Fibromyalgia syndrome: mechanisms of abnormal pain processing

Abstract

Fibromyalgia syndrome (FMS) pain is frequent in the general popula-tion, but its pathogenesis is only poorly understood. FMS patients lack consistent tissue abnormalities but display features of hyperalgesia (increased sensitivity to painful stimuli) and allodynia (lowered pain threshold). Many recent FMS studies have demonstrated central ner-vous system (CNS) pain processing abnormalities, including abnormal temporal summation of pain. However, increasing evidence points toward peripheral tissues as relevant contributors of painful impulse input to the spinal cord and brain that might either initiate or maintain central sensitization, or both. In the CNS, persistent nociceptive input from peripheral tissues can lead to neuroplastic changes resulting in central sensitization and pain. This mechanism appears to represent a hallmark of FMS and many other chronic-pain syndromes, includ-ing irritable bowel syndrome, temporomandibular disorder, migraine, and lower-back pain. Importantly, after central sensitization has been established, only minimal peripheral 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 sig-nificantly contribute to clinical FMS 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 FMS and other chronic-pain syndromes.

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ABSTRACT
Fibromyalgia syndrome (FMS) pain is frequent in the general popula-
tion, but its pathogenesis is only poorly understood. FMS patients lack
consistent tissue abnormalities but display features of hyperalgesia
(increased sensitivity to painful stimuli) and allodynia (lowered pain
threshold). Many recent FMS studies have demonstrated central ner-
vous system (CNS) pain processing abnormalities, including abnormal
temporal summation of pain. However, increasing evidence points
toward peripheral tissues as relevant contributors of painful impulse
input to the spinal cord and brain that might either initiate or maintain
central sensitization, or both. In the CNS, persistent nociceptive input
from peripheral tissues can lead to neuroplastic changes resulting in
central sensitization and pain. This mechanism appears to represent
a hallmark of FMS and many other chronic-pain syndromes, includ-
ing irritable bowel syndrome, temporomandibular disorder, migraine,
and lower-back pain. Importantly, after central sensitization has
been established, only minimal peripheral 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 sig-
nificantly contribute to clinical FMS 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
FMS and other chronic-pain syndromes.
Fibromyalgia Syndrome:
Mechanisms of Abnormal Pain Processing
Roland Staud, MD
INTRODUCTION
In 1990, the American College of Rheumatology defined the
criteria for fibromyalgia syndrome (FMS) as widespread pain
for >3 months with ≥11 out of 18 tender points present.1 In
addition, most FMS patients complain of interrupted sleep,
emotional distress, and pronounced fatigue. It is well established
that in the general population FMS represents the extreme end
of the spectrum of musculoskeletal pain. This chronic illness
disproportionately affects women (9:1 ratio of women to men
affected), mostly in the third to fifth decade of their lives. Like
many other clinical syndromes, FMS has no single specific
feature but represents a symptom complex of self-reported or
elicited findings. Because FMS represents the extreme end of the
chronic-pain spectrum in the general population, some physi-
cians have questioned its usefulness as a diagnostic label.2,3
FMS patients consistently complain of pain in the muscula-
ture but do not show evidence for consistent tissue abnormali-
ties. Furthermore, many recent studies have demonstrated that
FMS pain is related to sensitization of central nervous system
(CNS) pain pathways. The pathogenesis of FMS is unknown,
although abnormal concentration of CNS neuropeptides, bio-
CLINICAL FOCUS
Primary Psychiatry. 2006;13(9):66-71
FOCUS POINTS
• Pain is a complex biopsychosocial experience.
• Pain has multiple dimensions, including pain intensity
and unpleasantness.
• Peripheral and central mechanisms of pain play an impor-
tant role in fibromyalgia syndrome.
September 2006
Dr. Staud is professor of medicine in the Division of Rheumatology and Clinical Immunology at the McKnight Brain Institute at the University of Florida College of Medicine in Gainesville.
