurence Bradley, Ph.D. The genetic glitches that are the most substantial can be targets for early therapy. Currently, there are so many abnormalities in FMS that it is difficult, if not impossible, to know which ones appear first, and then cause other abnormalities to develop. Genetic studies will greatly clarify this confusion. As science progresses, there is also the hope that genetic knowledge can lead to genetically based treatments. Also commenting of the significance of this AFSA-funded project, medical advisor Robert Bennett, M.D., says, "This project will hopefully establish AFSA as a `major player' in FMS research."




Noradrenaline Deficient Mice as a Model for FMS
Principal Investigator: Luc Jasmin, M.D., Ph.D.
University of California at San Francisco
Award: $56,925 - July 2001

Wouldn't it be great to have an animal model for FMS in which therapies could be quickly and easily tested? Then medications such as morphine, which ought to obliterate the pain of FMS instead of just reducing it by 25-50%, could be tested to determine if the addition of some other chemical that works on the pain system might boost its action. These two goals are the primary aims of Jasmin's project.

With the aid of an NIH grant received two years ago, Jasmin has already looked at the effects of reduced levels of noradrenaline (NA) in rats. Not all the NA was depleted from the rats and the process was only temporary. However, when the NA was low, the rats were very pain sensitive and produced excessive amounts of substance P, a situation that is analogous to that of people with FMS. When the NA levels returned to normal (about two weeks later), the rats no longer showed any signs of being in pain.

The results from this ongoing study prompted Jasmin to take a genetic approach to modeling FMS. For the AFSA-funded project, he will study the pain behavior of mice that are missing the gene that codes for the enzyme that is needed for making NA. Despite the lack of NA in their nervous system, these mice develop normally ... just like FMS patients who show no obvious signs of disease. Yet, these mice show symptoms similar to FMS, such as increased pain responses to mild pain stimuli (hyperalgesia), difficulty in concentration on tasks, tiredness, and dysfunction of the autonomic nervous system (e.g., the "auto-pilot" system that controls heart rate, breathing, responses to stress, digestion, etc.).

In the coming year, Jasmin will be examining these mice to see if substance P is involved in producing their hyperalgesia. Because nerve growth factor is also significantly elevated in people with FMS, Jasmin will be looking at this substance as well. Key to his studies in these mice is that NA can be restored, allowing him to ensure that it is the absence of NA and not some unrecognized developmental effect of the gene deletion that is responsible for his findings. It is hoped that both the symptoms and the biochemical abnormalities (high levels of substance P and nerve growth factor) will make this mouse a reliable model for further evaluating new therapies for FMS as well as its underlying physiology.

Jasmin is taking his project one step further. He will also be looking at a therapy that should be highly effective for controlling FMS pain: morphine. Jasmin will test the pain relieving effects of this opioid by itself and in conjunction with adding NA . He hopes to determine if the low NA levels (which are known to be present in FMS patients) could be the reason why opioids do not work as optimally as they should in FMS. If so, then the addition of medications that increase NA could also boost the pain relieving action of opioids in people with FMS.


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Autoimmune Mechanisms of Disordered Pain Perception
Principal Investigator: Thomas Fasy, M.D., Ph.D.
Mount Sinai School of Medicine, New York
Award: $58,400 - March 2001

It is now well established that our bodies make natural anti-pain substances known as endorphins or endogenous opioids. These endogenous opioids are peptides, (i.e., very small proteins). From a chemical or structural point of view, they are quite distinct from morphine or demeral. Yet, from a functional or pharmacological point of view, they exert amazingly similar effects on the central nervous system. These effects include a marked dampening of pain perception (i.e., reduction in pain), an enhanced sense of well-being or even euphoria, a suppression of anxiety, and an improved ability to tolerate stress. Clearly, the endogenous opioid peptides constitute a class of neurotransmitters that, if somehow disturbed, could have important ramifications in producing the symptoms of FMS.



The first endogenous opioids, the enkephalins, were discovered in 1975. Beta-endorphin is one of the more commonly referred to enkephalins, but simply measuring beta-endorphin alone to determine if the body's internal opioid system is working okay would be a terrible oversight by today's standards. Currently more than 20 endogenous opioid peptides have been identified. In fact, the endomorphins (which are morphine-like substances) and nocistatin (another novel opioid peptide) were discovered as recently as 1997 and 1998, respectively. Consequently, it is possible that additional endogenous opioids produced by the human body still remain undiscovered. Moreover, all of the mechanisms by which these recently discovered endogenous opioids work have not yet been extensively studied and their involvement in painful diseases such as FMS remains unclear.

Despite all the new advances in medical research, the underlying cause(s) of FMS remain a mystery. Given the new insights that have developed in the area of endogenous opioids, it begs the question of whether any of these molecules could be disrupted, destroyed, or somehow inadequately produced in people with FMS—and it was Dr. Fasy who first came to AFSA with this question two years ago.

In Fasy's first award from AFSA (June 1999), he looked for the presence of antibodies to more than a dozen neuropeptide molecules. These antibodies could deplete or destroy important pain relieving substances produced by the body and, if present, Fasy postulated that they could be involved in generating the symptoms of FMS. First he screened ten strains of mice that might be producing such antibodies. Fasy found one particular strain that produced an abundance of antibodies to a few important neuropeptides that could attack pain-relieving substances, particularly the body's enkephalins and historphin. Historphin works not only to reduce pain but also is reported in the medical literature to influence various hormonal (endocrine) actions in the body, including bone mineralization. So, a dysregulation of historphin by antibodies might plausibly contribute to the hormonal abnormalities reported in FMS.

As it turns out, this mouse strain displays many of the symptoms of FMS, but more testing on pain sensitivity needs to be done. They are timid and lack aggression, suggesting the possibility that this strain of mice are excessively fatigued. Fasy has further analyzed how the antibodies produced in high quantity might be working in the mice ... and potentially in human FMS patients as well. These data were presented at the American College of Rheumatology (ACR) meeting last November. Fasy was interviewed at that time and the answers to certain aspects of his research are below.

Several features of FMS suggest the possibility that these patients have a neuroendocrine imbalance which might very well include either a suboptimal response to or a deficiency of endogenous opioids. Such a deficiency could result not only from insufficient synthesis of one or more endogenous opioids, but also from an acceleration of their breakdown or hastening of their removal from the fluids which bathe the nervous system (these latter two modes could be due to the production of autoantibodies).

Fasy's second award builds on the exciting findings of his first AFSA-funded study. He will now test the hypothesis that, in many patients with FMS, the opioid peptide signaling network is disrupted by autoantibodies which bind to enkephalins, nocistatin, or historphin. This should prevent their normal functions and create an autoantibody-induced depletion of these essential endogenous opioids needed for relieving many FMS-like symptoms. A second goal of this project is to develop mouse models which will make it possible to study the extent to which enkephalin-, nocistain-, and historphin-binding autoantibodies perturb normal mouse behavior, especially responses to mildly noxious stimuli.

First blood sera from 30 patients with primary FMS (but no other disease), 30 healthy controls, and 20 patients with secondary FMS (FMS plus another rheumatic disease such as lupus or RA), will be screened. This amounts to a total of 80 samples from project collaborator, I. Jon Russell, M.D., Ph.D., of UT at San Antonio. Then the next step in the project will be to identify the most significant autoantibody findings in the sera and analyze for these same autoantibodies in the cerebral spinal fluid taken from the same subjects from which the sera was drawn (naturally all sorts of symptom data have been recorded by Russell for all study participants as well). The most remarkable and consistent findings in FMS to date have been uncovered in the spinal fluid, such as several-fold increases in substance P and nerve growth factor concentrations. Thus, this latter phase of the project may be where the most "golden" findings are discovered.

