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Complex regional pain syndrome and methionine-enkephalin.

To the Editor:

Complex regional pain syndrome (CRPS), or reflex sympathetic dystrophy, develops after trauma or surgery and is characterized by pain that is disproportionate to the initial injury and is not confined to the nerve or nerve root distribution (1-5). Symptoms involve the autonomic, somatosensory, and sympathetic nervous systems. In response to injury, peripheral sensitization of C-terminals and A-delta terminals occurs along with release of inflammatory mediators and trophic factors, and with activation of genes for the production of new ion channels and other proteins (6-8). These processes give rise to central sensitization, a state of hyperexcitability in pain-projecting neurons of the central nervous system (7, 8).

Despite recent advances in the diagnosis and understanding of the pathology of CRPS, many mechanisms that initiate and maintain this syndrome are unknown. Treatment with antiinflammatory steroids stimulates the endogenous opioid system, which may play a role in CRPS (6). Early features of CRPS resemble the autonomic arousal associated with opioid withdrawal, such as excessive sweating, peripheral vascular instability, muscle and joint stiffness, and tremors (9). Thus, it has been hypothesized that, in response to injury, opioid peptide activity in regional sympathetic ganglia fails to increase, or tolerance develops to locally increased opioid activity, producing a hypersensitive or excessive response to autonomic activity (6, 9). Although there is no evidence for opioid dysfunction per se in CRPS, dysfunction may reside in the descending pain control systems that use endogenous opioids such as enkephalin.

We recently measured plasma methionine-enkephalin concentrations in patients during cardiac surgery and cardioplegic ischemia. Samples were collected, placed on ice, acid-extracted, and boiled. We then isolated methionine-enkephalin by size-exclusion chromatography and performed RIA quantification as described previously (10).

A particularly high concentration of methionine-enkephalin was measured in the plasma of a 78-year-old woman undergoing aortic valve replacement and coronary artery bypass graft surgery. This patient had suffered a Colles fracture of her right hand 12 months before the cardiac operation and had developed CRPS with classic symptoms of extreme pain, swelling, and limited movement in her wrist, which were treated with physiotherapy and nonsteroidal antiinflammatory agents. In this CRPS patient, plasma methionine-enkephalin concentrations measured before and after cardioplegic ischemia in the coronary sinus (CS) and femoral artery (ART) were markedly increased compared with our study group. Baseline mean (SD) CS and ART methionine-enkephalin concentrations in the study group (n = 24) were 16.2 (3.7) and 16.2 (3.8) ng/L, respectively. In contrast, the baseline concentrations in the CRPS patient were 309.5 and 1145.9 ng/L in the CS and ART, respectively (70-fold greater in the femoral ART compared with the study group). In the study group, 85 min of cardioplegic ischemia caused modest methio-nine-enkephalin increases in the CS [from 16.2 (3.7) to 27.7 (6.8) ng/L; P = 0.03] and ART [from 16.2 (3.8) to 26.6 (7.8) ng/L]. In the patient with CRPS, the already increased CS methionine-enkephalin concentration showed a further 3.4-fold increase after ischemia (from 309.5 to 1066.4 ng/L), and the ART concentration, although lower at reperfusion, remained higher than in the study group after ischemia (1145.9 vs 118.5 ng/L, respectively).

This serendipitous observation of markedly increased plasma methionine-enkephalin in a CRPS patient undergoing cardiac surgery more than a year after a Colles fracture suggests an overactive enkephalin opioid system. It remains to be determined whether this overactivity in the plasma originates from predominantly central and/or peripheral neuronal pathways. The role of endogenous opioids in CRPS may be important and merits further study.


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(3.) Schwartzman RJ. New treatments for reflex sympathetic dystrophy. N Engl J Med 2000; 343:654-6.

(4.) van de Beek WJ, Schwartzman RJ, van Nes SI, Delhaas EM, van Hilten JJ. Diagnostic criteria used in studies of reflex sympathetic dystrophy. Neurology 2002;58:522-6.

(5.) Grabow TS, Christo PJ, Raja SN. Complex regional pain syndrome: diagnostic controversies, psychological dysfunction, and emerging concepts. Adv Psychosom Med 2004;25:89101.

(6.) Figuerola ML, Levin G, Bertotti A, Ferreiro J, Barontini M. Normal sympathetic nervous system response in reflex sympathetic dystrophy. Funct Neurol 2002;17:77-81.

(7.) Janig W, Baron R. Complex regional pain syndrome: mystery explained? Lancet Neurol 2003;2:687-97.

(8.) Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288: 1765-9.

(9.) Hannington-Kiff JG. Does failed natural opioid modulation in regional sympathetic ganglia cause reflex sympathetic dystrophy? Lancet 1991;338:1125-7.

(10.) Younes A, Pepe S, Yoshishige D, Caffrey JL, Lakatta EG. Ischemic preconditioning increases the bioavailability of cardiac enkephalins. Am J Physiol 2005;289:H1652-61.

Olivier W.V. van den Brink

Michael A. Rowland

Silvana F. Marasco

Donald S. Esmore

Franklin L. Rosenfeldt

Salvatore Pepe *

Department of Cardiothoracic Surgery

Alfred Hospital and Baker Heart Research Institute

Monash University

Melbourne, Australia

* Address correspondence to this author at: Laboratory of Cardiac Surgical Research, Department of Cardiothoracic Surgery, Monash University, Alfred Hospital and Baker Heart Research Institute, PO Box 6492, St. Kilda Central, Melbourne VIC 8008, Australia. Fax 61-3 85321314; e-mail

DOI: 10.1373/clinchem.2005.062117
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Title Annotation:Letters
Author:van den Brink, Olivier W.V.; Rowland, Michael A.; Marasco, Silvana F.; Esmore, Donald S.; Rosenfeldt
Publication:Clinical Chemistry
Date:Mar 1, 2006
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