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Helmut Blumberg, Ulrike Hoffmann*, Mohsen Mohadjer and Rudolf Scheremet
Abstract 1. INTRODUCTION In the past, different terms have been used for clinical conditions in which pain was likely to be maintained by ongoing activity of the sympathetic nervous system, for example causalgia, algodystrophy, Sudeck`s atrophy etc. (see Bonica 1990). Such disorders were later subsumed under the global term " reflex sympathetic dystrophy" (RSD), which was first introduced by Evans (1946). Later, the term " sympathetically maintained pain" (SMP) was introduced by Roberts (1986) and subsequently used by others (Frost et al. 1988, Meyer et al. 1990, Campbell, Meyer & Raja 1992). This, however, did not end the discussion of terminology, and very recently, " complex regional pain syndrome" (CRPS) was suggested as a new term for RSD/SMP and causalgia (Merskey & Bogduk 1994). Historically, the idea of blocking sympathetic activity to treat these patients was mainly based on the observation of cold skin. This observation was related to sympathetic hyperactivity, which was thought to excite nociceptive fibres within the symptomatic area (Leriche 1923, Leriche 1949). At the same time, this sympathetic- sensory coupling was believed to be part of a vicious circle, where the abnormal afferent activity - via sensitized central nervous (spinal cord) structures - could maintain sympathetic hyperactivity and consequently pain (Livingston 1976). To this date, this model has been used to explain the relationship between the sympathetic system and pain in RSD/SMP. For each main aspect of this hypothesis there is supportive evidence as obtained by experiments on animals and by experimental investigations on humans (Bennett & Xie 1988, Bond, Charlton & Woolf 1991, Devor, Jänig & Michaelis 1994, Devor et al. 1991, Jänig 1990, Jänig & Koltzenburg 1991, Jänig & Schmidt 1992, Levine et al. 1985, Wall & Devor 1983, Willis 1992, Woolf, Shortland & Coggeshall 1992). However, with respect to this coupling as a cause of pain, there are certain observations, which remain a matter of discussion. First, the clinical picture of patients, who do respond to sympathetic blocks may differ among each other quite considerably, so that they may form different groups of patients (Blumberg & Jänig 1993). Second, a number of patients do not show signs of sympathetic hyperactivity. To the contrary, they may even exhibit warm and dry skin, but nevertheless get pain relief upon sympathetic blocks (de Takats 1943, Blumberg et al. 1994). Third, in a number of patients with cold extremities the pain may not be relieved by sympathetic blocks (Drummond, Finch & Smythe 1991). Finally, and most importantly, there is no study which defines the criteria for a complete interruption of the sympathetic innervation of a blocked extremity. As a consequence, there is a problem regarding the quality control of sympathetic blocks, which also makes it difficult to judge the outcome of sympatholytic strategies in RSD/SMP as far as pain mechanisms are concerned. 2. PAIN AND THE SYMPATHETIC SYSTEM - A CLINICAL REAPPRAISAL In view of the above mentioned observations, there seem to be good reasons for a clinical reappraisal of the relationship between the sympathetic nervous system and pain. In order to do so and to describe the patients in whom a sympathetic component of pain may be assumed, we divide these patients into three groups. The patients of the first group are characterized by the occurrence of a rather complex clinical symptomatology, in whom predominantly the distal part of the extremity is affected, where the symptoms - independently of the kind and location of a preceding lesion - appear in a glove- or sock-like distribution manner. In accordance with the literature, these patients are diagnosed as having RSD (CRPS type I, Merskey and Bogduk 1994). The relatively rare patients of the second group are diagnosed as having SMP (Blumberg 1992, Blumberg & Jänig 1993). They are characterized by the occurrence of two major symptoms, namely spontaneous pain and allodynia, which typically are found within the zone of a lesioned nerve. To illustrate the clinical picture of these two patient types, representative case reports will be given first, to be followed by discussions of the related clinical aspects of pains and the sympathetic system in these conditions. In addition, there is a very small group of patients who show signs of both, RSD and SMP. This condition, labelled causalgia, will be discussed briefly. Finally, we discuss the possible kinds of sympathetic- sensory coupling in these conditions. 