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EMERGING TREATMENT AND DIAGNOSIS | MANNING
initiation of persistent neuropathic pain, delayed IL-6 production
is a factor in the maintenance of such pain (10). Another
set of cytokines such as IL-10 serves to inhibit inflammation
and immune activation (11). Malfunction of this inflammatory/anti-inflammatory
cytokine balance could lead to chronic
pain and inflammatory syndromes. The widespread presence of
receptors for the cytokines in the sensory nervous system suggests
that these nerves serve as immunosensors (12) and form a
link between immune activation and neurobehavioral aspects of
chronic illness (13). Immune activation and cytokine release
have also been associated with decreased mood (14) and inhibition
of certain types of learning and memory (15). Evidence
from animal studies suggests that the action of tricyclic antidepressants
on pain and mood may derive from cytokine interactions
in the brain (16, 17).
Proinflammatory cytokines TNF and IL-6 are specifically
elevated in tissue fluid in CRPS-affected regions but not in
nonaffected regions (18). Cerebrospinal fluid levels of IL-6 and
IL-1 are elevated in patients with CRPS but not in patients
without pain or with chronic non-CRPS-related pain (19).
These findings suggest a specific association between cytokines
and CRPS.
Immunomodulation as a Strategy for Treating CRPS
IN IMMUNE-MEDIATED DISEASES, it is important to suppress
the pathologic elevations of cytokines rather than completely
blocking them. This approach, known as immunomodulation,
serves to restore the normal balance in immune function.
Immunosuppressive agents such as methotrexate (20) and
leflunomide (21) attenuate tactile hypersensitivity in rodent
radiculopathy and neuropathy models. Leflunomide is approved
for clinical use in rheumatoid arthritis and has several antiinflammatory
actions, including inhibition of IL-1, TNF,
and the expression of nitric oxide and COX-2 genes. However,
no clinical studies in chronic neuropathic pain conditions have
been reported. Caution is advised, because general immunosuppressants
can increase the risk and reduce the resolution of certain
types of infection.
A somewhat unexpected drug class for immunomodulation
is comprised of the statins or 3-hydroxy-3-methylglutaryl coenzyme
A (HMGCoA) reductase inhibitors. Reports that statin
treatment could produce improvement in a model of multiple
sclerosis (22) have sparked great interest in this class of drugs.
(23) Treatment with atorvastatin induced the secretion of antiinflammatory
cytokines (IL-4, IL-5, and IL-10) and inhibited
the secretion of Th-1 pro-inflammatory cytokines (IL-2, IL-12,
IFN, and TNF). Another statin, lovastatin, inhibited the
expression of TNF, IL-1, and IL-6 in rat astrocytes,
microglia, and macrophages (24). Statins decreased the expression
of inflammatory mediators in the CNS, including TNF
(25). The potential clinical benefit of using statins to treat neuropathic
pain is unexplored, but these agents may be effective
in preemptive use. How many postoperative or traumatic
neuropathic pain states have been avoided by concomitant use
of statins? Future studies may provide some guidance for the
use of these agents.
In addition, Shir et al. have reported that dietary fat can
reduce the neuropathic pain-related behaviors resulting from
partial sciatic nerve ligation (26). The consumption of unsaturated
corn or soy oils suppressed tactile allodynia and heat
hyperalgesia, an effect that was accentuated by dietary protein
from multiple sources (26). Dietary fats can modulate both
innate and adaptive immune responses through toll-like receptor-4
(TLR-4) receptors. TLR-4 functions in the innate
immune system as a pattern-recognition receptor for pathogens.
In the rat CNS TLR-4 occurs exclusively on microglia (27).
TLR-4 can be activated by bacterial wall molecules such as
endotoxins or lipopolysaccharides and by endogenous ligands
such as heat shock proteins, proteoglycans, and saturated fatty
acids released after neural injury and degeneration (28, 29). Saturated
fatty acids activate TLR-4, but omega-3 polyunsaturated
fatty acids inhibit agonist-induced TLR-4 activation (30). Partial
but significant reduction in hyperalgesia and allodynia
behavior can be accomplished by interfering with the function
of TLR-4 in microglia (31). This mechanism raises intriguing
therapeutic possibilities; however, much work remains.
Inhibitors of Cytokine Production and Function
GLUCOCORTICOIDS HAVE BEEN USED FOR MANY YEARS
to treat CRPS and inflammatory diseases. They can modulate
the immune system and inhibit the production of a wide range
of inflammatory mediators as well as stimulate the production
of anti-inflammatory agents. Glucocorticoid utility for chronic
diseases is severely compromised by a wide range of adverse
effects, including diabetes, impaired wound healing, and susceptibility
to infections, metabolic problems, and bone demineralization
(32). The search for safer and more effective
inhibitors of inflammatory mediators has yielded several new
therapeutic agents. Successful use of TNF monoclonal antibodies
(infliximab) or TNF-receptor fusion protein (etanercept)
has changed the therapy for rheumatoid arthritis and
several other chronic inflammatory diseases. Open-label clinical
reports have claimed rapid resolution of acute sciatica (involving
spinal root irritation) using TNF inhibitors infliximab
(33) or entanercept (34). These findings, however, were not
supported by a larger controlled study of acute radiculopathy
pain using infliximab (35). There are no reports of these agents
being used in trials of CRPS therapy. In one small experimental
report, elevated interstitial cytokine levels from CRPS-affected
regions are markedly reduced by infliximab treatment coincident
with a reduction in clinical symptoms (36). Anakinra is a
recombinant human IL-1-receptor antagonist approved for use
in rheumatoid arthritis (37), but no studies have looked at its
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