[1] 12w For personal use. Only reproduce with permission from The Lancet Publishing Group

[1] 259w Background Complex regional pain syndromes can be relieved by sympathetic blockage. The mechanisms of sympathetically maintained pain (SMP) are unclear. We aimed to establish the effect of physiological sympathetic cutaneous vasoconstrictor activity on pain and hyperalgesia in patients with complex regional pain syndromes.Methods High and low cutaneous vasoconstrictor activity was produced by whole-body cooling and warming (thermal suit) in 13 patients with type I disease and in ten controls. The degree of cutaneous vasoconstrictor discharge was monitored by measurement of skin blood flow and temperature at the arm and leg. Local skin temperature at the affected region was fixed at 35°C. Pain was quantified during high and low cutaneous vasoconstrictor activity (intensity of spontaneous pain, area of mechanical hyperalgesias, heat-pain thresholds). Furthermore, pain was measured before and after diagnostic sympathetic blockage to identify patients with SMP and sympathetically independent pain.Findings In patients with SMP, intensity of spontaneous pain significantly increased, by 22%, and spatial distribution of mechanical dynamic and punctate hyperalgesia increased by 42% and 27%, respectively, during high sympathetic activity compared with low activity. Heat-pain thresholds did not differ during high and low cutaneous vasoconstrictor activity (cold and warm state, 43•6ºC vs 44•6°C). Pain relief after sympathetic blockage correlated with augmentation of spontaneous pain after experimental stimulation of cutaneous vasoconstrictor activity (r=0⋅6, p=0•0244).Interpretation We have shown that in complex regional pain syndromes with SMP, physiological activation of cutaneous vasoconstrictor neurons projecting to the painful arm or leg enhances spontaneous pain and hyperalgesia. We postulate that there is a pathological interaction between sympathetic and afferent neurons within the skin.

[1] 260w Complex regional pain syndromes are painful disorders that can develop as a result of trauma affecting the limbs. [1][2][3] The clinical features are spontaneous pain, hyperalgesia, impairment of motor function, swelling, and autonomic abnormalities. Irrespective of the site of the precipitating event, these abnormalities show a tendency to spread, with generalised distal distribution that is not confined to innervation territories of peripheral nerves or roots. In type I complex regional pain syndromes (reflex sympathetic dystrophy), which typically develop after minor tissue trauma or bone fracture, no overt nerve lesion is detectable, whereas in type II disease (causalgia), a part peripheral nerve lesion is necessary for diagnosis. 4,5 Pain can be relieved by blockage of efferent sympathetic nerves to the affected area. 6,7 The pain component that depends on sympathetic activity is therefore referred to as sympathetically maintained pain (SMP). 8,9 Pain that is not dependent on sympathetic activity is called sympathetically independent pain (SIP). Studies in animals have provided evidence to account for the occurrence of SMP in man: peripheral nerve damage induces a functional change in the phenotype of primary C-nociceptors-these neurons start to express adrenoceptors at their membranes, become sensitive to adrenergic chemicals, and can be activated by sympathetic trunk stimulation. 2,10 Despite the results of these studies, we still do not have proof that discharge in sympathetic neurons enhances pain in painful disorders in man, and the idea of SMP is thus controversial. 2 We aimed to establish the effect of physiological sympathetic cutaneous vasoconstrictor activity on pain and hyperalgesia in patients with complex regional pain syndromes.

[1] 106w Local temperature at the nociceptor level affects spontaneous pain and hyperalgesia in pain states that are characterised by nociceptor sensitisation. 13 Therefore, it is of utmost importance to keep the local skin temperature at the painful site constant during the wholebody temperature change. In all experiments, the thermal suit did not cover the affected arm or leg, and a feedbackcontrolled heating device set to 35°C fixed local temperature in this area (figure 1). By this procedure, temperature effects on the receptor were kept to a minimum. Local temperature at the painful limb was monitored during the whole experiment with infrared thermometry at 5-min intervals (figure 2).

