Group Title: Arthritis Research & Therapy
Title: Biology and therapy of fibromyalgia : pain in fibromyalgia syndrome
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Title: Biology and therapy of fibromyalgia : pain in fibromyalgia syndrome
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Language: English
Creator: Staud, Roland
Publisher: Arthritis Research and Therapy
Publication Date: 2006
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Abstract: Fibromyalgia (FM) pain is frequent in the general population but its pathogenesis is only poorly understood. Many recent studies have emphasized the role of central nervous system pain processing abnormalities in FM, including central sensitization and inadequate pain inhibition. However, increasing evidence points towards peripheral tissues as relevant contributors of painful impulse input that might either initiate or maintain central sensitization, or both. It is well known that persistent or intense nociception can lead to neuroplastic changes in the spinal cord and brain, resulting in central sensitization and pain. This mechanism represents a hallmark of FM and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established only minimal nociceptive input is required for the maintenance of the chronic pain state. Additional factors, including pain related negative affect and poor sleep have been shown to significantly contribute to clinical FM pain. Better understanding of these mechanisms and their relationship to central sensitization and clinical pain will provide new approaches for the prevention and treatment of FM and other chronic pain syndromes.
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Review

Biology and therapy of fibromyalgia: pain in fibromyalgia

syndrome
Roland Staud


Division of Rheumatology and Clinical Immunology, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA


Corresponding author: Roland Staud, staudr@ufl.edu


Published: 24 April 2006
This article is online at http://arthritis-research.com/content/8/3/208
C 2006 BioMed Central Ltd



Abstract
Fibromyalgia (FM) pain is frequent in the general population but its
pathogenesis is only poorly understood. Many recent studies have
emphasized the role of central nervous system pain processing
abnormalities in FM, including central sensitization and inadequate
pain inhibition. However, increasing evidence points towards
peripheral tissues as relevant contributors of painful impulse input
that might either initiate or maintain central sensitization, or both. It
is well known that persistent or intense nociception can lead to
neuroplastic changes in the spinal cord and brain, resulting in
central sensitization and pain. This mechanism represents a
hallmark of FM and many other chronic pain syndromes, including
irritable bowel syndrome, temporomandibular disorder, migraine,
and low back pain. Importantly, after central sensitization has been
established only minimal nociceptive input is required for the
maintenance of the chronic pain state. Additional factors, including
pain related negative affect and poor sleep have been shown to
significantly contribute to clinical FM pain. Better understanding of
these mechanisms and their relationship to central sensitization
and clinical pain will provide new approaches for the prevention
and treatment of FM and other chronic pain syndromes.


Introduction
Fibromyalgia syndrome (FM) is a chronic pain syndrome that
has been defined by widespread pain for more than 3 months
and the presence of >11 out of 18 tender points [1]. In
addition, most FM patients complain of disturbed sleep,
emotional distress, and pronounced fatigue. FM represents
the extreme end of the spectrum of musculoskeletal pain in
the general population and is a chronic illness that
disproportionably affects women (9:1 ratio of women to men
affected). Like many other clinical syndromes, FM has no
single specific feature but represents a symptom complex of
self reported or elicited findings.

Pain in FM is consistently felt in the musculature and is
related to sensitization of central nervous system (CNS) pain
pathways. Although not specific for FM, abnormal
concentration of CNS neuropeptides, biogenic amines, and

CNS = central nervous system; FM = fibromyalgia; IL = interleukin; NMDA


Arthritis Research & Therapy 2006, 8:208 (doi:1 0.11 86/arl 950)


alterations of the hypothalamic-pituitary-adrenal axis have
been described [2-5]. There is a large body of evidence for a
generalized lowering of pressure pain thresholds in FM
patients [6-10], but the mechanical pain hypersensitivity
(allodynia) of FM patients is not limited to tender points and
appears to be widespread [10]. In addition, almost all studies
of FM patients have shown abnormalities of pain sensitivity
while using different methods of sensory testing.

Although relevant for many clinical pain syndromes like FM,
nociception alone cannot explain the human pain experience
because it always undergoes modulation in the CNS by
conscious and unconscious mental activity [11]. In addition,
socio-cultural influences, beliefs or biases can strongly
influence pain, particularly those related to cause, control,
duration, outcome, and blame. These beliefs are frequently
linked to negative emotions, like anger, fear, and depression
[12]. Generally, pain has two emotional components, including
the unpleasantness of the sensation (primary pain affect) as
well as negative feelings like depression, anger and fear
(secondary pain affect). This relationship of emotions with pain
is bidirectional because modulation of negative feelings can
powerfully alter the pain experience [13]. Due to the fact that
pain is a personal (first person) experience it can only be
partially captured by definitions. The International Association
for the Study of Pain has defined pain as an "unpleasant
sensory and emotional experience associated with actual and
potential tissue damage or described in terms of such damage"
[14]. This definition of pain, however, has significant short-
comings because it does not encompass all aspects of pain.