Based on just preliminary findings from this study, Fasy was successful in getting three scientific posters accepted for presentation at the September MYOPAIN 2001 meeting in Portland, OR. With a wealth of experience in molecular biology and genetics, autoimmune diseases, and pathology, it is now hoped that these two projects will launch Dr. Fasy into a career in FMS as well! What follows are the answers to just three of many questions that you might have regarding Fasy's exciting studies:

Q - When physicians order an autoantibody panel for a patient, which would include the ANA test, the findings typically come back negative. Does this mean that all autoimmune causes for their symptoms can be ruled out?

A - No, this approach doesn't cover the whole waterfront because the standard ANA test fails to detect some antinuclear antibodies. The binding sites on certain nuclear antigens may be buried and not accessible, so they just don't generate a colorful staining pattern that is needed for identifying antibodies with the standard test kits that are commercially available at laboratories. (In other words, Fasy's results can only be found in a high-tech research setting at this point in time, but it is possible to develop a standard test kit down the road, if warranted.)

Q - What about therapy options for patients who test positive for antibodies that may be destroying their enkephalins?

A - There are numerous potentially useful drugs that have been developed in the test tube that are awaiting clinical trials. So pharmacological interventions may be possible.

Q - The enkephalins mostly act on the delta opioid receptor, yet it is the mu receptor that morphine and other available opioids work on. What do you think about the work presented by AFSA-funded researcher Haiko Sprott, M.D., who found an 81-fold increase in the mRNA for the delta opioid receptor in the skin of FMS patients?

A - I think that disturbances of delta opioid receptors, which might also be called "enkephalin-receptors," may play a very important role in FMS. Maybe a small or large fraction of FMS patients have some difficulty in producing the enkephalin molecule that binds to delta opioid receptors to activate them. Perhaps there are autoantibodies or other processes accelerating the removal of enkephalins needed for turning on the delta receptor that delivers pain relief in the tissues.

(Fasy points out that promising delta opioid agonist drugs—which activate the delta opioid receptor—have already been developed by Astra Zenera, Smith-Kline-Beecham and other major pharmaceutical companies, but are still in the testing phase.)


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Opioid Receptors in the Skin and Muscle Tissue of FMS Patients - Part 2
Principal Investigator: Haiko Sprott, M.D.
Zurich, Switzerland
Award: $25,000 - April 2001

The purpose of Part 1 of Dr. Sprott's study was to look at the expression of opioid receptors on the cell surfaces of both skin and muscle tissue, with a focus on patients with FMS. There are three major types of opioid receptors: mu, kappa, and delta. Sprott measured the distribution of these various receptors in the skin and muscle tissue, and compared it to the normal brain tissue of one deceased age-matched woman. At the October 2000 American College of Rheumatology (ACR) meeting, he provided data that showed for the first time that a high population of opioid receptors, particularly kappa and delta, reside outside the central nervous system (i.e., the brain tissue). On the other hand, the mu receptor was not found in the skin and muscle tissues of healthy controls—only in the brain tissue.



Most prescription opioids work on the mu receptor, meaning that they must act within the central nervous system (CNS) and this can usually lead to unwanted side effects at doses needed to effectively alleviate the pain. Now that Sprott has established that the peripheral tissues are densely populated with delta and kappa opioid receptors (in particular the skin of FMS patients), this opens up other opportunities to treat pain without having to deal with the CNS side effects.

Preliminary data comparing the expression of delta and kappa opioid receptors in the skin and muscle tissue of FMS patients to that of healthy age-matched controls was also presented by Sprott and his colleague Souzan Salemi, Ph.D., at the ACR meeting. Based on half of the people to be tested, an 81-fold increase in delta and a 14-fold increase in kappa opioid receptors were found in the skin of FMS patients. Ironically, no differences could be found for these same receptors in the muscle tissues.

The findings in the muscle tissues may seem odd at first, because most patients will say that their muscles hurt. Sprott explained that FMS patients may not be able to distinguish between pain arising from the skin and pain arising from the muscle tissues beneath the skin. Also, the vast majority of findings on FMS point to a dysfunctional pain regulating system that thrives off of noxious inputs to the CNS from the peripheral tissues. The abnormalities in the skin of FMS patients could function as the "food" that keeps this pain state alive.

All of the above findings, funded in part by AFSA, are so amazing that Dr. Sprott has been awarded additional funding to continue his investigations in this area (Part 2). Not only are Sprott's initial findings novel, but the potential for treatments is high given that delta opioid agonists have only recently been developed.

Sprott is performing a number of tests to better understand why the opioid receptors in the tissues are present in abnormally high concentrations in FMS. At the September 2001 MYOPAIN meeting in Portland, OR, Sprott will be presenting both a lecture and a poster abstract to explain the findings just described. Then at the November 2001 ACR meeting in San Francisco, CA, he will present the results of two new findings that were funded in part by AFSA.

As Sprott continues with his investigations in this area, he is keeping an open mind as to the cause of his findings on delta opioid receptors in the skin of FMS patients. It is possible that the receptors may be damaged or flawed, so that the body's endogenous opioids don't work on them properly. Sprott will need a delta agonist to test this hypothesis, but they are not available yet. If the delta opioid receptors are abnormal, Sprott says the next step will be to create a delta-like drug that would fit these receptors to treat FMS patients. This would require more funding, but it can be done!


The Role of DNIC in FMS Pain and Treatment
Principal Investigator: Serge Marchand, Ph.D.
University of Quebec, Canada
Award: $49,407 - May 2000
Even if the origin of FMS is unclear, certain biochemical disturbances like serotonin and norepinephrine are well known. Now, these abnormalities may be easily evaluated in a test being used by University of Quebec neuroscientist Serge Marchand, Ph.D., and Pierre Arsenault, M.D., Ph.D., a researcher and practicing physician. This two-man team presented preliminary data at the October American Pain Society meeting indicating that the DNIC or diffuse noxious inhibitory control system is not working properly in FMS patients.

What is the DNIC supposed to do? When noxious or potentially painful signals enter the spinal cord in route to the brain, it is supposed to put a damper on them. The system relies heavily on serotonin and norepinephrine, which have been shown in studies to be low in FMS. Marchand and Arsenault have taken a small group of FMS patients and healthy controls to test the effectiveness of the DNIC in minimizing the pain produced by gradually submersing an arm into an uncomfortably hot or cold water bath. They begin by first submersing the fingertips, then they segmentally work up the arm in eight steps until the whole arm undergoes the painful submersion process.

The DNIC system in healthy people kicked in after just a small portion of the arm was submersed so that these people did not feel much difference between a hand submersed and a whole arm submersed. In the FMS patient group, the DNIC system didn’t appear to work. The more surface area exposed to the painful temperatures of the bath, the more pain the person with FMS experienced.

In the AFSA-funded study, the goal of the investigators is twofold: First, to see if the lack of DNIC system function in FMS patients can be used as a measure to distinguish them from healthy controls, those with depression and those with low back pain, a regional pain syndrome. And, second, to use Effexor-XR (the extended-released version) to determine whether this drug will improve the action of the DNIC system in FMS patients as well as improve their overall functional well-being.