[2] 131w Spontaneous pain was quantified by rating of intensity on a numeric rating scale (0-10). Furthermore, we analysed the spatial distribution of three different types of evoked pain, if present. The borders of mechanical hyperalgesia (present in 11 patients) were detected by stroking of the skin with a cotton swab (for dynamic mechanical hyperalgesia) and with a nylon filament with a bending force of 250 mN (stiff Von Frey hair; for punctate mechanical hyperalgesia). The areas of the different hyperalgesic zones were marked on the arm or leg with a pen in different colours, and after the experiment they were drawn on plastic film to measure the sizes with a digital planimeter (figure 1). Within the painful skin area, heat-pain thresholds (heat hyperalgesia) were identified with a thermotest device (Somedic, Hörby, Sweden).

[3] 27w All tests for quantitative pain assessment were done in duplicate for all patients-first during the presence of high sympathetic activity and second during low activity (figure 1).

[4] 102w Control experiments were done in ten healthy people to assess the effect of whole-body cooling and warming on perception of painful stimuli. Body temperature challenge was induced as described above, and the temperature of the right forearm (not covered by the thermal suit) was kept constant at 35°C. In this skin area, heat-pain thresholds were identified with a thermotest device during both whole-body warming and cooling (table 2). Furthermore, heart rate, systemic blood pressure, and body core temperature (tympanic membrane) were monitored (table 2). Since we recorded no differences in these measurements in controls, we did not monitor these variables in patients.

[5] 65w 13 patients with unilateral type I complex regional pain syndrome were included in the study (table 1). The arm was affected in eight patients and the leg in five. Mean duration of disease was 18•6 months (SD 14•6, range 2-60). In accordance with the definition of SMP (pain relief >50% after sympathetic block), seven patients were classified as having SMP and six as having SIP.

[6] 97w Whole-body cooling induced a bilateral drop of skin blood flow. Maximum cutaneous vasoconstriction indicated greatest activation of sympathetic neurons (table 2, figure 2). However, local skin temperature at the painful site was stabilised at 35°C to exclude any effect of local temperature on cutaneous nociceptors and pain perception (table 2, figure 2). In controls, heat-pain thresholds did not differ during high and low cutaneous vasoconstrictor activity (cold and warm state, 43•6°C vs 44•6°C; table 2). Furthermore, whole-body thermal stimulation had only small non-significant effects on systemic arterial blood pressure, heart rate, and body core temperature (table 2).

[7] 138w Physiological stimulation of sympathetic vasoconstrictor neurons that innervate the painful arm or leg had a considerable effect on pain perception in patients with complex regional pain syndromes who were classified as having SMP (n=7). First, during high cutaneous sympathetic vasoconstrictor activity, spontaneous pain rose significantly, by 22% (table 2), compared with low activity. Second, the area of dynamic and punctate mechanical hyperalgesia significantly increased by 42% and 27%, respectively, during high sympathetic activity compared with low activity (table 2). By contrast, in patients with complex regional pain syndromes who were classified as having SIP (n=6), there were no differences in these pain effects between high or low sympathetic activity. Heat-pain thresholds identified within the painful skin area did not differ significantly between low and high sympathetic activity in all patients with complex regional pain syndromes (SMP and SIP).

[8] 32w Pain relief after sympathetic blockage was compared with augmentation of spontaneous pain after experimental stimulation of sympathetic neurons in all 13 patients. There was significant positive correlation between both factors (r=0⋅6, p=0•0244).

[1] 52w We have shown that in patients with complex regional pain syndromes, physiological activation of sympathetic neurons projecting to the painful limb can enhance spontaneous pain and mechanical hyperalgesia. We achieved this result by a novel technique to alter the degree of sympathetic vasoconstrictor discharge under controlled conditions in people who were awake.

