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FEATURE | COMPLEX REGIONAL PAIN SYNDROME
Neuroimmunologic Approaches to
Emerging and Potential Therapies
for Complex Regional Pain
Syndrome (CRPS)
BY DONALD C. MANNING, MD, PhD
Despite a great deal of progress in defining
Complex Regional Pain Syndrome (CRPS),
there is still controversy regarding the
mechanisms involved.
THEORIES HAVE INCLUDED INFLAMMATION, neuropathic mechanisms,
ischemic injury and abnormal sympathetic nervous system
function. To date there is no approved treatment for
CRPS, and therapies for neuropathic or inflammatory pain
have given disappointing results, affording many patients only
partial relief at best (1). Therefore, it is time for a reevaluation
of CRPS mechanisms to enable new therapeutic opportunities.
The high female predominance (75%) and the combination of
inflammatory and neuropathic pain components could be consistent
with an autoimmune mechanism. Targeting therapies
toward immune activation involving cytokines, glia, or the
infiltration of immune cells is a new approach for pain therapy,
although it has already been employed with some success in
oncology and rheumatology.
Neuroimmune activation involves a bidirectional stimulation
of neurons and immune cells in response to trauma or
inflammation (2). Immune cells release inflammatory [e.g.,
cytokines tumor necrosis factor (TNF), interleukin (IL)-1
and IL-6] and anti-inflammatory (e.g., cytokine IL-10)
molecules and they, in turn, are modulated by neurotransmitters,
especially the sympathetic nervous system transmitter norepinephrine
(3,4). Cytokines are polypeptides that can act
locally, within tissues, or at a distance similar to hormones.
They regulate replication, development and activation of cells
in the immune, nervous and hematopoetic systems. The biology
of the cytokines is complicated in that different cells can
produce the same cytokine that can in turn have different
effects or different cytokines can have similar effects or antagonize
each other depending upon the local environment.
Cytokines as Chronic Pain Mediators
TNF, IL-1 AND IL-6 are the cytokines with the best-documented
pathological roles in neuropathic pain. In healthy animals,
the administration of IL-1 or TNF alone can produce
symptoms of neuropathic pain. Spinal neuron activation by
these cytokines can produce long-term alterations in neuronal
excitability. Activation of non-neuronal glial cells with extensive
interconnections within the spinal cord could account for central
cytokine release (5) as well as the spread of excitation
beyond traditional neuroanatomical boundaries and reactivation
of the pain system after new injuries (6). Infusion of IL-1 or
TNF for adjuvant cancer chemotherapy has been associated
with an incidence of nearly 50% of pain syndromes or complaints
of pain and tenderness at the injection site (7-9).
Whereas TNF and IL-1 play important roles in the
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