3. REFLEX SYMPATHETIC DYSTROPHY On the 7th of September in 1993, a 72 year old working man underwent surgical intervention because of dupytren`s contracture, involving the long flexor tendon of the left fourth finger. The day after surgery he complained about strong pain, which he felt localized under the palmar wound suture. Since the pain persisted together with the development of signs of a deep haematoma at that site, the suture was reopened three days after the initial intervention to treat the pain and the haematoma. At that time, there was no edema outside the treated area, no signs of inflammation and the fingers, except the treated one, could be moved freely. In the night following this secondary intervention, the patient suddenly experienced a drastic change of symptoms: The entire hand became swollen and warmer compared with the other hand, together with the occurrence of deep and severe pain which was felt diffusely inside the hand, also affecting most finger joints. The fingers and the wrist could no longer be moved actively, and there developed tremor of the hand and fingers. He got some pain relief by elevating the affected arm and by applying ice to the hand. There were no signs of local or systemic inflammation, and oral analgetics and physical therapy were applied for treatment. These, however, did not significantly ameliorate the symptoms. Later, intermittent exaggeration of the pain developed and brachial plexus anaesthesia was introduced. This stopped the pain for the duration of the anaesthesia and the swelling diminished. However, after the anaesthesia wore off, the symptoms and swelling returned. Finally, RSD was suspected, and the patient was sent to us, four weeks after the first surgical intervention. Upon neurological investigation, the following findings were observed. 3.1.1. Autonomic symptoms: The entire left hand was severely swollen (Photo 1/2), its volume being about 50% increased compared with the healthy hand (Fig. 1). The entire left hand was found to be warmer than the right one (see also below), and the patient reported that this hand did not cool as much as the right one when exposed to cold environment (see below). The palmar side showed dry skin on touch (hypohydrosis). Signs of trophic disturbances (e.g. increased hair or disturbed nail growth) were absent. 3.1.2. Motor symptoms: Active movement of the fingers and the hand joints were severely impaired, including flexion (Photo 1) and extension (Photo 2) functions, muscular strength was absent (plegia) and there was strong postural tremor of the left hand and fingers. Sensory symptoms: The patient complained about severe and diffuse pain, which he felt deep inside the entire hand, and which increased upon hanging down the hand and was somewhat alleviated when elevating the arm above the heart level (orthostatic component of the pain). Touch sensation of the left hand was impaired (hypoaesthesia) in a glove-like distribution, as was sensation of pin prick (hypoalgesia). Allodynia or hyperpathia (as defined by Merskey & Bogduk 1994) were not found. 3.1.3. Measurement of finger tip temperatures (left/right hand): 35.4/34.7 - 34.8/33.8 - 35.4/33.8 - 35.7/34.0 - 35.7/34.0 C. Each finger of the affected left side showed higher skin temperature (SkT) values than the corresponding spot on the healthy side, which gives rise to a so-called systematic side difference of SkT (Blumberg 1991). 3.1.4. Further diagnostic procedures: During ischemia of the left hand, being maintained for a couple of minutes (see below: Section 3.3.1.), pain was absent. Conventional three- phase bone scanning in all phases showed diffuse increase of radionuclide uptake in the affected hand (not illustrated). Since the patient did show abnormal behaviour of SkT under environmental thermal load, reflexive behaviour of SkT was investigated experimentally under whole body warming and cooling. Consistent with the case history, diminished skin vasoconstriction upon cooling was found in the sick hand compared with the healthy hand (Fig. 2A). To test a possible sympathetic contribution to the pain, an intravenous regional guanethidine blockade (Hannington-Kiff 1993) with 2.5 mg of the drug was applied, using some modifications of this technique (Hoffmann & Blumberg 1994). This yielded pain relief for more than one day, which was accompanied by reduction of the edema (Fig.1). 3.1.5. Treatment and follow up: Since pain and swelling returned, similar blocks were used several times, as indicated in Fig.1, after which the patient finally became free of pain and swelling, together with an improvement of all the other symptoms. At the end of treatment, about four weeks later, he went back to work. At three-month (Photo 3/4) and nine-month follow up, swelling was absent and motor functions were normal, and there were no symptoms of RSD, including a regular behaviour of SkT under resting conditions (lack of systematic side difference of SkT) and under thermal load (Fig. 2B). 3.2. On the description and incidence of RSD symptoms Currently, it is uncertain which clinical approach should be applied in order to get a systematic description of the relevant symptoms of RSD. According to our approach, which is in agreement with the guidelines of the new classification of chronic pain (Merskey & Bogduk 1994) regarding RSD, the changes associated with RSD occur distally in the affected extremity, showing a triad of autonomic, motor, and sensory symptoms (Blumberg 1991, Blumberg & Jänig 1993, Kurvers et al. 1995). On the basis of our observations (Blumberg & Jänig 1993), the type and incidence of major symptoms in 121 RSD cases with an affected upper extremity are indicated in Table I, column A. Other studies list the symptoms of RSD without putting them into certain categories (for ref. see Schwartzmann & McLellan 1987), or relate them to categories like