Project Update
At the American Pain Society (APS) meeting in April 2001, Serge Marchand, Ph.D., explained that there are at least three pain control systems in the body. One is the ascending system that works to minimize the influence of the inputs or signals from the tissues that are traveling to the spinal cord. Another system involves the network of pain processing centers in the brain. The third is the diffuse noxious inhibitory control (DNIC) system. It works mostly in the spinal cord to filter out signals traveling to the brain.



Referring to all three systems, Marchand says the first two seem to be working somewhat in FMS patients, but not perfectly. On the other hand, he says, "The DNIC system doesn't seem to be working at all." Marchand offered three explanations: "a reduction of serotonin, noradrenaline, and maybe an effect of hormones."

Marchand went through his elaborate studies comparing the DNIC function in FMS patients to that of healthy controls. In controls, the DNIC system kicks into action as soon as the pain becomes too intense. In FMS patients, the DNIC doesn't even appear to "turn on" when the painful stimulation gets to be too much. "FMS patients do not have a break from the pain," says Marchand. After a while, the processing centers in the brain become dysfunctional as well.

"What is the future direction for researching the DNIC problem?" asks Marchand. "It's looking at the role of serotonin and noradrenaline drugs on pain perception." With funding from AFSA, Marchand is testing to see if Effexor-ER can restore the functioning of the DNIC system in FMS. Effexor is a drug that increases the CNS levels of both serotonin and noradrenaline. Only half of the study participants had been entered into the trial a the time of his speech. Perhaps at next year's APS meeting, Marchand and his co-investigator, Pierre Arsenault, M.D., Ph.D., will be able to present their final results.


Molecular Biology of Opioid Receptors in Skin and Muscle Tissue of FMS Patients
Principal Investigator: Haiko Sprott, M.D.
Zurich, Switzerland
Award: $49,947 - June 1999

Fibromyalgia affects approximately 3% of Americans and Europeans. The chronic pain is so severe that it adversely impacts both the quality of life and the productivity of individuals in their prime of life. The treatments that are currently available are largely ineffective, claims the principal investigator of this study, Haiko Sprott, M.D. He explains that this is due in part to the relatively recent recognition of this disease and in part to its complexity. In response to this predicament, Sprott proposes that the recent introduction of novel molecular biology techniques be employed. These types of techniques have provided new insights into the mechanisms underlying other disease processes and offers the means necessary to test novel hypotheses that may form the basis for more effective therapies.

Sprott and coworkers propose that patients with FMS undergo a change in the expression of the receptors that recognize opioid molecules in their muscle tissue; that is, in the peripheral nervous system. Opioids are a group of analgesic molecules that are produced by the body, as well as being used in pain therapy. Upon interacting with their specific receptors, opioids modify the ability to perceive pain.

According to our hypothesis, says Sprott, the receptors for opioids are down-regulated in the skin and/or muscle tissue of patients with FMS, leading to the pain of the disease and interfering with the ability of opioid-type medications to fully alleviate the pain of FMS. (By “down-regulated”, Sprott means that the opioid receptors are either not present in the tissues or that they are not functioning properly. In fact, he presented preliminary data at the 1998 American College of Rheumatology meeting to imply that this is very likely the case, at least in the skin of many patients with FMS.)

Sprott proposes to test the above hypothesis by characterizing the expression of the opioid receptors in the skin and muscle biopsy tissue from patients with fibromyalgia and comparing the quantities of the specific types of receptors (Delta, Kappa and Mu) with those in a group of control patients. The level of opioids produced by the body and secreted into the plasma will also be measured as another indicator of the body’s pain regulating dynamics. These analyses will shed light on the biology of the disease and then serve as a basis for designing therapeutic interventions.

In a small scale study by Sprott, he found that the Kappa and Mu opioid receptors in the skin of FMS patients were down-regulated (a significantly smaller quantity was found in patients when compared to healthy controls). However, the Delta receptors seemed to be present in normal quantities and may be the target for future therapies. If Sprott’s data can be duplicated in this expanded study, he suggests that a topical cream that works on the Delta receptors could be developed and tested to determine if it will help minimize FMS pain. No commercially available opioid medication specifically targets the Delta receptor. Those most commonly prescribed work at the Mu receptor which may not be present in sufficient quantities in FMS patients to provide adequate pain relief. This can lead to a situation in which the higher opioid dose required for analgesia (if it is attainable) may create unmanageable side effects for patients.

Dr. Sprott has extensive experience in both the clinical care of patients with fibromyalgia and the use of molecular biology tools. He has been involved in FMS research since 1991 and has collaborated with investigators world-wide to help advance the science of this condition.


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Autoantibodies to Neuropeptides in Fibromyalgia
Principal Investigator: Thomas Fasy, M.D., Ph.D.
Mount Sinai School of Medicine, New York
Award: $40,000 - June 1999

FMS, as well as CFS, is often characterized by various immunologic abnormalities such as allergies and/or evidence of autoimmune (anti-self) responsiveness. In this project, Thomas Fasy, M.D. is going to search for autoantibodies which bind to various neuropeptides (neurotransmitters and hormones) that are suspected to be malfunctioning in people with FMS. This binding process, if detected, could interfere with the ability of neuropeptides to function properly. Many experts now believe that a key feature of FMS is a disruption of the normal processing of pain and sensory stimuli in the brain, apparently due, at least in part, to neuroendocrine disturbances. The nature and location of these disturbances remain to be identified and clarified.

This research project is designed to test an autoimmune hypothesis for the suspected neuroendocrine disturbances in the pain processing centers in the central nervous system; namely, that patients with FMS, as well as some autoimmune mice, produce autoantibodies which specifically bind to one or more neuropeptides or hormonal factors relevant to the pathogenesis of FMS. Say for example, that people with FMS produce antibodies that bind to a substance that is crucial in the regulation of pain. Then identifying such an antibody would be vital for understanding FMS and developing therapeutic interventions.

Fasy proposes to search for antibodies to more than a dozen neuropeptides that might plausibly be involved in generating the symptoms of FMS. He will be analyzing both the serum and spinal fluid of well-characterized patients with FMS. Fasy will also be screening the sera from eleven strains of mice that already exhibit autoimmune diseases. If neuropeptide-binding autoantibodies are found in a given strain of mice, then this could assist in understanding the physiological effects of the autoantibodies and potentially hasten new treatment approaches.

The project proposed by Fasy is extremely timely (see box below). Along with looking for autoantibodies to neuropeptides, such a substance P, he will also be searching for autoantibodies which bind to the two recently discovered opioid-like substances, nociceptin and nocistatin. The structures of these two functionally antagonistic neuropeptides were only recently determined and may turn out to be essential clues to understanding the neurobiology of FMS, CFS and other related pain syndromes.

All in all, Dr. Fasy’s search for neuropeptide-binding autoantibodies that correlate with FMS symptoms represents an important first step in clarifying the neuro-hormonal dysfunction that occurs in people with this condition.


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Randomized Clinical Trial of Clonazepam versus Placebo in FMS/CFS
Principal Investigator: Don L. Goldenberg, M.D.
Newton-Wellesley Hospital, MA
Award: $24,450 - January 1999

At the American Association for CFS in October '98, several physicians stated that clonazepam (brand name Klonopin) was one of the more effective single agents that they used for patients with CFS and FMS. Clonazepam is an anti-seizure, benzodiazepine and it's one of the drugs of choice for treating two sleep disorders that tend to cluster in people with FMS/CFS: restless leg syndrome (RLS) and periodic limb movements during sleep (PLMS). Both conditions cause annoying, uncontrollable movements of the arms and legs, making it difficult for a person to achieve a good night's sleep. Living with a persistent sleep disruption of this serious nature may also lead to a breakdown in the body's rhythmic production of many essential hormones, chemical transmitters and immune system substances.