[2] 137w As shown by microneurographic recordings in human skin nerves, cutaneous vasoconstrictor neurons are wholly inhibited during whole-body warming, and activation is at a maximum during whole-body cooling. 12 Therefore, we can reasonably assume that this temperature challenge covers the maximum range of activity that arises in sympathetic neurons under physiological conditions (figure 2). The experimental setup that we used is, therefore, an ideal way to analyse the effect of different levels of cutaneous sympathetic activity on pain perception in man. [14][15][16] Low local skin temperature induced by cutaneous vasoconstriction counteracts C-nociceptor sensitisation, relieves continuing pain, and could therefore interfere with the sympathetic effect on pain during whole-body cooling. 13 By fixing the skin temperature of the affected painful limb at 35°C during temperature challenge (table 2, figure 2) we avoided temperature effects at the sensory receptor level.

[3] 121w Could central nervous system factors during thermoregulation interfere with pain perception? Wholebody cooling and warming might have effects on central pain transmission. Thus, activation of descending paininhibitory pathways could ascertain the sympathetic effect on pain during whole-body temperature change. 17 Since control experiments in healthy people did not show any difference between the heat-pain thresholds identified during whole-body cooling or warming (table 2), we conclude that thermal stimulation of the body does not affect pain perception itself, provided that the temperature at the painful site is kept constant. Furthermore, thermal challenge did not significantly change body core temperature, arterial blood pressure, or heart rate ( Table 2: Effects of high and low sympathetic activity (induced by maximum whole-body cooling and warming)

[4] 409w The striking response of some patients with complex regional pain syndromes to sympatholytic procedures suggests that the efferent sympathetic nervous system can generate or enhance pain (SMP). 6,7 Results in animals have shown that after complete and part nerve injury, damaged and undamaged primary afferent nociceptors both acquire chemical sensitivity to noradrenergic agents and can be activated by sympathetic trunk stimulation. 2,10 This sympatho-afferent transmission is thought to be mediated by ␣ 2 -adrenoreceptors. Accordingly, mRNA of ␣ 2A -adrenoceptors is upregulated in dorsal root ganglion neurons after nerve transection. 18 Although these studies were done in animals with artificially induced nerve lesions, some of the results might apply to patients with type I complex regional pain syndromes who, by definition, have no major nerve injury. The discovery that, even after small nerve lesions, many intact neurons in the same peripheral nerve acquire pathological discharge properties could lend support to this notion. 19,20 So far, several clinical studies in man of pharmacological interventions accord with the idea that nociceptors develop catecholamine sensitivity after nerve lesion or trauma. After limb amputation, injection of physiological doses of epinephrine around a stump neuroma is reported to be intensely painful. 21,22 In complex regional pain syndromes and post-traumatic neuralgias, intracutaneous application of norepinephrine into a symptomatic area rekindles spontaneous pain and dynamic mechanical hyperalgesia that had been relieved by sympathetic blockage. 9 Similarly, spontaneous pain and mechanical hyperalgesia are enhanced after intracutaneous injection of epinephrine or phenylephrine in post-herpetic neuralgia. 23 Intradermal administration of norepinephrine in physiologically relevant doses evoked greater pain in the affected regions of patients with complex regional pain syndromes with SMP than in the contralateral unaffected limb and in controls, 24 which corresponds with these results. Accordingly, results of autoradiographic studies show that the number of ␣ 1 -adrenoceptors in hyperalgesic skin of such patients with SMP is substantially larger than that in the skin of people without this painful disorder. 25 Injection of drugs into painful sites, however, only approximates sympathetic activation and endogeneous norepinephrine release that happens physiologically. Therefore, we activated and modulated the sympathetic cutaneous vasoconstrictor system in a physiological range to analyse the effect of sympathetic activity on pain. By this approach, we showed that in a group of patients with complex regional pain syndromes, spontaneous pain and mechanical hyperalgesia are augmented when sympathetic vasoconstrictor neurons to the skin are turned on. We have drawn four conclusions about the underlying pathophysiological mechanisms from these observations.