Thus, abnormalities of pain processing appear to play an
important role for FM pain, particularly those related to deep
tissue impulse input, central sensitization, and mood
abnormalities. Some of the important contributions of abnormal
central pain mechanisms to clinical FM pain include temporal
summation of pain (or windup) and central sensitization.


N-methyl-D-aspartate.


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Pathogenesis of fibromyalgia pain
FM is a pain amplification syndrome of patients who are highly
sensitive to painful and non-painful stimuli, including touch,
heat, cold, chemicals, light, sound, and smell. The cause for
the heightened sensitivity of FM patients is unknown, but is
likely to involve abnormalities in CNS sensory processing as
well as peripheral tissue abnormalities. Central abnormalities
appear to be related to blunting of the hypothalamic-pituitary
axis responses to stressors [15,16], increased levels of
substance P [2,17], excitatory amino acids [18] and
neurotrophins [19] in the cerebro-spinal fluid of FM patients.

Although previous FM studies did not show consistent
peripheral tissue abnormalities [20], more recent evidence
points to possibly relevant alterations in skin and muscles.
These abnormalities include increased substance P in muscle
tissue [21], DNA fragmentation of muscle fibers [22],
increased IL-1 in cutaneous tissues [23], and muscle
perfusion deficits [24,25]. These peripheral changes may
contribute to increased tonic nociceptive input into the spinal
cord that results in augmented windup and central
sensitization. In addition, there is compelling evidence for the
contribution of peripheral pain to overall clinical pain in FM
[26]. In a large study of FM patients, ratings of peripheral pain
areas accounted for 27% of the variance of overall clinical
pain [26], thus emphasizing the important role of peripheral
impulse input for FM pain. These findings represent a
possible link between peripheral input and FM pain.
Importantly, nociceptive activity in peripheral tissues of FM
patients does not necessarily have to be extensive, because
central sensitization requires little sustained input for the
maintenance of the sensitized state and chronic pain [26].

Despite increasing evidence emphasizing the role of sensory
abnormalities in chronic widespread pain in FM, the
contribution of psychological factors to FM pain must also be
recognized. Several psychological risk factors for FM are
common in Western populations, including somatic symp-
toms, negative life events [27], psychological distress [28],
increased focus on bodily symptoms [29], and passive pain-
coping mechanisms [30]. Both community and clinic patients
with FM are also more likely than the general population to
have a diagnosis of psychiatric disorders, particularly
depression and anxiety [31,32]. In a prospective study of 214
women with self-reported pain, 39 (18%) were diagnosed
with FM at study entry, and 33% satisfied FM criteria after
5.5 years of follow up [33]. Self-reported depression at
baseline was associated with a more than six-fold increased
likelihood of reporting FM symptoms at follow up and was
found to be the strongest independent predictor. In addition,
psychosocial factors, including high levels of distress, fatigue,
and frequent health care seeking behavior, are strong
predictors for chronic widespread pain and FM [34].

In this context, several studies have reported FM to be co-
morbid with major depressive disorder [35,36]. A recent


large family study of FM subjects showed that FM and major
depressive disorder are characterized by shared, familial risk
factors [37], thus emphasizing the strong relationship
between negative affect and FM pain.

Peripheral and central sensitization
Although heightened pain sensitivity is a hallmark of FM, little
is known about the genetic and other factors that contribute
to this abnormality. Tissue sensitization after injury has long
been recognized as making an important contribution to pain.
This form of sensitization is related to changes in the
properties of primary nociceptive afferents (peripheral
sensitization), whereas central sensitization requires functional
changes in the CNS (neuroplasticity). Such CNS changes
can result in central sensitization, which manifests itself in
several ways, including increased excitability of spinal cord
neurons after an injury, enlargement of the receptive fields of
these neurons, reduction in pain threshold, or recruitment of
novel afferent inputs. Behaviorally, centrally sensitized
patients like FM sufferers report abnormal or heightened pain
sensitivity with spreading of hypersensitivity to uninjured sites
and the generation of pain by low threshold mechano-
receptors that are normally silent in pain processing. Thus,
tissue injury might not only cause pain but also an expansion
of dorsal horn receptive fields and central sensitization.