At the November '98 American College of Rheumatology meeting, a small pilot study using lorazepam (brand name Ativan) showed great promise. In fact, during the special meeting on FMS, Don Goldenberg, M.D., of Boston, MA, brought attention to this study, indicating that further investigation of agents in this class of benzodiazepines is warranted.

How do drugs such as clonazepam work in patients with FMS/CFS? Does it just improve sleep problems and reduce anxiety? Or, does this type of medication also lead to a reduction in pain? Benzodiazepines work at the body's GABA receptors. The GABA system is partially responsible for inhibiting pain signals traveling down the spinal cord from the brain and out to the tissues. So, it is possible that drugs like clonazepam not only work to reduce sleep disruption, but they may also play a significant role in FMS/CFS to minimize pain.

Goldenberg has been awarded an AFSA grant to evaluate the effectiveness of clonazepam in treating people with FMS and CFS. "Most FMS/CFS patients have sleep disturbances and medications that improve these sleep abnormalities and that also decrease pain perception have been of most therapeutic benefit in this condition," says Goldenberg.

"Our experience suggests that clonazepam is helpful in many FMS/CFS patients. We have also found it very safe and free of most adverse side effects. However, its efficacy has not been established in FMS/CFS. We will be evaluating a low dose of clonazepam in a randomized, double blind controlled study. Every patient will receive clonazepam for three months and a placebo for three months, in a cross-over study design."

Goldenberg's clinical experience and that of many other physicians, indicates that clonazepam works in a subgroup of patients, but this has to be proven in a placebo controlled study. Also, for patients who do respond well to clonazepam, there are other questions to be answered: What areas of improvement does the drug provide? And, can any predictions be made based on a patient's symptoms as to whether they will be a clonazepam responder? It's not good enough to show that a given drug works in "some" patients. It's important to know in whom the drug works best and why.

If the anecdotal experience of several physicians is that clonazepam works and that at low doses it is a safe drug, why bother with the study? Clonazepam is in the benzodiazepine class of medications and a large number of treating physicians have cast this category of drugs aside, claiming that they are all bad. As a result, patients are being denied the chance of even a trial prescription of clonazepam. And, if a patient does find that clonazepam works for them, they still face having the drug yanked away from them at a later date because many physicians view benzodiazepines as habit-forming. In other words, these drugs may be reserved for short-term use and this creates a serious dilemma when a person has a long-term illness.

A controlled trial of clonazepam by a prestigious clinician such as Dr. Goldenberg will go a long way to help calm the concerns of physicians who want to help their patients, but are afraid to prescribe a drug previously believed to be a potentially addictive agent. In many ways, a large number of physicians fear prescribing benzodiazepines almost as much as they fear prescribing opioids for chronic pain syndromes. Recent developments in researching both medications have shown that they can be prescribed safely and responsibly to people with chronic illnesses. Yet, without published studies to provide more concrete evidence that drugs--such as clonazepam--are safe and effective in FMS/CFS, patients will continue to be denied promising therapies based on the prescribing fears of their treating physician.


Fibromyalgia: Chronic Effects of Nerve Growth Factor (NFG) in the Spinal Cord
Principal Investigator: Alice Larson, Ph.D.
Professor of Neuroscience
University of Minnesota, St. Paul
Award: $28,752 - June 1998
Substance P (SP) and nerve growth factor (NGF) are three to four times higher in the spinal fluid of people with FMS. These chemicals are elevated to the point of pathological significance and they are known to be major players in the pain system.

So why doesn't your doctor just prescribe something to tame down these substances so that you don't have to endure so much pain? The answer is simple: No one knows why SP and NGF are elevated, nor how they interact with one another to possibly produce the diffuse, chronic pain of FMS ... and likely that of CFS. This is one of many reasons why research in FMS/CFS is at a crucial point. It is disheartening to know that these significant abnormalities exist and not know what to make of them!

The high SP levels in FMS have been well-documented by I. Jon Russell, M.D., Ph.D., at the University of Texas in San Antonio. Dr. Russell has started looking at the SP levels in other painful conditions, but so far no other condition compares with the threefold increase in FMS patients. The average increase of NGF in the spinal fluid of FMS patients is fourfold, although it varies among patients. This finding was recently determined by Alice Larson, Ph.D., of the University of Minnesota in St. Paul, using spinal fluid samples provided by Dr. Russell.

At the American Pain Society meeting last October, there was a special discussion session devoted to NGF. As you might guess, NGF's primary role in the body is to stimulate the growth of nerves. With this in mind, a clinical trial using NGF for treating the loss of tactile sensations in the hands and feet of people with diabetic neuropathy was described. The purpose was to regrow the small nerves in the hands and feet with weekly injections of synthetic NGF. The researchers didn't know what dose to start at, and initially gave the patients in the trial far too much NGF. The result: horrible widespread pain that persisted for over a week! Cutting the dose several fold produced soreness only at the injection site, but the nerves did regrow and the study was deemed a success.

How could NGF produce severe pain? Dr. Larson says that NGF enhances the production and release of SP which could lead to the widespread pain in FMS. Unfortunately, the relationship between NGF and SP isn't straightforward. SP is broken down into two parts: one that relieves pain (SP1-7) and one that actually promotes pain. Not only can SP1-7 reduce the impact of NGF, studies also indicate that decreasing the activity of the sympathetic portion of your autonomic nervous system could lead to reduced NGF-induced pain. The sympathetic arm of your nervous system controls your fight-or-flight stress response mechanisms, among other things. The feedback loops of the nervous system are complex, but this background information should help you understand the importance of the projects funded by AFSA in mid-1998.



FMS appears to involve altered activity of chemicals in the brain that generate the sensation of pain when released in the spinal cord in response to tissue damage. FMS may become a chronic condition because of a change in the interaction between NGF and SP.

In animals and humans, injection of NGF can lead to profound pain that lasts for several days. A possible mechanism by which NGF may do so is by increasing the synthesis of other peptides, including SP, in nerves that transmit pain signals. It is unclear if the excess NGF associated with FMS is the underlying cause of the elevated SP concentrations in the spinal fluid. It is also unclear whether SP is important in the increase in pain transmission associated with fibromyalgia, or whether the pain-relieving SP1-7 metabolites are instrumental in inhibiting NGF activity.

The effect of NGF on pain transmission has only been studied over short time intervals. Dr. Larson's study is designed to determine whether an elevated concentration of NGF in the spinal cords of rats is sufficient to produce a long-term enhancement of pain (perhaps an animal model for FMS?); whether the enhanced pain produced by NGF requires SP at its site in the spinal cord; or whether SP1-7 metabolites in the spinal cord work to counteract NGF-induced pain. These studies will basically mimic the spinal fluid concentrations of NGF and SP that are found in humans with FMS, so that their relationship to the painful symptoms of this condition can be better understood. The project will help determine the importance of SP in the action of NGF. It will also determine whether drugs for FMS might best be designed to inhibit the action of SP, the parent compound, or enhance the action of SP1-7 metabolites.