inflammatory, neurological, and sympathetic (as done by Veldman et al. 1993). By applying the scheme of the RSD triad to the latter study of 829 cases with RSD (Table I, column B), and comparing the incidence of symptoms with that of our study, a similar incidence is found for most symptoms, especially for the motor symptoms (Table I). Interestingly, allodynia, which has a low incidence in our study, was not even mentioned as a symptom of RSD in the study of Veldman et al. (1993), but had a high incidence in other studies (Bonelli et al. 1983, Drummond, Finch & Smythe 1991, Kurvers et al. 1995, Price, Long & Huitt 1992). The reasons for these differences remain uncertain. The following discussion of RSD will concentrate on the various aspects of pain and the sympathetic system in this condition. 3.3. Characteristics of the pain and quality control of sympathetic blocks in RSD The pain in RSD may be of throbbing, shooting or burning or other quality (for. ref. see Bonica 1990). Typically, the pain is reduced by elevating the affected extremity and worsens when the extremity is allowed to hang freely. This phenomenon, for which no diagnostic importance has been attached in the literature, recently was called the orthostatic component of the pain in RSD (Blumberg 1988, Blumberg & Jänig 1993). In the following, the response of the pain in RSD upon regionally applied ischemia and upon sympatholytic strategies will be discussed. Such strategies also need to be discussed with respect to their quality control. 3.3.1. Pain behaviour under regionally applied ischemia It occasionally has been observed that interrupting the circulation of the distal part of the affected extremity in cases with RSD leads to complete relief of pain for the duration of the interruption (de Takats 1945, Loh, Nathan & Schott 1981, Gracely, Lynch & Bennett 1990). Later on, in RSD this phenomenon was studied systematically by wrapping an Esmarch bandage (or an equivalent) around the hand or foot (to reduce its volume), followed by the application of a suprasystolic cuff directly proximal to this bandage (to stop arterial inflow). This so-called ischemia test, which does not block nerve conduction, typically leads to prompt - within one minute - and complete pain relief for the duration of the cuff (Blumberg & Hoffmann 1992). The mechanisms of the pain-suppressing (positive) effect of this test are not clear, but changes of the microcirculation, being induced by the test procedure, might be involved. Interestingly, the outcome of the ischemia test was positive in those of the 38 out of 40 RSD patients, who had an orthostatic component in their pain (Blumberg & Hoffmann 1994). 3.2.2 Effect of sympatholytic strategies Beneficial results are often reported when sympatholytic strategies are applied for RSD. Accordingly, textbooks recommend this kind of therapy (Wall & Melzack 1993, Bonica 1990, Cousins & Bridenbaugh 1988). However, in all of these studies there were also non-responders, sometimes up to around 25% to 50% of patients (Arnér 1991, Driessen et al. 1983, Bonelli et al. 1983, Wang, Johnson & Ilstrup 1985), with no obvious differences associated with the kind of sympathetic block chosen (e.g. stellate ganglion or guanethidine block). In these studies, it was not mentioned whether the clinical picture of these non- responders differed from that of the responders. Concerning this aspect, recent findings in 40 RSD patients seem to indicate that a positive ischemia test predicts a positive response to sympathetic block in RSD, both procedures leading to a similar and statistically significant reduction in pain (Blumberg & Hoffmann 1994). In any case, the degree of technical success of sympathetic blocks should be known in order to accurately interpret the test results. Assesment of the outcome of sympathetic blocks is discussed below. 3.2.3. Quality control of sympathetic blocks To fulfill the aim of the procedure, sympatholytic interventions should lead to complete interruption of sympathetic activity - in case of stellate ganglion or lumbar chain blockades with local anaesthetics - or to complete depletion of noradrenaline from sympathetic postganglionic vasoconstrictor endings - in case of intravenous regional guanethidine blocks. However, these interventions do not lead inevitably to a complete block. Thus, one has to prove the technical efficacy of sympathetic blocks in every single case. For this purpose, the behaviour of the sympathetic effector organs needs to be evaluated within the painful area. For cases with RSD in the upper extremity the textbooks note that a Horner sign (ptosis and miosis at the ipsilateral eye) can be used to assess the quality of the stellate ganglion block (Bonica 1990, Cousins & Bridenbaugh 1988, Wall & Melzack 1993), but there is no study which has shown that the occurrence of that sign is necessarily combined with a sympathetic block of the ipsilateral extremity. For the lower extremity, a similar sign does not exist. As a more reasonable way to evaluate a sympathetic block, measurements of skin blood flow/ SkT have been suggested (Bonica 1990, Wall & Melzack 1993). Of the methods available (e.g. laser doppler flowmetry, thermometry, pulse plethysmography), thermometry is the only one which