Disclosure: Dr. Staud is on the speaker’s bureau of Merck; and has received grant support from the National Institutes of Health and Pfizer.
Please direct all correspondence to: Roland Staud, MD, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610-0221; Tel: 352-273-5345; Fax: 352-392-8483; E-mail: staudr@ufl.edu.

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genic amines, and alterations of the hypothalamic-pituitary-adre-
nal axis (HPA) have been described.4-7 There is a large body of
evidence for a generalized lowering of pressure-pain thresholds in
FMS patients.8-12 Importantly, the mechanical pain hypersensi-
tivity (allodynia) of FMS patients is not limited to tender points
but appears to be widespread.12 In addition, almost all studies of
FMS patients have shown abnormalities of pain sensitivity while
using different methods of sensory testing.
Although relevant for many clinical pain syndromes like FMS,
nociception alone cannot explain an individual’s pain because
of the subsequent modulation of peripheral pain signals in the
CNS by conscious and unconscious mental activity.13 In addi-
tion, sociocultural influences, beliefs, or biases strongly influence
pain, particularly those related to cause, control, duration, out-
come, and blame. These beliefs are frequently linked to negative
emotions such as anger, fear, and depression.14 Generally, the
two emotional components of pain are the unpleasantness of the
sensation (primary pain affect), and negative feelings like depres-
sion, anger, and fear (secondary pain affect). This relationship of
emotions with pain is bidirectional because modulation of nega-
tive feelings can powerfully alter the pain experience.15 Pain is a
complex biopsychosocial experience which 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.”16 However, this
definition of pain has significant shortcomings because it is not
encompassing all aspects of pain.
In general, abnormalities of pain processing appear to play an
important role for FMS pain, particularly those related to deep-
tissue impulse input, central sensitization, and negative affect.
Particularly, alterations of central-pain processing, including
increased temporal summation of pain (or windup) and central
sensitization, appear to be relevant for clinical FMS pain.
PATHOGENESIS OF FMS PAIN
FMS is a pain amplification syndrome of patients who are
highly sensitive to painful and nonpainful stimuli, including
touch, heat, cold, chemicals, light, sound, and smell. The cause
for the heightened sensitivity of FMS patients is unknown. Most
FMS patients show blunting of the HPA responses to stress-
ors,17,18 as well as increased levels of substance P,4,19 excitatory
amino acids,20 and neurotrophins21 in the cerebrospinal fluid.
Although most previous FMS studies did not show consistent
peripheral tissue abnormalities,22 more recent evidence points
to possibly relevant alterations in skin and muscles. These
abnormalities include increased substance P in muscle tissue,23
deoxyribonucleic acid fragmentation of muscle fibers,24 increased
interleukin-1 (IL-1) in cutaneous tissues,25 elevated inducible
nitric oxide synthase,26 and muscle-perfusion deficits.27,28 These
peripheral changes may contribute to increased tonic nociceptive
input into the spinal cord that results in augmented pain pro-
cessing and central sensitization. In addition, there is compelling
evidence for the contribution of peripheral pain to overall clini-
cal pain in FMS.29 In a large study of FMS patients, ratings of
peripheral pain areas accounted for 27% of the variance of overall
clinical pain,29 thus emphasizing the important role of peripheral
impulse input for FMS pain. These findings indicate a possible
link between peripheral input and FMS pain. Importantly, noci-
ceptive activity in peripheral tissues of FMS patients does not
necessarily have to be extensive, because central sensitization
requires little sustained input for the maintenance of the sensi-
tized state and chronic pain.29
Despite increasing evidence emphasizing the role of sen-
sory abnormalities for chronic widespread pain in FMS, the
contribution of psychologic factors to FMS pain must also be
recognized. Several psychologic risk factors for FMS are com-
mon in Western populations, including negative life events,30
psychologic distress,31 increased focus on bodily symptoms,32
and passive pain-coping mechanisms.33 Both community and
clinic patients with FMS are also more likely than the general
population to have a diagnosis of psychiatric disorders, par-
ticularly depression and anxiety.34,35 In a prospective study of
214 women with self-reported pain, 39 patients (18%) were
diagnosed with FMS at study entry and 33% satisfied FMS
criteria after 5.5 years of follow-up.36 Self-reported depression
at baseline was associated with a more than six-fold increased
likelihood of reporting FMS 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 healthcare-seeking behavior, are strong predictors
for chronic widespread pain and FMS.37
In this context, several studies have reported FMS to be
comorbid with major depressive disorder (MDD).38,39 A recent
large family study of FMS patients showed that FMS and MDD
shared familial risk factors,40 emphasizing the strong relationship
between negative affect and FMS pain.