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Cloning a Pain Neuropeptide Receptor
Principal Investigator: John Stewart, Ph.D.
Professor of Biochemistry, School of Medicine
University of Colorado, Denver
Award: $24,560 - June 1998

We desperately need new drugs to help keep the horrible pain of FMS under control! This project offers hope.

When we experience excessive pain, there are two possible ways to help. If we know the cause of the pain and can treat it, as is the case with an infected wound, we kill the infecting micro-organisms with antibiotics. This minimizes inflammation, promotes wound healing, and eventually alleviates the pain. Unfortunately, this simple approach does not work for FMS pain.

The second approach is to block pain signals from getting to the brain, where we actually produce the pain sensation. This is the only approach possible if we do not know the cause of the pain (as is the case in FMS and CFS) or if we can't control the cause. Often, analgesics, such as aspirin, are used when inflammation is present or if the pain is mild. Morphine or other opioids may be prescribed when the pain is severe. Pain signals are carried by neurons (nerves), which use neurotransmitters such as peptides (baby proteins) as messengers to pass signals from one neuron to the next on the way to the brain. One neurotransmitter for pain signals is the peptide SP. Morphine may block pain by preventing the release of SP from pain-sensing neurons.



SP is a true double-barreled molecule when it comes to pain. On one hand, SP helps produce the pain sensation. On the other hand, it can help block pain signals. This is true because SP can be cut by enzymes to produce two different molecules (metabolites). One of the molecules produces pain, while the other blocks the pain sensation and helps control the severity of pain (SP1-7). Scientists have learned a great deal about the "bad" part of SP that produces the pain, but relatively little is known about the "good" part of SP that blocks pain. If we can learn more about how the good part of SP works, we may be able to design new drugs to block FMS pain.

Neurotransmitters like SP work by combining with "receptors" that only they recognize. These receptors are made of specialized protein molecules in the target cells of the neurons (i.e., they are the receivers of information). If the neurotransmitter is the key, then the receptor can be viewed as the perfectly molded keyhole. Scientists have extensively studied the receptors for the "bad" part of SP, but drugs that have been developed to block this receptor cause terrible side effects. Ironically, nothing is known about the molecule that is the receptor for the "good" part of SP. This project will furnish that information, and should provide important new knowledge on the mechanisms of pain production and its control.

Dr. Stewart and his co-workers will use modern molecular biology techniques to find the gene for the receptor and transfer it into cells grown in tissue culture. By doing so, a "clone" of the good SP peptide can be synthesized and will lead the way for new drug developments for FMS. The investigators will use computer programs that produce three-dimensional models of the receptors and the peptides. This in turn will further aid in the design of even better molecules that can be tested for their effectiveness in treating pain and related symptoms. The best new molecules can then be tried in FMS patients after FDA approval.


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The Effect of Graded Exercise on Temporal Summation of Second Pain (Wind-Up) in Patients with FMS
Principal Investigator: Roland Staud, M.D.
Rheumatology, University of FL, Gainesville
Award: $30,000 - June 1998

Pain in FMS, as well as CFS, is consistently felt in the musculature and may be related to specific abnormalities of central nervous system (CNS) pain pathways. In a small pilot study with FMS patients, Dr. Staud used a non-invasive method of repetitive stimulation of the nerve endings. Although the stimulations were mild, the repetition caused the false perception of significantly increased pain (wind-up) in people with FMS compared to healthy controls. This rather simple test method appears useful for the evaluation of the CNS pain pathways (or mechanisms) that are present in FMS patients as well as serving as a useful tool for testing the effectiveness of drugs for FMS.

For this study, a Peltier thermode (heated plate) will be applied in a series of brief contacts to different sites on the palm of the patient's hands. Repetitive contacts on the skin areas of the palms are able to increase the perceived intensity of heat sensations that follows each contact. This technique appears to be capable of measuring the input from specific C-type nerve fibers that may be "turned on" to sensitize the pain system and amplify pain sensations. Ordinarily, these fibers release SP when tissues are injured, but Staud suspects that they are abnormally activated in FMS patients by events that should not lead to pain, such as mild exercise. This may be important in FMS.



Staud's technique is expected to provide information regarding the status of specific CNS receptor systems that are implicated in chronic pain conditions such as FMS (e.g., the N-Methyl-D-Aspartate or NMDA receptors that reside in the spinal cord and brain). Unlike SP-generated pain, opioids are not as effective in combating NMDA-generated pain. Ironically, SP is a potent facilitator of NMDA receptors.

During the pilot study with FMS patients, Staud has been able to show excessive wind-up (or pain build-up) at a high rate of heat stimulation and abnormal wind-up at a slow rate. Not only do these findings indicate that people with FMS are extremely sensitive to pain stimuli, but they also serve to highlight abnormalities of central pain processing in FMS patients that likely involves the NMDA receptors.

Based on reports that most FMS and CFS patients indicate a worsening of their symptoms with physical exercise and improvement with rest, Staud hypothesizes that wind-up (as measured by his novel technique) may correlate with the level/duration of exercise in this patient group. In contrast, Staud's previous studies using healthy, pain-free individuals have shown pronounced attenuation (e.g., blocking) of wind-up after strenuous exercise.

Project investigators postulate that exercise will accentuate the abnormalities of wind-up in FMS patients, particularly in comparison to healthy controls. The results of this study will improve our understanding of the status of the pain modulatory systems in FMS patients. In addition, the non-invasive technique should serve to help design and evaluate future therapeutic trials in FMS as well as CFS pain.


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Cytokines, Fibromyalgia Subsets and the Th1/Th2 Axis
Principal Investigator: Daniel Wallace, M.D.
Professor Cedars-Sinai/UCLA
Award: $24,000 - June 1998

The cause of fibromyalgia syndrome (FMS) is unknown, but reports have suggested that patients with FMS have an under-responsive autonomic nervous system as indicated in studies showing low cortisol "stress" response, increased levels of SP and NGF in the spinal fluid, and decreased levels of growth hormone which doesn't allow muscles to repair properly from normal wear and tear. As part of an attempt to link the hormonal changes, autonomic dysfunction, and neurotransmitter abnormalities associated with FMS, investigators have looked at substances known as cytokines, which include interferons, interleukins, and tumor necrosis factors. The chemicals signal cells of the immune system to perform different actions. Also, cytokines can produce pain or relieve pain, produce cognitive impairment, promote or suppress inflammation, induce sleep, and activate or suppress stress responses.



Lymphocytes are a type of white blood cell that serves as our immunologic memory. They remember past insults and protect our immune system by making antibodies or formulating an inflammatory response. There are two principal types of lymphocytes: Th1 and Th2.

Certain cytokines help create a predominantly Th1 environment in which inflammation is best supported, while others promote a Th2 environment of elevated antibodies and decreased inflammation which is also seen in pregnancy and allergies. Activation of the stress-cortisol process, for example, promotes Th2 cytokines and decreased levels of Th1 cytokines. Research findings suggest that FMS (and perhaps CFS) might start out as a chronically activated stress-cortisol state, but over time, the system gradually "tires," producing a low cortisol "stress" response even when the body continues to be challenged by stressors. As for the role of cytokines in FMS/CFS, few studies have examined their potential for producing the symptoms and no surveys have looked for Th1 and Th2 axis imbalances in these syndromes.