[5] 176w First, in a subgroup of patients with complex regional pain syndromes classified as having SMP, a pathological interaction between sympathetic activity and afferent neurons takes place; pain is maintained by activity in cutaneous sympathetic vasoconstrictor neurons. However, the exact mechanism of sympathetic-afferent coupling remains unknown. Since local skin temperature at the painful site was carefully controlled and kept constant, an effect of sympathetic vasoconstriction on cold-sensitive primary afferents in the skin (eg, cold allodynia) can be excluded. Evidence from work in animals favours the idea that sympathetic activity can sensitise nociceptors chemically via norepinephrine released from sympathetic fibres acting directly on adrenoreceptors expressed on afferent fibres. 10,18 Furthermore, amplified excitability of nociceptors might be generated indirectly-ie, via the vascular bed (eg, change of blood flow) 10 or by other components such as inflammatory cells around nociceptive neurons, which might have a permissive effect on sympathetic to nociceptor coupling-or they might be modulated directly by molecules released from sympathetic postganglionic neurons. 26 The experimental setup we used does not allow us to distinguish between these two possibilities.

[6] 142w Second, together with the sympathetic effect on spontaneous pain, the spatial distribution of dynamic and punctate mechanical hyperalgesia was also affected by sympathetic activity. This finding accords with ideas about the pathophysiological mechanisms underlying mechanically evoked pain types. 27 Mechanical hyperalgesia develops if a barrage of nociceptive activity, which is thought to correlate with spontaneous pain, enters the spinal cord and induces sensitisation of central multireceptive neurons. Heat hyperalgesia, by contrast, is induced by peripheral sensitisation of heat-sensitive primary afferents. Since heat-pain thresholds at the painful arm or leg did not depend on the degree of sympathetic activity, we can conclude that specific heatsensitive neurons are not, or are only marginally, affected by sympathetic activity. This observation also lends support to an alternative idea that low threshold A␤ afferent neurons that are associated with mechanical hyperalgesia might be implicated in sympathetic-afferent coupling.

[7] 78w Third, in all our patients with complex regional pain syndromes (both SMP and SIP), pain relief after diagnostic sympathetic blockage correlated significantly with augmentation of spontaneous pain after experimental stimulation of sympathetic vasoconstrictor neurons. This observation suggests that the sympathetically maintained pain component in patients with complex regional pain syndromes might form a continuum. Also, in patients classified as SIP (pain relief <50% after sympathetic block) there might be a pain component (<50%) that depends on sympathetic activity.

[8] 205w Finally, the experimental setup we used selectively altered sympathetic cutaneous vasoconstrictor activity without affecting other sympathetic systems innervating the arms or legs-ie, pilo arrector, sudomotor, and muscle vasoconstrictor neurons. Therefore, the interaction of sympathetic and afferent neurons is probably located within the skin, as predicted by the pain-enhancing effect of intracutaneous norepinephrine injections. 9, 23,24 Relief of spontaneous pain after sympathetic blockage was more pronounced than changes in spontaneous pain that could be induced experimentally by sympathetic activation (table 2). One explanation for this discrepancy might be that a complete sympathetic block affects all sympathetic outflow channels projecting to the affected limb. In addition to a coupling in the skin, a sympatheticafferent interaction is likely to happen in other tissues, particularly in deep somatic domains such as bone, muscle, or joints. These structures are especially painful in some people with complex regional pain syndromes, [1][2][3]28 which lends support to this notion. Furthermore, patients might exist who are characterised by a selective or predominant sympathetic-afferent interaction in deep somatic tissues sparing the skin. This particular group of patients would not be classified as having sympathetically dependent pain by the experimental setup we used. 29 For personal use. Only reproduce with permission from The Lancet Publishing Group.

[9] 68w Contributors R Baron designed the study protocol, did the experiments, obtained data, and wrote and edited the report. J Schattschneider and A Binder were responsible for clinical assessments, did experiments, obtained and analysed data, and edited the report. D Siebrecht was responsible for clinical assessments, did sympathetic blockage, and edited the report. G Wasner designed the study protocol, did experiments, obtained and analysed data, and edited the report.

