for Abnormal Pain Processing in FM Patients
Robert Bennett MD
There have been many sophisticated studies of
fibromyalgia patients that provide overwhelming evidence for a
neuropathophysiologic basis for their increased pain perception.
There is still much to learn in terms of genetic predisposition,
environmental triggers and the role of the psyche in modulating
chronic pain states. But the fact that fibromyalgia patients
have all the hallmarks of “central sensitization” has been
pivotal in understanding why these patients have so many diverse
symptoms (that have often been ascribed to hypochondriasis,
hysteria, somatization or malingering). These studies are
briefly described in the paragraphs below; for more detailed
information please consult the references that are given at the
Qualitative differences in pain
An objective measure of applied
force to a tender point can be obtained by dolorimetry (1). A
study using an electronic dolorimeter recorded the subject’s
assessment of pain intensity on a 0 to 10-cm visual analogue
scale (VAS) at varying levels of applied force (2). Distinctly
different response curves were obtained for controls and
fibromyalgia patients. Similar abnormalities of pain processing
in fibromyalgia patients have also been reported for heat and
cold (3;4). These studies are just a more sophisticated way of
showing that fibromyalgia patients are more sensitive to
Deficient pain modulation in
response to repeated thermal stimuli
An improvement of pain
threshold can be demonstrated in normal individuals by
subjecting them to repeated non-noxious skin stimulation. The
physiological basis for this effect is the inhibition of dorsal
horn neuron excitability by persistent stimulation of type A
myelinated axons (5). This effect, known as diffuse noxious
inhibitory control (DNIC) has been examined in fibromyalgia
patients (6;7). In these studies tonic thermal stimuli at
painful and non-painful intensities were used to induce pain
inhibition. Concurrent tonic thermal stimuli, at both painful
and non-painful levels, significantly increased the electrical
pain threshold in the healthy subjects but not in the
fibromyalgia patients. It was concluded that DNIC was deficient
in fibromyalgia patients, suggesting that they either had
deficient pain modulation (8). These studies support the notion
that fibromyalgia patients have defective processing of sensory
Somatosensory induced potentials
refer to the electrophysiological activity in the brain that can
be measured by skull electrodes in response to peripheral
sensory stimulation. Gibson et al reported an increased late
nociceptive (CO2-laser stimulation of skin) evoked somatosensory
response in 10 fibromyalgia patients compared to 10 matched
controls (9). Lorenz et al (10) have reported increased
amplitude of the N170 and P390 brain somatosensory potentials in
fibromyalgia compared to controls evoked by laser stimulation of
the skin. Furthermore they observed a response in both
hemispheres, whereas in controls the response was localized to
one side of the brain. These 2 studies provide objective
evidence that fibromyalgia patients have an altered processing
of painful stimuli in comparison to pain free controls.
Secondary hyperalgesia on
Primary hyperalgesia is the normal
perception of pain from nociceptor stimulation in an injured
tissue. Secondary hyperalgesia refers to pain elicited from
uninjured tissues (11). Arroyo and Cohen, while attempting to
treat fibromyalgia patients with electrical nerve stimulation
reported sensory phenomena characteristic of secondary
hyperalgesia (12). This is a direct example of central
sensitization in fibromyalgia patients.
Elevated levels of substance P
in the CSF
Substance P is an important
nociceptive neurotransmitter. There are 3 definitive studies
that have shown a 3 fold increase of substance P in the CSF of
fibromyalgia patients compared to controls (13-15). Animal
models of hyperalgesia and hypoalgesia have implicated substance
P as a major etiological factor in central sensitization and
have highlighted the relevance of substance P in human pain
states (16). This finding provides impressive evidence for an
abnormal biochemistry of pain related molecules in fibromyalgia
compared to healthy controls.
Elevated levels of nerve growth
Nerve growth factor (NGF) is
required for the normal development of sympathetic and sensory
neurons. Giovengo has reported a 4 fold elevation of NGF in the
CSF of patients with primary fibromyalgia compared with healthy
controls and other pain patients (17). The intravenous
administration of recombinant nerve growth factor in humans
results in a muscle pain syndrome resembling fibromyalgia which
lasts for up to a week after the initial injection. The
mechanism whereby NGF causes hyperalgesia is hypothesized to be
related to its stimulation of protein synthesis in the CNS (18).
This finding provides more impressive evidence for an abnormal
biochemistry of pain related molecules in fibromyalgia compared
to healthy controls.
