There is a relatively long history of the use of the α-adrenergic antagonist, phenoxybenzamine, for the treatment of complex regional pain syndrome (CRPS). One form of this syndrome, CRPS I, was originally termed reflex sympathetic dystrophy (RSD) because of an apparent dysregulation of the sympathetic nervous system in the region of an extremity that had been subjected to an injury or surgical procedure. The syndrome develops in the absence of any apparent continuation of the inciting trauma. Hallmarks of the condition are allodynia (pain perceived from a nonpainful stimulus) and hyperalgesia (exaggerated pain response to a painful stimulus). In addition to severe, unremitting burning pain, the affected limb is typically warm and edematous in the early weeks after trauma but then progresses to a primarily cold, dry limb in later weeks and months. The later stages are frequently characterized by changes to skin texture and nail deformities, hypertrichosis, muscle atrophy, and bone demineralization. Earlier treatments of CRPS syndromes were primarily focused on blocking sympathetic outflow to an affected extremity. The use of an α-adrenergic antagonist such as phenoxybenzamine followed from this perspective. However, the current consensus on the etiology of CRPS favors an interpretation of the symptomatology as an evidence of decreased sympathetic activity to the injured limb and a resulting upregulation of adrenergic sensitivity. The clinical use of phenoxybenzamine for the treatment of CRPS is reviewed, and mechanisms of action that include potential immunomodulatory/anti-inflammatory effects are presented. Also, a recent study identified phenoxybenzamine as a potential intervention for pain mediation from its effects on gene expression in human cell lines; on this basis, it was tested and found to be capable of reducing pain behavior in a classical animal model of chronic pain. 1. Introduction Complex regional pain syndrome (CRPS), types I and II, is the current accepted nomenclature for related neuropathic pain syndromes that typically develop following injury or surgery to an extremity [1]. Type I designation originally referred to conditions that were not believed to have been associated with nerve injury; this condition was previously called reflex sympathetic dystrophy (RSD). Type II CRPS was earlier termed causalgia and was associated with clear evidence of nerve damage [2]. In view of evidence that small nociceptive fibers may be damaged in CRPS I, the validity of an important distinction between type I and type II syndromes, in terms of
References
[1]
M. Stanton-Hicks, W. Janig, S. Hassenbusch, J. D. Haddox, R. Boas, and P. Wilson, “Reflex sympathetic dystrophy: changing concepts and taxonomy,” Pain, vol. 63, no. 1, pp. 127–133, 1995.
[2]
R. J. Schwartzman, G. M. Alexander, and J. Grothusen, “Pathophysiology of complex regional pain syndrome,” Expert Review of Neurotherapeutics, vol. 6, no. 5, pp. 669–681, 2006.
[3]
H. Merskey and N. Bogduk, “Descriptions of chronic pain syndromes and definitions of pain terms,” in Classification of Chronic Pain, pp. 40–43, IASP Press, Seattle, Wash, USA, 1994.
[4]
P. J. Albrecht, S. Hines, E. Eisenberg et al., “Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome,” Pain, vol. 120, no. 3, pp. 244–266, 2006.
[5]
A. L. Oaklander, J. G. Rissmiller, L. B. Gelman, L. Zheng, Y. Chang, and R. Gott, “Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy),” Pain, vol. 120, no. 3, pp. 235–243, 2006.
[6]
T. C. Westfall and D. P. Westfall, “Adrenergic agonists and antagonists,” in Goodman and Gilman's, the Pharmacological Basis of Therapeutics, L. L. Brunton, Ed., pp. 267–268, McGraw-Hill, New York, NY, USA, 2006.
[7]
C. Hamilton, H. Dalrymple, and J. Reid, “Recovery in vivo and in vitro of α-adrenoceptor responses and radioligand binding after phenoxybenzamine,” Journal of Cardiovascular Pharmacology, vol. 4, no. 1, supplement, pp. S125–S128, 1982.
[8]
T. N. Weingarten, J. P. Cata, J. F. O'Hara et al., “Comparison of two preoperative medical management strategies for laparoscopic resection of pheochromocytoma,” Urology, vol. 76, no. 2, pp. 508–511, 2010.
