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FEATURE | COMPLEX REGIONAL PAIN SYNDROME
By changing our perspective and looking beyond traditional neuroanatomy
and neurophysiology to understand the body’s response to injury, we may
uncover new therapeutic strategies.
ability to alter the development or maintenance of other
chronic pain states.
Thalidomide was developed as a sedative and antinausea
drug, but its teratogenic effects and propensity to cause peripheral
neuropathy with prolonged use have limited its use. It is
orally active and functions as an immunomodulator by inhibiting
the production of a broad range of pro-inflammatory mediators,
including TNF, IL-1, and IL-6 and by increasing the
level of IL-10, IL-2, and IFN. It also inhibits the production
of TNF from human microglial cells (39). Clinically, thalidomide
has been reported to reduce pain and hyperalgesia in
Complex Regional Pain Syndrome (CRPS) Type I (40-43).
Medicinal chemistry efforts have produced several
generations of immunomodulatory agents derived from thalidomide
that have decreased toxicity. Lenalidomide, a novel
immunomodulatory drug with anti-inflammatory properties,
potently inhibits the secretion of pro-inflammatory cytokines
(e.g., TNF, IL-1 and IL-6) and stimulates the secretion of
anti-inflammatory cytokines (e.g., Il-10). Lenalidomide is currently
approved in the U.S. for the treatment of patients with
transfusion-dependent anemia due to low- or intermediate-1-
risk myelodysplastic syndromes with a deletion 5q cytogenetic
abnormality with or without additional cytogenetic abnormalities.
Based upon reports of symptomatic improvement of CRPS
in response to treatment with thalidomide, as well as upon the
pharmacological properties of lenalidomide, a pilot study was
undertaken to assess the safety and preliminary efficacy of
lenalidomide in subjects with unilateral CRPS Type I (44).
Lenalidomide was used in an open-label study of 40
patients with unilateral CRPS of at least 1-year duration, optimal
conventional therapy, and with entry pain levels registering
at least 4 on a 0-10 pain scale (44). The patients had high levels
of pain, on average, at baseline (7.1 out of 10) and were taking,
on average, more than 4 concomitant CRPS pain medications.
Despite this high degree of prior and current treatment, over
one third of subjects reported at least 30% improvement and
one half reported a 20% improvement in pain levels as well as
broad and significant reductions in CRPS symptoms and sleep
disturbance. Of the original 40 subjects, 28 continued into an
extension phase and 14 are still in the study, with continued
benefit after more than 2 years on the study drug. Data from
this study demonstrated a good overall safety profile; however,
as the study was uncontrolled, it is difficult to interpret the precise
relationship of adverse events to study treatment. Most
adverse events were mild to moderate in severity and many were
attributed to the disease rather than to a reaction to the study
drug. Few subjects required dose reductions or discontinuation
due to adverse events. The results of this study demonstrate a
level of safety and efficacy justifying additional study for the
treatment of CRPS. Controlled studies are currently underway
in subjects with CRPS.
Summary
WE NEED TO FIND NEW APPROACHES to the treatment of
chronic neuropathic pain and CRPS. By changing our perspective
and looking beyond traditional neuroanatomy and neurophysiology
to understand the body’s response to injury, we may
uncover new therapeutic strategies. This short article cannot
possibly provide adequate coverage of the extensive literature
supporting immune- and nervous system interaction, especially
in pain states. An appreciation of the role played by the
immune system in injury-induced pain states, as summarized in
this article, represents a new opportunity. Currently available
immunomodulators and immunosuppressive agents need to be
cautiously evaluated for their pain-modulating ability. The
results of these initial studies will certainly foster more extensive
therapeutic development efforts.
REFERENCES
1. Kingery, WS. A critical review of controlled clinical trials for peripheral
neuropathic pain and complex regional pain syndromes. Pain. 1997;
73:123-139.
2. DeLeo JA, Yezierski RP. The role of neuroinflammation and neuroimmune
activation in persistent pain. Pain. 2001; 90:1-6.
3. Straub, R. Bottom-up and top-down signaling of IL-6 with and without
habituation? Brain, Behavior and Immunity. 2006 January; 20: 1; 37-39.
4. Spengler RN, Allen RM, Remick DG, Strieter RM, Kunkel SL. Stimulation of
alpha-adrenergic receptor augments the production of macrophagederived
tumor necrosis factor. J Immunol. 1990; 145:1430-1434.
5. Aloisi F. Immune function of microglia. Glia. 2001; 36:165-179.
6. Carmignoto G. Reciprocal communication systems between astrocytes
and neurones. Prog Neurobiol. 2000; 62:561-581.
7. Kemeny N, Childs B, Larchian W, Rosado K, Kelsen D. A phase II trial of
recombinant tumor necrosis factor in patients with advanced colorectal
carcinoma. Cancer. 1990; 66:659-663.
8. Del Mastro L, et al. Intraperitoneal infusion of recombinant human tumor
necrosis factor and mitoxantrone in neoplastic ascites: a feasibility study.
Anticancer Res. 1995; 15:2207-2212.
9. Elkordy M, et al. A phase I trial of recombinant human interleukin-1 beta
(OCT-43) following high-dose chemotherapy and autologous bone marrow
transplantation. Bone Marrow Transplant. 1997; 19:315-322.
10. Murphy PG, Grondin J, Altares M, Richardson PM. Induction of interleukin-6
in axotomized sensory neurons. J Neurosci. 1995; 15:5130-5138.
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