PERIPHERAL AND CENTRAL
SENSITIZATION
Although heightened pain sensitivity is a hallmark of FMS,
little is known about the genetic and other factors that contribute
to this abnormality. Particularly, tissue sensitization after injury
has long been recognized as making an important contribution

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to pain. This form of sensitization is related to heightened sensi-
tivity of primary nociceptive afferents (peripheral sensitization),
whereas central sensitization requires functional changes in the
CNS (neuroplasticity). Central sensitization can manifest itself
in several ways, including increased excitability of spinal cord
neurons, enlargement of their receptive fields, reduction in pain
threshold, and/or recruitment of novel afferent inputs. FMS
sufferers are centrally sensitized patients that report abnormal or
heightened pain sensitivity to innocuous or painful stimuli with
spreading of hypersensitivity to uninjured sites. Pain is generated
by low-threshold mechano-receptors that are normally silent in
pain processing. Thus, tissue injury may not only result in affer-
ent nociceptive input, but also expansion of dorsal horn recep-
tive fields and central sensitization.
Central sensitization, which can occur as an immediate or
delayed phenomenon,41 is associated with increased sensitivity of
wide dynamic range and nociception specific neurons of the spi-
nal cord. Whereas delayed central sensitization mostly depends
on transcriptional and translational neuronal changes during
afferent barrage, immediate central sensitization relies on dorsal
horn receptor mechanisms, including the N-methyl-D-aspartate
(NMDA) and neurokinin-1 receptors.42
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 result in increased neuronal firing and
pain. Although only supported by indirect evidence at this
time, peripheral pain mechanisms seem to play an important
role for FMS pain.29 Impulses from peripheral nociceptors
are transmitted to the CNS by myelinated A-δ (first pain)
and unmyelinated C-fibers (second pain). A-δ–mediated pain
signals are rapidly conducted to the CNS (approximately 10
meters/second), whereas C-fiber impulses travel relatively
slowly (approximately 1.6 meters/second). When the distance
of C-fiber transmission is sufficiently long (like the length of
an extremity), this delay of C-fiber compared to A-δ–fiber
impulses can be easily detected by study subjects. An impor-
tant test of central pain amplification relies on summation of
second pain or windup (WU).43 This technique reveals sensi-
tivity to input from unmyelinated (C) afferents and the status
of the NMDA receptor system44 that is implicated in a variety
of chronic pain conditions. Thermal, mechanical, or electri-
cal WU stimuli can be applied to the skin or musculature of
patients, and commercial neurosensory stimulators are readily
available for WU testing.