Dr. Wallace and co-workers propose to study a group of FMS patients and healthy individuals. They will look at cytokine levels in an effort to assess their Th1 and Th2 balance. This assessment will be further refined by examining patients who developed the syndrome after an accident or infection. Patients with the often associated malfunctioning of the autonomic nervous system (neurally-mediated hypotension) will also be subdivided to determine if their cytokine profile is different. Duration of symptoms will also be assessed to see if this influences cytokine production.

Wallace hopes to derive insights which will increase the understanding of how cytokines and white blood cells influence, for example, pain, cognitive functioning, sleep, headaches, irritable bowel, and chemical sensitivities. Research on cytokines and the agents that block their production or activity are in progress and could produce novel drug therapies. The results of this project could help assess whether novel cytokine-directed therapies should be tested in FMS/CFS and, if so, identify which subgroup of patients might benefit the most.

In addition to the above project to detect cytokine irregularities, Dr. Wallace has agreed to further look into the specific genes that regulate any cytokines that are found to be significantly higher or lower than normal. Indeed, this study is quite an undertaking!




A Double Blind, Placebo Controlled Study to Determine Whether Dextromethorphan is More Effective Than a Placebo in the Treatment of FMS Pain
Principal Investigator: Robert Bennett, M.D.
Oregon Health Sciences University, Portland
Award: $16,140 - July 1997
Award: $4,000 - July 1998 for modified design


The pain of FMS/CFS is thought to be caused by a "hypersensitized" central nervous system (CNS). A Swedish research team recently showed that three different drugs aimed at taming this hypersensitized state provided varying degrees of pain relief in 18 FMS patients (Journal of Rheumatology, August 1997). The three drugs used were morphine (an opioid), ketamine (an NMDA blocker that works to reduce pain amplification in the CNS), and lidocaine (an anesthetic that blocks the amount of noxious inputs going to the CNS). Intravenous ketamine provided the longest duration of pain relief--it lasted up to five days in some patients. Unfortunately, ketamine is not available in pill form and it has too many side effects to be administered on a routine basis.

Dextromethorphan is a commercially available NMDA blocker. It has less side effects than ketamine and can be compounded in pill form (it's in over-the-counter liquid form, Delsym, in 30 mg adult dosing but this can't be used in the study because it would unblind participants ... patients would know what they were getting). Dr. Bennett will be giving specially formulated dextromethorphan to FMS patients in increasing doses until they either obtain a significant relief of pain or experience unacceptable side effects.

Initially, Bennett began the first phase of the study by bringing patients up to the dose of dextromethorphan that eased the pain. However, after six patients had entered the study and they were taking greater than 200 mg daily doses of dextromethorphan, they indicated that while they had very little pain, they also were experiencing significant concentration difficulties. Dextromethorphan can block pain amplification in the spinal cord, but when it reaches the higher centers in the brain, it can interfere with one's ability to think. Dr. Bennett was kind enough to alert AFSA of this problem up front and suggested an alternative study design that includes the combination of Ultram with dextromethorphan.

Ultram (tramadal) is a weak opioid that can be easily prescribed by physicians (it's not a controlled substance). By using Ultram, a lower dose of dextromethorphan will likely be needed to reach a level of significant pain relief. In addition, the combination therapy should be superior than Ultram by itself. Therefore the original study has been changed to compare the effectiveness of Ultram versus the combination of Ultram plus dextromethorphan. Those patients obtaining sufficient pain relief will be randomized to continue on either dextromethorphan/Ultram combo or Ultram/Benadryl combo for 30 days (the Benadryl causes mild drowsiness similar to that of dextromethorphan and serves as an "active" placebo). Both the physician and patient will be blinded as to which pill is administered. The major end point will be whether the addition of dextromethorphan to Ultram results in a significant improvement in pain and other measures, compared to the use of Ultram alone. This study will also help determine the typical dose of dextromethorphan that is effective with the least amount of side effects.

The ground-breaking work of the Swedish team using ketamine in FMS patients shows promise for the effectiveness of NMDA receptor antagonists in the management of FMS pain (it also shows that opioids may be beneficial as well). Although ketamine has too many side effects, the use of high doses of a less potent NMDA receptor blocker, such as dextromethorphan, may be helpful for the treatment of chronic pain.

If the outcome of this study is positive, then this trial will allow for more sophisticated, long term studies using this combination drug therapy. It may also pave the way for testing other combination therapies that include dextromethorphan.

Project Update

At the October 2000 American College of Rheumatology (ACR) meeting, Drs. Bennett and Clark presented their findings to date on the use of dextromethorphan (DM) to boost the pain relieving action of Ultram (a weak opioid commonly prescribed for FMS).

This double-blind, placebo controlled study looked at the dropout rate of FMS patients who were initially taking both Ultram and DM, but were blindly switched to Ultram plus a placebo pill that was made to look just like the DM. The placebo used was Benadryl, so it had some mild side effects that were intended to help "blind" patients who were taken off of DM. Most patients on the placebo (but still taking Ultram) had dropped out at the time of the ACR meeting, implying that the pain reducing abilities of DM were very real for those who responded to it. (Bennett says the study is now complete and he plans to prepare the results for publication.)


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Role of the Limbic Brain System in Abnormal Pain Perception in FMS
Principal Investigator: Laurence Bradley, Ph.D.
University of Alabama, Birmingham
Award: $30,000 - June 1997

Dr. Bradley is measuring changes in the brain blood flow when mild electrical stimulus is applied to several body sites on people with and without FMS. This will provide researchers more insight as to what happens in the brain of patients as they receive new stimuli that may produce unpleasant or even painful sensations.



In addition to just looking at the thalamus and the caudate nucleus, two pain processing centers that are already known to have low blood flow levels when patients are at rest, there are other important structures within the limbic system that are involved in pain perception and stress response mechanisms. Bradley is using SPECT (single-photon-emission computed tomography) in combination with MRI to analyze the blood flow in three other brain limbic structures to shed more light on what other areas of the brain could be functioning abnormally in patients. One structure in particular that is being assessed is the locus coeruleus, which is involved not only in the regulation of pain, but also that of sleep and stress response mechanisms.

The hypersensitivity that FMS patients display to a variety of stimuli is poorly understood and is often viewed as a psychological phenomenon. If Dr. Bradley's study is successful, it may provide evidence for a physiological basis for the perception of pain among FMS patients in response to low intensity stimuli that are generally not painful or unpleasant to healthy people. It may also clarify the role of the interactions between abnormal functional brain activity and abnormal hypothalamic-pituitary-adrenal function, as well as lead to the development of improved drug therapies.

Research Update

Laurence Bradley, Ph.D., presented his first AFSA-funded study at the October 2000 ACR meeting. Then at the April 2001 American Pain Society meeting (pictured at right), he presented the preliminary findings of his second project. Here are the highlights of his two brain imaging studies involving the use of SPECT scans:

The heightened pain sensitivity to painful stimuli is not an imagined phenomenon. The mere suggestion of giving a painful stimulus to FMS patients who are already burdenedby pain-related anxieties causes an increased blood flow or "activation" in pain control centers in the brain. Both drug and non-drug therapies for anxieties—often brought on by past painful experiences—may help minimize FMS pain.
People with depression have a normal pain threshold and their brain imaging response to a painful stimulus closely resembles that of healthy people. Both of these findings are different for FMS patients. (Bradley will present more details at the November 2001 ACR.)