[1] 180w We included 13 patients (two men, 11 women) with a mean age of 41•4 years (SD 13•2, range 19-60) who were diagnosed with unilateral type I complex regional pain syndromes and who were referred to the Interdisciplinary Pain Centre at the University Clinic of Kiel between December, 1999, and February, 2001 (table 1). Type I disease was diagnosed by an independent doctor (an anaesthetist in the interdisciplinary group), and this diagnosis was confirmed by the whole team of investigators at this institution in accordance with criteria defined by Evans 11 and with novel clinical criteria defined by the International Association for the Study of Pain (IASP). 1,[3][4][5] Therefore, the frequency of false-positive diagnoses was kept to a minimum. We did a general physical and neurological examination and a three-phase bone scan to support this diagnosis. Controls were ten healthy volunteers (seven men, three women) with a mean age of 27•6 years (SD 4•43). We excluded patients and controls who had cardiovascular diseases or who were treated with drugs affecting vascular function (hypertension, cardiac arrhythmia, heart failure, or coronary heart disease).

[2] 36w The aim of the study and the nature of the tests were explained to the individuals in accordance with the Helsinki Declaration. The local ethics committee approved the study and all individuals gave written informed consent.

[3] 148w Before the experiments, all patients underwent diagnostic sympathetic blocks to assess which component of their pain depended on efferent sympathetic activity (SMP vs SIP). We used local anaesthetic for sympathetic block at either the stellate ganglion for complex regional pain syndromes in the arm (bupivacaine 0⋅5%, 10 mL) or the sympathetic chain ganglia L1-3 for those in the leg (bupivacaine 0•175%, 20 mL). Spontaneous pain was quantified with a numeric rating scale (0-10) within 10 min before the block (baseline) and within 30 min, 3 h, 6 h, and 24 h after the block. Patients were classified as having SMP if a correctly applied sympathetic block (defined by an increase of ipsilateral skin temperature to >34°C after the block) reduced pain by more than 50% at any time within 24 h after the block. This positive effect had to be duplicated (in a maximum of three diagnostic blocks).

[4] 75w We changed the activity of cutaneous sympathetic vasoconstrictor neurons projecting to the affected limb under controlled conditions. We used thermoregulatory reflexes to induce physiological tonic stimulation of sympathetic activity. This stimulation was achieved by alteration of environmental temperature. Individuals lay in a thermal suit, in which circulating water of 12°C or 50°C (inflow ARTICLES 1656 temperature) was used to cool or warm the whole body, respectively. The suit did not cover the arms or legs.

[5] 187w Whole-body cooling is the most effective stimulus to activate cutaneous vasoconstrictor neurons, as shown by microneurographic recordings. 12 By contrast, whole-body warming inhibits vasoconstrictor activity almost totally. By this method, sympathetic cutaneous activity can be selectively switched on and off in a controlled manner, whereas sympathetic muscle vasoconstrictor activity remains nearly unchanged. We assessed the effect of skin sympathetic vasoconstrictor activity-ie, the amount of cutaneous vasoconstriction-by measurement of cutaneous blood flow (perfusion units) at the index finger or toe and skin temperature at all fingers or toes, which were not covered by the suit. This measurement was made by infrared thermometry, with a laser doppler perfusion monitor (Perimed PF 4001, Perimed, Järfälla, Sweden) and an integrating probe (PF 413, Perimed), with a 12-kHz filter scale and a time constant of 0•2 s (figure 1). Pain-intensity assessment was done in duplicate, during high and low cutaneous sympathetic vasoconstrictor activity. High sympathetic activity was defined as a reduction of skin temperature at the unaffected limb to less than 26°C during the cooling session; low sympathetic activity was a rise in temperature to greater than 34°C during the warming session.

[1] 52w We analysed laser doppler perfusion monitor, blood pressure, and heart rate data online. Skin temperature and blood-flow measurements were recorded at intervals of 5 min. Wilcoxon's test was used for comparison of paired data under high and low sympathetic activity. For correlation analysis, Spearman's test was used. P<0⋅05 was regarded as significant.

[2] 22w The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.