Alpha-adrenoceptors, in particular -1-adrenoceptors, have been implicated as the mediators of sympathetically mediated pain [3]. We hypothesized that during the development of reflex sympathetic dystrophy, hypoactivity of the sympathetic nervous system occurs, resulting in hyper-responsiveness of -adrenoceptors to noradrenaline in blood vessels and nociceptive nerve endings. To test this hypothesis, we studied the responsiveness of the vascular -adrenoceptor in the dorsal superficial hand vein of patients with reflex sympathetic dystrophy to local infusions of graded doses of noradrenaline.

Methods

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The study was reviewed and approved by our university review board for health sciences research involving human subjects, and all participants gave written informed consent.

Between December 1, 1988 and July 31, 1990, 11 patients (8 men, 3 women; mean age [± SE], 66 ± 4 years) diagnosed with unilateral upper-limb reflex sympathetic dystrophy were identified from the inpatient and outpatient services of the London, Ontario, teaching hospitals. All patients had pain and tenderness in the affected limb, which were associated with vasomotor instability, particularly temperature and color changes, and generalized swelling in the extremity. The mean time from onset of symptoms to study was 15 ± 2 months in the six patients with hemiplegia (ischemic stroke was confirmed by computed tomography) and 15 ± 3 months in the five patients with local trauma. Other disorders, such as traumatic peripheral nerve pain, inflammatory lesions, myofascial pain, and vascular disease, were excluded on the basis of the history and clinical examination. Patients were compared with 11 normal controls (6 men, 5 women; mean age, 69 ± 1 years) who had no history or clinical evidence of upper-limb vascular or neurologic abnormality. Controls were identified during the same period as the study patients and participated with the knowledge that they would derive no direct benefit from the study.

All medications were withheld 24 hours before each assessment. Patients were assessed in the supine position, resting quietly with forearm and hand comfortably elevated in a temperature-controlled room (20 to 24 °C). A short (1.9 cm) 25-gauge needle (Butterfly-Abbocath Butterfly-Abbot, Ireland Ltd., Sligo, Ireland) was inserted into a dorsal superficial hand vein with a long straight section and no visible tributaries. Normal saline (0.9%) was infused at 0.1 mL/min. After calibration on a micrometer gauge, the linear variable differential transformer, an electromechanical device consisting of primary and secondary coils with a lightweight movable ferromagnetic core [4], was vertically placed over the summit of that vein, 10 mm proximal to the tip of the needle. Hand vein distention was measured as the difference between the position of the core within the transformer at the baseline before inflation of an upper-arm blood pressure cuff and the height of the plateau during cuff inflation (45 mm Hg for 3 min).

After 30 min, at least two recordings of hand vein distention during saline infusion were obtained to ensure a stable baseline, and the mean was calculated to serve as the control distention. Graded sequential local infusions (0.1 mL/min) of noradrenaline diluted in saline (0.5, 1, 2, 4, 8, 16, 32, 64, 128, and 256 ng/min) were administered, with at least a 5-min saline infusion given between each noradrenaline dose. Hand vein distention was measured after a 5-min infusion at each concentration and expressed as a percent reduction from the control value. Measurements were repeated in an identical fashion in the opposite limb in all patients and normal controls. Blood pressure, measured by mercury sphygmomanometry, and pulse rate were monitored in the contralateral arm.

Dose-response curves (semi-logarithmic) were constructed using a nonlinear curve-fitting program (GraphPad InPlot, version 4.0, GraphPad Software, San Diego, California). The effective dose (ED₅₀) of noradrenaline required to cause 50% constriction of the control hand vein diameter at 45 mm Hg was computed as the geometric mean. Other values are expressed as the arithmetic mean ± SE. Between-group comparisons were done with the Student two-tailed t-test for paired or unpaired data as appropriate; the Bonferroni test was applied for multiple comparisons [5].

Results

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Hand vein distention was the same in both limbs of normal controls (0.85 ± 0.05 mm in the left limb compared with 0.82 ± 0.05 mm in the right limb; P > 0.2). The study vein was larger in the affected limb (1.15 ± 0.03 mm) than in the unaffected limb (0.89 ± 0.04 mm; P = 0.001) of patients with reflex sympathetic dystrophy or when compared with the corresponding vein in normal controls (0.85 ± 0.05 mm, P = 0.001).