Central sensitization can occur as an immediate or delayed
phenomenon [38], resulting in increased sensitivity of wide
dynamic range and nociception specific neurons of the spinal
cord. Whereas delayed central sensitization depends mostly
on transcriptional and translational neuronal changes during
afferent barrage, immediate central sensitization relies mainly
on dorsal horn receptor mechanisms, including the N-methyl-
D-aspartate (NMDA) and neurokinin-1 receptors [39].

Peripheral and central pain amplification
Peripheral nociceptors can become increasingly sensitive
after tissue trauma and/or after up-regulation of nociceptor
expression in peripheral nerve endings. Subsequent
activation of these receptors will lead to increased firing rates
and pain. This mechanism (peripheral sensitization) seems to
play an important role in FM pain, although only indirect
evidence is available at this time to support this assumption
[26]. Impulses from peripheral nociceptors are transmitted to
the CNS by myelinated A-8 (first pain) and unmyelinated
C-fibers (second pain). A-8 mediated pain signals are rapidly
conducted to the CNS (at about 10 m/s), whereas C-fiber
impulses travel relatively slowly (at about 1.6 m/s). When the
distance of C-fiber transmission is sufficiently long (like the
length of the arm or leg) this delay of C-fiber compared to A-8
fiber impulses can be easily detected by study subjects. An
important test of central pain amplification relies on
summation of second pain or windup [40]. This technique
reveals sensitivity to input from unmyelinated (C) afferents
and the status of the NMDA receptor system [41], which is
implicated in a variety of chronic pain conditions. Thermal,


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Figure 1


I
Stimuli of Equal Intensity
and Duration


Time Axis


Temporal summation of second pain (windup). When identical stimuli are applied to normal subjects at frequencies of >0.33 Hz, pain sensations
will not return to baseline during the interstimulatory interval. Windup is strongly dependent on stimulus frequency and is inversely correlated with
interstimulatory interval [75]. In contrast to normal subjects, FM patients windup at frequencies of <0.33 Hz and require lower stimulus intensities
[40].


mechanical, or electrical windup stimuli can be applied to the
skin or musculature of patients and commercial neurosensory
stimulators are readily available for windup testing.

Temporal summation of second pain or windup
In 1965, Mendell and Wall described for the first time that
repetitive C-fiber stimulation can result in a progressive
increase of electrical discharges from second order neurons
in the spinal cord [42]. This important mechanism of pain
amplification in the dorsal horn neurons of the spinal cord is
related to temporal summation of second pain or windup.
First pain, which is conducted by myelinated A-8 pain fibers,
is often described as sharp or lancinating and can be readily
distinguished from second pain by most study subjects. In
contrast, second pain (transmitted by unmyelinated C-fibers),
which is strongly related to chronic pain states, is most
frequently reported as dull, aching, or burning. Second pain
increases in intensity when painful stimuli are applied more
often than once every three seconds (Figure 1). This
progressive increase represents temporal summation or
windup and has been demonstrated to result from central
rather than a peripheral nervous system mechanism
(Figure 1). Animal studies have demonstrated similar windup
of C afferent-mediated responses of dorsal horn nociceptive
neurons and this summation has been found to involve NMDA
receptor mechanisms. Importantly, windup and second pain
can be inhibited by NMDA receptor antagonists, including
dextromethorphan and ketamine [43-45].

Abnormal windup of fibromyalgia patients
Recent investigations in FM patients have focused on windup
and central sensitization because this chronic pain syndrome
is associated with extensive secondary hyperalgesia and


allodynia [46]. Several studies provided psychophysical
evidence that input to central nociceptive pathways is
abnormal in FM patients [40,47-51]. When windup pain is
evoked both in FM patients and in normal controls, the
perceived pain increase by experimental stimuli (mechanical,
heat, cold, or electricity) is greater for FM patients compared
with control subjects, as is the amount of temporal
summation or windup within a series of stimuli (Figure 2).
Following a series of stimuli, windup after-sensations are
greater in magnitude, last longer and are more frequently
painful in FM subjects. These results indicate both augmen-
tation and prolonged decay of nociceptive input in FM
patients and provide convincing evidence for a role for central
sensitization in the pathogenesis of this syndrome.