[9]
R. S. Perez, P. E. Zollinger, P. U. Dijkstra et al., “Evidence based guidelines for complex regional pain syndrome type 1,” BMC Neurology, vol. 10, article 20, 2010.
[10]
L. Cossins, R. W. Okell, H. Cameron, B. Simpson, H. M. Poole, and A. Goebel, “Treatment of complex regional pain syndrome in adults: a systematic review of randomized controlled trials published from June 2000 to February 2012,” European Journal of Pain, vol. 17, pp. 158–173, 2013.
[11]
American Hospital Formulary Service, American Society of Health-System Pharmacists, Bethesda, Md, USA, 2013.
[12]
D. S. Bennett and D. Brookoff, “Complex regional pain syndromes (reflex sympathetic dystrophy and causalgia) and spinal cord stimulation,” Pain Medicine, vol. 7, no. 1, pp. S64–S96, 2006.
[13]
M. MOSER, A. G. PRANDONI, J. A. ORBISON, and T. W. MATTINGLY, “Clinical experience with sympathetic blocking agents in peripheral vascular disease,” Annals of Internal Medicine, vol. 38, no. 6, pp. 1245–1264, 1953.
[14]
S. Y. Ghostine, Y. G. Comair, and D. M. Turner, “Phenoxybenzamine in the treatment of causalgia. Report of 40 cases,” Journal of Neurosurgery, vol. 60, no. 6, pp. 1263–1268, 1984.
[15]
J. P. Muizelaar, M. Kleyer, I. A. M. Hertogs, and D. C. DeLange, “Complex regional pain syndrome (reflex sympathetic dystrophy and causalgia): management with the calcium channel blocker nifedipine and/or the α-sympathetic blocker phenoxybenzamine in 59 patients,” Clinical Neurology and Neurosurgery, vol. 99, no. 1, pp. 26–30, 1997.
[16]
T. P. Lefkoe and D. D. Cardenas, “Reflex sympathetic dystrophy of the lower extremity in tetraplegia: case report,” Spinal Cord, vol. 34, no. 4, pp. 239–242, 1996.
[17]
V. K. Malik, M. A. Inchiosa Jr., K. Mustafa, M. Sanapati, M. C. Pimentel Jr., and E. A. M. Frost, “Intravenous regional phenoxybenzamine in the treatment of reflex sympathetic dystrophy,” Anesthesiology, vol. 88, no. 3, pp. 823–827, 1998.
[18]
M. De Mos, M. C. J. M. Sturkenboom, and F. J. P. M. Huygen, “Current understandings on complex regional pain syndrome,” Pain Practice, vol. 9, no. 2, pp. 86–99, 2009.
[19]
M. A. Inchiosa Jr. and G. Kizelshteyn, “Treatment of complex regional pain syndrome type I with oral phenoxybenzamine: rationale and case reports,” Pain Practice, vol. 8, no. 2, pp. 125–132, 2008.
[20]
R. N. Harden, S. Bruehl, M. Stanton-Hicks, and P. R. Wilson, “Proposed new diagnostic criteria for complex regional pain syndrome,” Pain Medicine, vol. 8, no. 4, pp. 326–331, 2007.
[21]
R. Baron and C. Maier, “Reflex sympathetic dystrophy: skin blood flow, sympathetic vasoconstrictor reflexes and pain before and after surgical sympathectomy,” Pain, vol. 67, no. 2-3, pp. 317–326, 1996.
[22]
P. D. Drummond, S. Skipworth, and P. M. Finch, “α1-Adrenoceptors in normal and hyperalgesic human skin,” Clinical Science, vol. 91, no. 1, pp. 73–77, 1996.
[23]
W. J？nig and R. Baron, “Complex regional pain syndrome: mystery explained?” The Lancet Neurology, vol. 2, no. 11, pp. 687–697, 2003.
[24]
G. Wasner, J. Schattschneider, K. Heckmann, C. Maier, and R. Baron, “Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): mechanisms and diagnostic value,” Brain, vol. 124, no. 3, pp. 587–599, 2001.
[25]
P. D. Drummond, P. M. Finch, S. Skipworth, and P. Blockey, “Pain increases during sympathetic arousal in patients with complex regional pain syndrome,” Neurology, vol. 57, no. 7, pp. 1296–1303, 2001.