TEMPORAL SUMMATION OF SECOND
PAIN OR WINDUP
In 1965, Mendell and Wall45 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. This important mechanism of pain amplification in the
dorsal horn neurons of the spinal cord is related to temporal
summation of second pain or WU. First pain, which is con-
ducted by myelinated A-δ 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 burn-
ing. Second pain reliably increases in intensity when painful
stimuli are applied more often than once every 3 seconds, and
is positively correlated to stimulus frequency (Figure). This pro-
gressive increase represents temporal summation or WU and has
been demonstrated to result from a CNS rather than peripheral
nervous system mechanism. Animal studies have demonstrated
similar WU of C afferent-mediated responses of dorsal horn
nociceptive neurons, and this summation has been found to
involve NMDA receptor mechanisms. Importantly, WU and
second pain can be inhibited by NMDA receptor antagonists,
including dextromethorphan and ketamine.46-48
Windup is Abnormal in FMS Patients
Recent investigations in FMS patients have focused on
WU and central sensitization because this chronic pain
syndrome is associated with extensive secondary hyperalge-
sia and allodynia.49 Several studies provided psychophysi-
cal evidence that input to central nociceptive pathways is
abnormal in FMS patients.43,50-54 When WU pain is evoked
both in FMS patients and in normal controls, the perceived
pain increase by experimental stimuli (mechanical, heat,
cold, or electricity) is greater for FMS patients compared
with control subjects, as is the magnitude of temporal
summation or WU within a series of stimuli. Following a
series of stimuli, WU aftersensations are also increased, last
longer, and are more frequently painful in FMS subjects.
These results indicate both augmentation and prolonged
decay of nociceptive input in FMS patients, and provide
convincing evidence for a role for central sensitization
in the pathogenesis of this syndrome. Several important
points are relevant for clinical practice. As previously men-
tioned, when central sensitization has occurred in chronic
pain patients, little additional nociceptive input is required
to maintain the sensitized state. Thus, seemingly innocu-

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ous daily activities may contribute to the maintenance of
chronic pain. In addition, the decay of painful sensations
is prolonged in FMS, resulting in slow reductions of their
pain levels during rest as well as brief therapeutic inter-
ventions. 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.
Windup Measures Can Predict FMS Pain Intensity
The important role of central pain mechanisms for clini-
cal pain is also supported by their usefulness as predictors of
clinical pain intensity of FMS patients. Thermal WU ratings
correlate well with clinical pain intensity (Pearson’s r=.53),
thus emphasizing the important role of this pain mechanism
for FMS. In addition, hierarchical regression models that
include tender point count, pain-related negative affect, and
WU ratings have been shown to account for 50% of the vari-
ance in FMS clinical pain intensity.55
MECHANISMS OF ABNORMAL PAIN
SENSITIVITY
The mechanisms underlying the central sensitization that
occurs in patients with FMS 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 noci-
ceptive input to the brain as well as the perception of pain.
Specifically, intense or prolonged impulse input from A-δ 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.
Glia and Central Sensitization
Accumulating evidence suggests that dorsal horn glia cells
might have an important role in producing and maintaining
abnormal pain sensitivity.56,57 Synapses within the CNS are
encapsulated by glia that do not normally respond to noci-
ceptive 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 prostaglan-
dins. Once activated, glia cells release pro-inflammatory
cytokines, including tumor necrosis factor, IL-6 and IL-1,
substance P, nitric oxide, prostaglandins, excitatory amino
acids, adenosine triphosphate (ATP), and fractalkine.58
These, in turn, further increase the discharge of excitatory
amino acids and substance P from the A-δ and C afferents
that synapse in the dorsal horn, and also enhance the hyper-
excitability of the dorsal horn neurons.56,59 Recent evidence
also points toward a possible role of NMDA receptors in
glial activation and pain.60
FIGURE
TEMPORAL SUMMATION OF SECOND PAIN IN NORMAL
SUBJECTS
Mean (±SD) windup ratings of 10 normal study participants. The subjects received either 10
repetitive 520C (A) or 510C (B) heat pulses (P) to the hands at 0.33 Hz. Mixed model analysis
of variance showed a significant increase of pain ratings from first (P1) to tenth heat pulse
(P10) (P<.001). There was a significant pulse x temperature interaction noted (P<.005),
indicating that increasing stimulus temperatures resulted in augmented windup. Windup
aftersensations rapidly decayed below painful levels 15 seconds after the last pulse in all
participants. A numerical pain scale was used (0–100). The shaded areas represent pain
ratings below threshold.