Several important points appear relevant for clinical practice.
As previously mentioned, when central sensitization has
occurred in chronic pain patients, including FM patients, little
additional nociceptive input is required to maintain the
sensitized state. Thus, seemingly innocuous daily activities
might contribute to the maintenance of the chronic pain state.
In addition, the decay of painful sensations is very prolonged
in FM and patients do not seem to experience drastic
changes in their pain levels during brief therapeutic
interventions. Many frequently used analgesic medications do
not improve central sensitization, and some medications,
including opioids, have been shown to maintain or even
worsen this CNS phenomenon. Sustained administration of
opioids in rodents over one week can not only elicit
hyperalgesia but also induce neurochemical CNS changes
commonly seen with inflammatory pain [52]. Thus, long-term
analgesic therapy may sometimes result in unintended
worsening of the targeted pain processing abnormalities.


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---A--- NC-5sec
-*-- FM-5sec


m.
10- T


T1 T5 T10 T15

Windup pain ratings of normal control (NC) and fibromyalgia syndrome
(FM) patients. All subjects received 15 mechanical stimuli (taps (T)) to
the adductor pollicis muscles of the hands at interstimulatory intervals
of 3 s and 5 s. FM patients showed mechanical hyperalgesia during
the first tap and greater temporal summation than NCs at both
interstimulatory intervals. A numerical pain scale was used (0 to 100).
The shaded area represents pain threshold.



Windup measures as predictors of
fibromyalgia pain intensity
The important role of central pain mechanisms for clinical
pain is also supported by their usefulness as predictors of
clinical pain intensity in FM patients. Thermal windup ratings
correlate well with clinical pain intensity (Peason's r= 0.53),
thus emphasizing the important role of this pain mechanism
for FM. In addition, hierarchical regression models that
include tender point count, pain related negative affect, and
windup ratings have been shown to account for 50% of the
variance in FM clinical pain intensity [53].

Mechanisms underlying abnormal pain
sensitivity
The mechanisms underlying the central sensitization that
occurs in patients with FM relies on hyperexcitability of spinal
dorsal horn neurons that transmit nociceptive input to the
brain. As a consequence, low intensity stimuli delivered to the
skin or deep muscle tissue generate high levels of nociceptive
input to the brain as well as the perception of pain.
Specifically, intense or prolonged impulse input from A-8 and
C afferents sufficiently depolarizes the dorsal horn neurons
and results in the removal of the Mg2+ block of NMDA-gated
ion channels. This is followed by the influx of extracellular Ca2+
and production of nitric oxide, which diffuses out of the dorsal
horn neurons. Nitric oxide, in turn, promotes the exaggerated
release of excitatory amino acids and substance P from
presynaptic afferent terminals and causes the dorsal horn
neurons to become hyperexcitable. Subsequently, low
intensity stimuli evoked by minor physical activity may be
amplified in the spinal cord resulting in painful sensations.


Figure 2


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--0-. NC-3sec
--- FM-3sec


Role of glia in central sensitization
Accumulating evidence suggests that dorsal horn glia cells
might have an important role in producing and maintaining
abnormal pain sensitivity [54,55]. Synapses within the CNS
are encapsulated by glia that do not normally respond to
nociceptive input from local sites. Following the initiation of
central sensitization, however, spinal glia cells are activated
by a wide array of factors that contribute to hyperalgesia,
such as immune activation within the spinal cord, substance
P, excitatory amino acids, nitric oxide, and prostaglandins.
Precipitating events known to induce glial activation include
viral infections, including HIV, hepatitis C, and influenza [56].
Once activated, glia cells release proinflammatory cytokines,
including tumor necrosis factor, IL-6 and IL-1, substance P,
nitric oxide, prostaglandins, excitatory amino acids, ATP, and
fractalkine [57], that, in turn, further increase the discharge of
excitatory amino acids and substance P from the A-8 and C
afferents that synapse in the dorsal horn and also enhance
the hyper-excitability of the dorsal horn neurons [54,58].
Recent evidence also points towards a possible role for
NMDA receptors in glial activation and pain [59]