[26]
R. N. Spengler, R. M. Allen, D. G. Remick, R. M. Strieter, and S. L. Kunkel, “Stimulation of α-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor,” Journal of Immunology, vol. 145, no. 5, pp. 1430–1434, 1990.
[27]
I. J. Elenkov, R. L. Wilder, G. P. Chrousos, and E. S. Vizi, “The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system,” Pharmacological Reviews, vol. 52, no. 4, pp. 595–638, 2000.
[28]
M. Weber, F. Birklein, B. Neund？rfer, and M. Schmelz, “Facilitated neurogenic inflammation in complex regional pain syndrome,” Pain, vol. 91, no. 3, pp. 251–257, 2001.
[29]
P. E. Molina, “Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury,” Shock, vol. 24, no. 1, pp. 3–10, 2005.
[30]
R. Bertini, S. Garattini, R. Delgado, and P. Ghezzi, “Pharmacological activities of chlorpromazine involved in the inhibition of tumour necrosis factor production in vivo in mice,” Immunology, vol. 79, no. 2, pp. 217–219, 1993.
[31]
N. Bloksma, F. Hofhuis, B. Benaissa-Trouw, and J. Willers, “Endotoxin-induced release of tumour necrosis factor and interferon in vivo is inhibited by prior adrenoceptor blockade,” Cancer Immunology, Immunotherapy, vol. 14, no. 1, pp. 41–45, 1982.
[32]
C.-J. Lo, I. Garcia, H. G. Cryer, and R. V. Maier, “Calcium and calmodulin regulate lipopolysaccharide-induced alveolar macrophage production of tumor necrosis factor and procoagulant activity,” Archives of Surgery, vol. 131, no. 1, pp. 44–50, 1996.
[33]
C. Q. Earl, W. C. Prozialeck, and B. Weiss, “Interaction of alpha adrenergic antagonists with calmodulin,” Life Sciences, vol. 35, no. 5, pp. 525–534, 1984.
[34]
T. J. Lukas, D. R. Marshak, and D. M. Watterson, “Drug-protein interactions: isolation and characterization of covalent adducts of phenoxybenzamine and calmodulin,” Biochemistry, vol. 24, no. 1, pp. 151–157, 1985.
[35]
M. Chang, S. Smith, A. Thorpe, M. J. Barratt, and F. Karim, “Evaluation of phenoxybenzamine in the CFA model of pain following gene expression studies and connectivity mapping,” Molecular Pain, vol. 6, article 56, 2010.
[36]
J. Lamb, E. D. Crawford, D. Peck et al., “The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease,” Science, vol. 313, no. 5795, pp. 1929–1935, 2006.
[37]
A. E. Te, “A modern rationale for the use of phenoxybenzamine in urinary tract disorders and other conditions,” Clinical Therapeutics, vol. 24, no. 6, pp. 851–861, 2002.
[38]
O. Nettesheim, G. H？ffken, M. Gahr, and M. Breidert, “Haematemesis and dysphagia in a 20-year-old woman with congenital spine malformation and situs inversus partialis,” Zeitschrift fur Gastroenterologie, vol. 41, no. 4, pp. 319–324, 2003.
[39]
S. Vaidyanathan, P. Mansour, B. M. Soni, P. L. Hughes, and G. Singh, “Chronic lymphocytic leukaemia, synchronous small cell carcinoma and squamous neoplasia of the urinary bladder in a paraplegic man following long-term phenoxybenzamine therapy,” Spinal Cord, vol. 44, no. 3, pp. 188–191, 2006.
[40]
G. D. Friedman, S.-F. Jiang, N. Udaltsova, C. P. Quesenberry Jr., J. Chan, and L. A. Habel, “Epidemiologic evaluation of pharmaceuticals with limited evidence of carcinogenicity,” International Journal of Cancer, vol. 125, no. 9, pp. 2173–2178, 2009.
[41]
A. Goebel and F. Blaes, “Complex regional pain syndrome, prototype of a novel kind of autoimmune disease,” Autoimmunity Reviews, vol. 12, pp. 682–686, 2013.