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Sensitization in FMS and CFS - with and without Chemical Intolerance
Principal Investigator: Iris Bell, M.D., Ph.D.
University of Arizona, Tucson
Award: $29,957 - June 1997

Chemical sensitivity studies by Dr. Bell suggest that chemical intolerance may be a measurable indicator of your brain's ability to amplify symptoms (including pain) or sensations, such as that of odors that may not be noxious to other people. Airborne chemicals and infectious agents are not the only factors believed to lead to or aggravate chemical sensitivities. High levels of body chemicals such as substance P (which is known to be extremely elevated in FMS patients) can also cause your brain to become sensitized and produce amplification of symptoms due to a malfunctioning of the brain.

If chemical intolerance is present, then repeat exposure to various substances will likely lead to further amplification of the brain's abnormal response. One part of the brain controlling this amplification is the limbic system, which is also involved in the development of craving for drugs such as stimulants and foods such as sugar. These substances give the individual a short-lived boost of energy. This same area of the brain responds to substance P as though it, too, were a rewarding drug-like substance. It's known that FMS patients have increased levels of substance P released in their central nervous system and that people with chemical intolerance often crave sweets even though they feel ill after consuming them. These, along with other abnormalities, may form a biochemical link between FMS/CFS and chemical intolerance.

Many different substances can cross-sensitize with one another in the body. What this means is that one substance can cause the same amplified effect that a high level exposure to some other substance has previously triggered into motion. This cross-sensitization may allow many different substances that are abnormally produced or present in patients to then create amplified symptoms that were initially set off by another substance or stressor. These amplified symptoms may include pain, fatigue and other problems that FMS/CFS patients have.

Dr. Bell hypothesizes that FMS/CFS and chemical intolerance patients suffer from increased susceptibility to sensitization from internal factors like substance P and also from environmental factors, such as foods and airborne chemicals or pollutants. If this is so, FMS/CFS patients may have sensitization to certain foods like sugar.

A series of repeat exposure to a common stimulus will be used to test the study hypotheses. Data collection will employ: symptom checklist, health history questionnaires, examinations, and repeated laboratory tests that measure brain waves, heart rate, and blood pressure.

Half of the 30 FMS/CFS patients to be tested will also have chemical intolerance. A normal, healthy control group will undergo the same testing.

This study could lead to increased understanding of how the brain might contribute to the long term symptoms of FMS/CFS. The outcome of this study may favorably influence treatment rationales for preventing and/or reversing the abnormal brain function in patients.

Dr. Bell has finished this study and will be presenting her data at a medical conference in March of 1999. Once her data become public, we will discuss them further in the AFSA Update.


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The Role of Zinc in FMS
Principal Investigator: I. Jon Russell, M.D., Ph.D.
University of Texas, San Antonio
Award: $22,000 - June 1997

I. Jon Russell, M.D., Ph.D. has discovered that the serotonin storage in the platelets in the blood of FMS patients is decreased as opposed to people without FMS. Serotonin plays a number of roles in the body, such as regulating sleep and reducing pain sensations. As for the platelets, they are the cells in the blood that clump together to help stop bleeding at the site of an injury. This clumping process may not be working properly. In this study, Dr. Russell hypothesizes that many of the blood abnormalities might be related to zinc.

Zinc is needed for certain immune system functions and is also involved in the growth hormone-induced release of IGF-1 from the platelets into the serum. IGF-1 helps repair cells and has been found to be low in the serum of FMS patients. Zinc is concentrated in the central nervous system in areas that may be involved in pain inhibition. Russell suspects that zinc might reduce the pain-producing effects of high substance P and nerve growth factor (meaning that low zinc stores could be a problem).

Thirty FMS/CFS patients and age/sex matched healthy controls will have their blood drawn for zinc analysis on the first day of the study. They will be evaluated in terms of pain scores and many other symptom measures, as well as a dietary assessment. The blood assays and symptom assessments will serve as the baseline scores for each individual. FMS patients and healthy controls will be instructed to take coded tablets that either contain a placebo or zinc supplement. After a few days, the subjects will return to Dr. Russell's laboratory where the tests will be repeated.

Dr. Russell does not recommend that patients increase zinc supplementation before the results of this study are known. There is a potential risk of upsetting the body's copper/zinc balance when too much zinc is ingested. However, if a zinc abnormality can be found, then the next step for researchers would be to determine how to solve this problem.

Dr. Russell has finished this study and is analyzing his data for formal publication.


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Pain Induced Changes in Basal Ganglia and Limbic System Function Among Patients with FMS, CFS, and Healthy Controls versus People with Major Depression
Principal Investigator: Laurence Bradley, Ph.D.
University of Alabama, Birmingham
Award: $29,773 - October 1997

Tag-on Project to Ongoing NIH Study

Dr. Bradley's team has indicated that FMS patients at rest have abnormally low cerebral blood flow levels in their caudate nucleus and a tendency toward reduced blood flow in the thalamus. These structures are located in the basal ganglia and work to inhibit pain. The processing of stressors, emotions, and one's perceptions of pain and other stimuli, are all accomplished in the limbic system of the brain. This system has a network of connections to a multitude of other regions in the brain and is responsible for making sense out of the incoming signals and developing an appropriate response.

We can only speculate what happens to cerebral blood flow when a painful stimulus is given to people with FMS, CFS, and major depression as opposed to healthy controls. Fortunately, these questions are being addressed by an NIH grant, except for the part about testing individuals with major depression. AFSA has given Dr. Bradley the opportunity to answer this question.

All too often, findings in FMS and CFS are attributed to depression. Addressing this problem, Bradley writes: "It's important to determine whether FMS and CFS are associated with functional abnormalities in the basal ganglia or limbic system structures independently of effects of depression."

After an initial baseline scan, here is what Bradley is proposing will happen on the second SPECT scan performed when FMS patients are subjected to pressure pain stimulus on the right side of their body:

l The increase in blood to the pain processing areas (basal ganglia) will be significantly less in FMS patients than depressed or healthy control subjects.

l Both FMS and depressed people will have higher levels of blood flow to the limbic structures as compared to healthy controls. This is because painful stimulus to these two patient groups will understandably elicit more distress. Elevated levels of distress may be the primary physiological link between FMS and major depression.

Bradley's team is attempting to demonstrate that FMS and CFS are distinct neurosomatosensory processing disorders. In other words, they don't represent a form of depression.




Positron Emission Tomography (PET) in FMS and Pain-Free Controls
Principal Investigator: Muhammad Yunus, M.D.
University of Illinois College of Medicine at Peoria
Award: $30,000 - June 1996

The goal of this project was to investigate possible abnormalities in the brain by PET scanning patients with FMS and comparing them to pain-free healthy controls. PET can measure the rate of glucose metabolism in important centers in the brain that may be involved in producing the painful symptoms of FMS. Dr. Yunus and co-workers hypothesized that there would be abnormalities in the pain processing and transmission centers in the brains of FMS patients.

Elevated substance P in the spinal fluid and low serum serotonin levels (among other problems) suggest neurochemical dysfunctions in the brain of patients with FMS. What brain structures are really involved in such dysfunctions or abnormalities? Functional imaging of the brain by single-photon-emission computed tomography (SPECT) has already shown interesting abnormalities in the blood flow through various structures in the brain. More specifically, SPECT has identified those areas of the brain that are involved in pain perception, such as the caudate nucleus and the thalamus.

While SPECT studies in FMS and CFS are ongoing, PET is believed to be more sensitive at pinpointing brain abnormalities with a higher degree of accuracy. Although the FDA has yet to approve tracer drugs for tagging receptor sites of various neurotransmitters, such as serotonin, norepinephrine, substance P, and dopamine, the development of such tracers for PET remains hopeful.