Possible causes of central sensitization
As a normal response to tissue trauma, injury is followed by
repair and healing. Inflammation occurs, which results in a
cascade of electrophysiological and chemical events that
resolve over time and the patient becomes pain free. In
persistent pain, however, the local, spinal, and even
supraspinal responses are considerably different from those
that occur during acute pain. While defining the relationship
between tissue events and pain is necessary for
understanding the clinical context of these pathologies,
defining the relationship between injury and specific and
relevant nociceptive responses is crucial for understanding
the central mechanisms of persistent pain in FM. It must be
emphasized, however, that specific abnormalities in persons
with FM have not been identified that might produce the
prolonged impulse input that is necessary to initiate the
events underlying the development of central sensitization
and/or spinal glia cell activation. After central sensitization
has occurred, low threshold A-P afferents, which normally do
not serve to transmit a pain response, are recruited to
transmit spontaneous and movement-induced pain. This
central hyperexcitability is characterized by a 'windup'
response of repetitive C fiber stimulation, expanding receptive
field areas, and spinal neurons taking on properties of wide
dynamic range neurons [60]. Ultimately, A-P fibers stimulate
postsynaptic neurons to transmit pain, where these A-P fibers
previously had no role in pain transmission, all leading to
central sensitization. Nociceptive information is transmitted
from the spinal cord to supraspinal sites, such as the
thalamus and cerebral cortex, by ascending pathways.

Muscle tissue as a source of nociceptive input
A potential source of nociceptive input that might account for
FM pain is muscle tissue [61]. Several types of muscle













abnormalities have been reported in FM patients, including
the appearance of ragged red fibers, inflammatory infiltrates,
and moth-eaten fibers [62-64]. Possible mechanisms for
such muscle changes might include repetitive muscle
microtrauma, which could contribute to the postexertional
pain and other painful symptoms experienced by these
patients. In addition, prolonged muscle tension and ischemia
was found in muscles of FM patients [25,65,66]. Changes in
muscle pH related to ischemia [67] might provide a powerful
mechanism for the sensitization of spinal and supraspinal pain
pathways [68]. Investigations using 31P nuclear magnetic
resonance spectroscopy have shown that FM patients
display significantly lower phosphorylation potential and total
oxidative capacity in the quadriceps muscle during rest and
exercise [69]. FM patients also exhibit significantly lower
levels of muscle phosphocreatine and ATP, as well as a lower
phosphocreatine/inorganic phosphate ratio [62,63]. Further-
more, nuclear magnetic resonance testing of muscles in FM
patients showed an increased prevalence of phosphodiester
peaks, which have been associated with sarcolemmal
membrane damage [69,70].

Focal muscle abnormalities, including trigger points, are
frequently detectable in FM patients and may play an
important role as pain generators. Using sensitive
microdialysis techniques, concentrations of protons,
bradykinin, calcitonin gene-related peptide, substance P,
tumor necrosis factor-a, IL-1b, serotonin, and norepinephrine
have been found to be significantly higher in trigger points
than normal muscle tissue [71,72]. Recent studies have
shown that advanced glycation end products may also be
relevant for FM pain. These can trigger the synthesis of
cytokines, particularly IL-1b and tumor necrosis factor-a, and
elevated advanced glycation end product levels have been
detected in interstitial connective tissue of muscles and in
serum of FM patients [73]. All these biochemical mediators
can sensitize muscle nociceptors and thus indirectly
contribute to central sensitization and chronic pain. Because
nociceptive input from muscles is very powerful in inducing
and maintaining central sensitization [74], FM muscle
abnormalities may strongly contribute to pain through
important mechanisms of pain amplification.

Conclusion
FM is a chronic pain syndrome that is characterized by
widespread pain in peripheral tissues, psychological distress,
and central sensitization. Whereas the role of psychological
factors in FM patients' pain has been well established, little is
known about the origin of the sensory abnormalities for pain.
Deep tissue impulse input is most likely relevant for the
initiation and/or maintenance of abnormal central pain
processing and represents an important opportunity for new
treatments and prevention of this chronic pain syndrome.
Three important strategies for FM therapy appear useful at
this time: reduction of peripheral nociceptive input,
particularly from muscles; improvement or prevention of


Available online http://arthritis-research.com/content/8/3/208



central sensitization; and treatment of negative affect,
particularly depression. The first strategy is most likely
relevant for acute FM pain exacerbations and includes
physical therapy, muscle relaxants, muscle injections, and
anti-inflammatory analgesics. Central sensitization can be
successfully ameliorated by cognitive behavioral therapy,
sleep improvement, NMDA receptor antagonists, and anti-
seizure medications. The pharmacological and behavioral
treatment of secondary pain affect (anxiety, anger,
depression) is equally important and may currently be one of
the most powerful interventions for FM pain. Whether
narcotics are useful for the treatment of FM pain is currently
unknown because of insufficient trial experience.

Competing interests
The author declares that they have no competing interests.

Acknowledgments
Supported by NIH grant NS-38767 and the American Fibromyalgia
Syndrome Association.

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