AS15=aftersensensation 15 seconds; AS30=aftersensation 30 seconds.
Staud R. Primary Psychiatry. Vol 13, No 9. 2006.
70
60
50
40
30
20
10
0
A
B
52˚ C
51˚ C
70
60
50
40
30
20
10
0
Pain Rating (0-100)
P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 AS15 AS30
P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 AS15 AS30

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FACTORS RELATED TO CENTRAL
SENSITIZATION
As a normal response to tissue trauma, injury is followed
by repair and healing. Inflammation occurs, which results in a
cascade of electrophysiologic and chemical events that resolve
over time, and the patient becomes pain free. However, in per-
sistent pain 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
FMS. It must be emphasized, however, that in patients with
FMS, specific abnormalities 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-β 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, expand-
ing receptive field areas, and spinal neurons taking on proper-
ties of wide dynamic-range neurons.61 Ultimately, A-β fibers
stimulate postsynaptic neurons to transmit pain, where these
A-β 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.
ROLE OF MUSCLE TISSUE FOR
CHRONIC PAIN
A potential source of nociceptive input that might account
for FMS pain is muscle tissue.62 Several types of muscle
abnormalities have been reported in FMS patients, including
the appearance of ragged red fibers, inflammatory infiltrates,
and moth-eaten fibers.63-65 Possible mechanisms for such
muscle changes might include repetitive muscle microtrau-
ma, which could contribute to the postexertional pain and
other painful symptoms experienced by these patients. In
addition, prolonged muscle tension and ischemia were found
in muscles of FMS patients.28,66,67 Changes in muscle pH
related to ischemia68 might provide a powerful mechanisms
for the sensitization of spinal and supraspinal pain path-
ways.69 Investigations using 31P nuclear magnetic resonance
spectroscopy have shown that FMS patients display sig-
nificantly lower phosphorylation potential and total oxidative
capacity in the quadriceps muscle during rest and exercise.70
FMS patients also exhibit significantly lower levels of muscle
phosphocreatine and ATP, as well as a lower phosphocreatine/
inorganic phosphate ratio.63,64 Because nociceptive input from
muscles is very powerful in inducing and maintaining central
sensitization,71 muscle abnormalities may strongly contribute
to this important mechanism of pain amplification.
CONCLUSION
FMS is a chronic-pain syndrome that is characterized by
widespread pain in peripheral tissues, psychologic distress,
and central sensitization. Whereas the role of psychologic
factors for FMS 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 target for new
treatments of this chronic-pain syndrome.29,72 Therefore,
future research should not only focus on central pain-pro-
cessing abnormalities in FMS, but also on the important
role of peripheral-impulse input for chronic pain. Despite
limited trial experience, three important strategies for FMS
therapy appear useful at this time. They include reduction
of peripheral nociceptive input, particularly from muscles;
improvement or prevention of central sensitization; and
treatment of negative affect, particularly depression. The
first strategy is most likely relevant for acute FMS pain
exacerbations and includes physical therapy, muscle relax-
ants, muscle injections, and anti-inflammatory analgesics.
Central sensitization can be successfully ameliorated by
cognitive-behavioral therapy, sleep improvement, NMDA
receptor antagonists, and antiseizure medications. The
pharmacologic and behavioral treatment of secondary pain
affect (anxiety, anger, depression) is equally important and
is currently one of the most powerful interventions for FMS
pain. The coaggregation of FMS with major depressive
disorder in family studies suggests a shared role of biogenic
amines for both illnesses.73 Antidepressants, particularly
combined serotonin norepinephrine reuptake inhibitors,
seemed to be efficacious for FMS pain in several clinical
trials.74 However, up to now no pharmacologic therapy has
received Food and Drug Administration approval for the
treatment of FMS pain. Whether narcotics are useful for the
treatment of FMS pain is unknown at this time because of
insufficient trial experience. PP

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