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.