Twelve FMS/CFS patients and seven normal pain-free healthy controls with a similar age distribution were evaluated by PET scan. The scan involves an intravenous injection of a radioactive chemical called 18-fluorodeoxyglucose (FDG) and scanning of the brain 30 minutes later to study glucose metabolism (i.e., the uptake of the FDG) in different regions of the brain.

Study Results - Presented at 1997 ACR

Dr. Yunus performed glucose evaluations while patients were at rest in a dark, quiet room. This tranquil state did not demonstrate a significant difference between FMS/CFS patients and healthy controls, however, it may still provide important clues as to what is happening in patients. Yunus' work may explain the phenomenon that you battle each day: if you take it easy, you may be able to reduce some of your symptoms. This may be why the PET scan didn't pick up anything abnormal in the tranquil state. Yet, the harder you function and the more you try to get accomplished during your day, the worse you feel.

Yunus adds that the PET scans of FMS/CFS patients were not characteristic of people with major depression.


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Melatonin in Patients with FMS and CFS
Principal Investigator: Leslie Crofford, M.D.
University of Michigan, Ann Arbor
Award: $30,000 - June 1996

There were two main goals of this project. One was to determine if the rhythm of production of melatonin (i.e., its circadian rhythm) is abnormal in FMS and CFS patients. The other was to measure the total 24-hour output of melatonin to determine if it differs from that of healthy age and sex-matched controls. Dr. Crofford and co-workers hypothesized that patients with FMS and CFS would display a disturbed melatonin secretory pattern. In addition, the total daily output of melatonin might also be abnormal.



Melatonin is a hormone produced by the pineal gland at the base of your brain. It is important for transmitting information that synchronizes the daily 24-hour circadian rhythms of your neuro-hormones. In other words, melatonin operates somewhat like an internal clock: its secretion cycle signals when certain brain hormones should be released or when they should be shut off.

Abnormalities in the pattern of melatonin secretion have been associated with fatigue, sleep disorders, and mood disturbances in conditions such as jet lag and shift work. Patients with FMS and CFS display similar symptoms, suggesting that there may be abnormalities of melatonin secretion. In addition to symptoms, there are other reasons to believe melatonin secretion may be disturbed in patients with FMS and CFS, such as:

melatonin is manufactured in the brain from tryptophan or serotonin, and both of these precursor molecules have been shown to be low in patients.
several abnormalities of the sympathetic nervous system (fight or flight responses) have been found, which directly stimulates melatonin synthesis and secretion.
disturbances in the circadian rhythms of other hormones such as cortisol have been found and this could reflect a generalized disruption of the body's natural circadian rhythms.
Blood was collected every hour over a 24-hour period from 20 patients with the diagnosis of FMS, CFS or both, and from 20 healthy controls. The pattern of secretion of melatonin (circadian rhythm) was determined along with the total 24-hour melatonin output from the pineal gland. This data was also correlated with the person's cortisol secretion. Comparison is important because increases in cortisol production are believed to inhibit the secretion of melatonin. In addition, symptoms of fatigue, pain, sleep disorder, and mood disturbance were correlated with the melatonin and cortisol findings.

Melatonin levels can be manipulated by supplementation, psychoactive medications, sympathetic nervous system blockade, or by bright light. However, it is only by rigorous investigation of the secretory characteristics of melatonin in individuals with FMS and CFS that one can predict the therapeutic impact of manipulation of melatonin levels.

Preliminary Results - Presented at the 1997 ACR
Dr. Crofford found that the nighttime plasma melatonin levels in patients were significantly higher than in healthy controls. The large burst of melatonin secretion occurred at the right time of night, but when it was compared to the peak production time of cortisol, it was delayed by 76 minutes. Melatonin is supposed to set your body clock, but Crofford's findings indicate that this internal clock may not be working right. Dr. Crofford has already used the data collected by this study to obtain an NIH grant to further her work in this area as well as attempt to relate these findings to disturbances in pain control mechanisms. She is also submitting the study for medical journal publication.


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Neuroendocrine Therapies for FMS and CFS
Principal Investigator: Robert McMurray, M.D.
University of Mississippi, Jackson
Award: $29,704 - June 1996

Dr. McMurray's project goal was to conduct a double-blind, placebo-controlled study of two different therapies taken at night for FMS: 6 mg of melatonin or 2.5 mg of bromocriptine. Multiple neuroendocrine abnormalities may occur in FMS patients and these therapies may help correct them. Dr. McMurray suspects that FMS is a circadian rhythm disease that alters the function of important neuro-hormones. His hypothesis is that patients will have decreased pain, improved sleep, and increased function in response to one or both of the medications tested.

Serotonin abnormalities are thought to exist in FMS and may hamper the body's natural production of melatonin in the pineal gland. Supplementation with melatonin may directly improve symptoms in patients or may even reduce some symptoms by increasing the amount of available serotonin because less will be needed in the brain for making melatonin.

Bromocriptine acts like the neurotransmitter dopamine, and also reduces the production of a pituitary hormone called prolactin. The spinal fluid level of the dopamine metabolite, homovanillic acid, has been shown in one study to be significantly low in FMS patients. Low homovanillic acid is a good indicator that dopamine in the central nervous system might be low as well.

The most common disease characterized by low dopamine levels is Parkinson's disease in which movement disorders occur (such as uncontrollable tremors). Other movement disorders like restless legs syndrome, bruxism (teeth grinding or clinching), and periodic limb movements during sleep (PLMS or nocturnal myoclonus) occur in at least 20% of FMS patients. Low dopamine levels may be at the root of these problems as well.

What about bromocriptine's effect on reducing prolactin secretion? By suppressing prolactin secretion, bromocriptine is thought to relieve anxiety and stress--both of which may reduce the HPA system abnormalities. This drug has also been shown to be useful in the treatment of premenstrual syndrome.

A small pilot study by Dr. McMurray (published in Journal of Rheumatology, November 1995) indicated that the use of bromocriptine in lupus patients actually reduced many symptoms that are also found in FMS: fatigue, cognitive dysfunction, depression, muscle pain and headaches. In addition, the drug was found to be well tolerated.

Thirty-five FMS/CFS patients were to be enrolled in this study that was completed in 1998. Each patient was randomly placed in a series of three treatments each lasting four months: melatonin, bromocriptine and placebo. There were placebo "washout" periods between the two drugs, melatonin and bromocriptine, so that the effects of one drug would not carry over into the other trial. None of the patients knew what they were getting--all pills were specially formulated to look the same. With this study design, patients functioned as their own control during the placebo phase of the drug trial.

Throughout the trial period, the investigators assessed the patient's symptoms and drew blood each month to test for the following: melatonin, prolactin and cortisol. Other tests to determine how the brain-pituitary system is working were done as well. Therefore, this is much more than just a standard drug trial that tells whether or not a particular therapy reduces the symptoms. This study is designed to also determine why and how melatonin and/or bromocriptine work in patients with FMS/CFS. This is a crucial element of the project because one therapy may not be as helpful for all patients and at least the investigators will be left with a few clues as to why this might be so.

Although some treatments for FMS have been transiently effective, 66% of FMS patients still have significant symptoms no matter what therapies they try. As stated above, this is no ordinary drug trial; it can have a high impact on our current understanding of this devastating disease. Dr. McMurray completed the trial in February of 1999 and is in the process of analyzing the study results.

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