Beneficial response to an NMDA
The excitatory amino acid glutamine reacting with
NMDA (N-Methyl-D-Aspartic acid) receptors plays a central role
in the generation of non-nociceptive pain. Two studies have
reported that intravenous ketamine (an NMDA receptor antagonist)
attenuates pain and increases pain threshold, as well as
improving muscle endurance in fibromyalgia patients (19). The
experimental induction of pain summation and referral by
intramuscular hypertonic saline in fibromyalgia is attenuated by
the use of ketamine (20). This study provides direct
experimental evidence that the "biochemical signature" of
central sensitization (i.e. activation of NMDA receptors) is
present in fibromyalgia patients.
Experimentally induced central hyperexcitability
Temporal summation of nociceptive impulses at the
level of the spinal cord normally occurs when unmyelinated C
fiber input exceeds a rate of one impulse every 2-3 seconds.
There is good experimental evidence that this neurophysiological
process is a critical event in the development of central
sensitization (21). An amplification of temporal summation has
been demonstrated after repetitive thermal stimulation of the
palmar skin in fibromyalgia patients (22) and after
intramuscular electrical stimulation of muscle (23). A recent
study reported increased temporal summation in fibromyalgia
subjects compared to controls after direct repetitive mechanical
stimulation of muscle (24). These finding provides crucial
confirmation that fibromyalgia patients amplify sensory impulses
according to the concepts of “central sensitization”.
“Tender skin” is a common complaint of
fibromyalgia patients. There have been repeated observations
going back nearly 25 years that fibromyalgia patients have an
increased susceptibility to neurogenic inflammation
(dermatographia) after scratching the skin (25). Neurogenic
inflammation is now understood in terms of antidromic (i.e.
retrograde) impulses in type C fibers evoking the release of
histamine, substance P and inflammatory cytokines from
nociceptors in the skin (26). A recent study has now
demonstrated that fibromyalgia patients, in comparison to
healthy controls, have increased levels of messenger RNA for
inflammatory cytokines (IL-1, TNFa and IL-6) in their skin (27).
This observation provides validation for another common symptom
reported by fibromyalgia patients, namely increased skin
Functional MRI imaging (fMRI) is a technique for
visualizing metabolic activity in the brain in “real time”. A
2002 study confirmed that fibromyalgia patients have increased
brain activity from a stimulus intensity that does not activate
the brain of healthy controls (28). The authors’ concluded that
their findings support the notion that fibromyalgia is
characterized by cortical or subcortical augmentation of pain
processing – i.e. “central sensitization”. This study validates
the report of pain in fibromyalgia patients in terms of
increased brain activity in locations that are known to be
involved in the cortical and sub-cortical response to pain. In
other words if a patient says they “have pain” that statement
can be verified in this type of experimental setting.
Spinal Flexion Reflex
This reflex is an entirely objective
response that evaluates the degree of central sensitization at
the level of the spinal cord. It is demonstrated by
electrically stimulating a purely sensory nerve (the sural nerve
that lies just below the lateral malleolus – the outside
prominence of the ankle) and recording the electromyographic
reflex contraction of the biceps femoris muscle (a hamstring
muscle). In this test the amount of electrical current applied
to the sural nerve is gradually increased (from 1 mA up to 100
mA) until a contraction is registered electromyographically in
the biceps femoris muscle. The current at which this occurs is
referred to as "the reflex threshold" (RT) There are two studies
that have shown a facilitated RT in fibromyalgia subjects, and
in one of these studies similar findings were found in patients
with chronic pain after whiplash injuries.
In the first study Swiss investigators evaluated 85 patients
with fibromyalgia compared to 40 healthy controls (29). The
median RT threshold in patients with FM (22.7 mA]) was
significantly decreased compared with that in healthy controls
(33 mA). A cutoff value of <27.6 mA for the RT provided
sensitivity of 73% and specificity of 80% for detecting central
allodynia in the setting of fibromyalgia. In the second study.
In the second study, Danish investigators evaluated 22 patients
with fibromyalgia, 27 patients with chronic whiplash pain and 29
healthy controls (30). They found that RTs were significantly
lower in both the whiplash and fibromyalgia subjects compared
with the control subjects. It was surmised that these results
provided good objective evidence for spinal cord
hyperexcitability in patients with chronic pain after whiplash
injury and in fibromyalgia patients. The authors commented that
"this spinal hypersensitivity may explain pain in the absence of
detectable tissue damage, in both fibromyalgia and chronic pain
following whiplash injuries".
These articles were summed up by a 2002 Editorial
in Arthritis and Rheumatism (the leading journal of American
Rheumatologists): “Taken together, the data on pain processing
in fibromyalgia demonstrate that the central representation of
pain correlates with patient reports of pain, and that purely
behavioral or psychological factors are not primarily
responsible for the pain and tenderness seen in fibromyalgia”.
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