Individual dose-response curves for the left hand of normal controls and for the affected limb in patients with reflex sympathetic dystrophy are shown in Figure 1. The noradrenaline ED₅₀ was the same in the left (27.4 ng/min) and right (28.3 ng/min) hands of normal controls but was markedly reduced in the affected limb of patients (1.5 ng/min) when compared with the unaffected limb (6.8 ng/min, P = 0.001) (Figure 2). No difference was found in the ED₅₀ of affected limbs when patients who had hemiplegia were compared with those who had trauma (1.49 compared with 1.53 ng/min, respectively; P > 0.2). The ED₅₀ in the unaffected limb of patients was lower than the value found in age-similar normal controls (6.8 compared with 27.4 ng/min; P = 0.001), and the ED₅₀ in hemiplegic patients was lower than that seen in trauma patients (3.8 compared with 13.8 ng/min; P = 0.001). No difference was observed in duration of symptoms between these two subgroups.

View larger version (27K): [in this window] [in a new window]   Figure 1. Individual dose-response curves for hand vein distention at 45 mm Hg to local sequential graded infusions of noradrenaline, expressed as a percentage of distention observed during 0.9% saline infusion. NS = not significant; RSD = reflex sympathetic dystrophy.

View larger version (16K): [in this window] [in a new window]   Figure 2. The estimated dose of noradrenaline required to cause a 50% constriction of the dorsal hand vein in the left and right hands of normal controls and of the affected and unaffected hands of patients with reflex sympathetic dystrophy. ED50 = estimated effective dose of noradrenaline to cause a 50% constriction in the hand vein; RSD = reflex sympathetic dystrophy. = patients with reflex sympathetic dystrophy after trauma; = patients with reflex sympathetic dystrophy after hemiplegia.

Discussion

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Our study provides direct in-vivo evidence for increased responsiveness of venous -adrenoceptors to locally infused noradrenaline in limbs affected by reflex sympathetic dystrophy. The results were consistent in all patients and contrasted markedly with those obtained in normal controls, who required nearly a 20-fold increase in noradrenaline concentration to produce 50% venoconstriction. The results do not represent an effect of local edema in reflex sympathetic dystrophy because the measurements were calculated as a percentage of each study participant's vein distention after saline infusion (control), which was greater in the patients, implying possible vasodilation at baseline. This latter observation would be consistent with diminished vascular tone and hypoactivity of the sympathetic nervous system; however, we did not measure plasma catecholamine levels or other indicators of sympathetic activity. Although the changes we observed are similar to those that occur after denervation or autonomic failure from various sources [6], we did not determine whether they were due to reduced reuptake of noradrenaline presynaptically or increased sensitivity of the postsynaptic receptor.

The concept of reduced sympathetic nervous system outflow to the affected limb in reflex sympathetic dystrophy is supported by Drummond and colleagues, [7] who noted that plasma levels of noradrenaline and its intracellular metabolite 3, 4-dihydroxyphenylethyleneglycol were lower in the limb affected with reflex sympathetic dystrophy when compared with the unaffected limb. Rosen and colleagues [8] found that the cold pressor test caused a mean decrease in blood flow of 37.5% in control patients but only a decrease of 0% to 8% in patients with reflex sympathetic dystrophy. The superficial dorsal veins of the unaffected hands in patients with reflex sympathetic dystrophy were also abnormal when compared with normal veins in controls, which is compatible with the clinical observation that patients with reflex sympathetic dystrophy are at risk for developing the condition in the "unaffected" limb. It is also consistent with the findings of Bej and Schwartzman [1], who noted that the response of cutaneous blood flow in the "unaffected" extremity to peripheral and central autonomic stimuli was more similar to that in the affected extremity than to that in the extremity of a healthy subject.

If increased responsiveness of -adrenoceptors was also to occur in peripheral nociceptors and mechanoreceptors, it could help explain the hyperalgesia and allodynia, respectively, that these patients experience. Sweet and Poletti [9] have suggested that somatic afferents may become hypersensitive to noradrenaline in causalgia and reflex sympathetic dystrophy, a concept supported by the findings of Drummond and colleagues [7]. The concept is strongly supported by the observed effects of phenoxybenzamine blockade, phentolamine infusion, or guanethidine blocks, all of which can result in alleviation of symptoms of reflex sympathetic dystrophy, presumably through -adrenergic blockade. Wallin and colleagues [10] reported that after sympathectomy, which cured reflex sympathetic dystrophy, the local application of adrenaline reproduced or accentuated the pain of reflex sympathetic dystrophy when applied to the affected area but not when applied outside the affected area. These findings support the hypothesis that noradrenaline and a heightened peripheral -adrenoceptor response may be the primary mediators of the hypersensitive peripheral nociception seen in reflex sympathetic dystrophy.

Although our study does not explain how reflex sympathetic dystrophy is initiated, the demonstration of an increased responsiveness of venous -adrenoreceptors to infused noradrenaline may aid in understanding the pathogenesis of the disorder and provide clues for developing specific therapy.