delivers absolute values - in terms of SkT. Thus, this method is favorable for the standardization of the quality control of sympathetic blocks. The SkT should increase under each kind of sympathetic block due to the interruption of the sympathetic vasoconstrictor action on the vessels. However, the level of SkT to be reached under the block is uncertain. Textbooks, for example, state that an increase of a few degrees is a sufficient sign of a sympathetic block (Bonica 1990, Cousins & Bridenbaugh 1988, Wall & Melzack 1993), which has been taken up by related studies (Bonelli et al. 1983, Cooper, Drummond, Finch & Smythe 1991, Erickson & Hogan 1993, Hoffman et al. 1993, Olcott et al. 1991, Price, Long & Huitt 1992, Torebjörk et al. 1995, Uematsu et al. 1981, Wang, Johnson & Ilstrup 1985). Such notions are too vague, since if the block is applied under room temperature conditions, the possible range of SkT changes is defined by the initial SkT, which may be rather low in case of RSD with cold skin (e.g. around 20 C, see Thermogram 1), and by the body core temperature (around 36.5 C). According to physiological principles, under a complete block core temperature should nearly be reached at the skin (see Thermogram 3). However, previous studies show inconclusive results with variable values of SkT under a sympathetic block, including spinal anaesthesia, with about 25 C at the lower level and seldom exceed 35 C (Bengsston 1984, Irazuta, Berde & Sethna 1992, Treede et al 1992). Thus, this important aspect of the quality control of sympathetic blocks remains to be clarified. Furthermore, beside complete or failed interruption of sympathetic activity as a consequence of sympatholytic strategies, one also has to consider the possibility of certain partial effects (see Thermogram 2). In most studies of sympatholytic strategies in RSD, measurements of sympathetic reflexes have not been conducted to prove completeness of the blocks (Arnér 1991, Blumberg & Hoffmann 1994, Blanchard et al.1990, Bonelli et al. 1983, Cooper, DeLee & Ramamurthy 1989, Davidoff et al. 1988, Drummond, Finch & Smythe 1991, Erickson & Hogan 1993, Evans 1946, Hoffmann & Blumberg 1994, Hoffman et al. 1993, Irazuzta, Berde & Sethna 1992, Olcott et al. 1991, Price, Long & Huitt 1992, Uematsu et al. 1981, Wang, Johnson & Ilstrup 1985, Wilder et al. 1992). Therefore, it remains open whether patients who did not benefit from a sympathetic block, failed to benefit because the block was incomplete. To summarize, more work is needed to define the necessary standard of the quality control of sympathetic blocks in RSD. The nature of the pain in RSD will be discussed below (see: Section 6.). 3.4. Indications for disturbed sympathetic functions in RSD It is generally assumed that sympathetic functions are disturbed in RSD, based on the clinical observation of side differences of SkT and of sweating in these patients. Tests of resting and reflex behaviour of sympathetic effector organ activity have been done in patients with RSD and the results of such studies, as well as of studies related to the nature of the edema in RSD, are discussed below. 3.4.1. Behaviour of resting SkT in RSD In many clinical studies reporting on changes of SkT in terms of warm or cold skin in RSD, the criteria underlying these reports have not been explicitly stated (Arnér 1991, Blanchard et al. 1990, Davidoff et al. 1988, Evans 1946, Pak et al 1970, Patman, Thompson & Persson 1973, Price, Long & Huitt 1992, Veldman et al 1993, Wilder et al. 1992). In only a few studies, SkT measurements were applied in RSD, most of which were done focally (Bonelli et al. 1983, Irazuzta, Berde & Sethna 1992, Kurvers et al. 1995, Wang, Johnson & Ilstrup 1985), and only occasionally in a more systematic manner, for example by measuring the SkT of all finger- or toes of both sides (Blumberg 1988, Blumberg 1991, Blumberg & Jänig 1993), or more extensive areas were monitored by applying thermography (Feldman 1991, Pochaczevsky 1987, Sherman et al 1994) According to the studies with a systematic measurement of SkT, the skin in most of the patients on the affected extremity was warmer compared with the healthy side (Blumberg & Jänig 1993). This was especially true for cases with early RSD, its duration not exceeding ten days, who only rarely exhibit cold skin (Blumberg 1991). Naturally, the observation of warm skin speaks against the assumption of generally abnormal high sympathetic tone in RSD. This is also true for the finding of lowered plasma catecholamine levels - which, interestingly, often was combined with cold skin - and of increased subcutaneous blood flow in RSD extremities compared with the healthy side (Drummond, Finch & Smythe 1991, Christensen & Henriksen 1983). 3.4.2 Reflex behaviour of SkT in RSD Patients with RSD may recognize an abnormal behaviour of SkT, especially when exposed to low environmental temperature. This was verified under experimental conditions, in which whole body cooling by means of a thermal suit was used to reflexively stimulate the skin sympathetic vasoconstrictor activity. Under this condition, RSD patients developed either more or less vasoconstriction on the affected side compared with the healthy side, giving raise to side differences of SkT, which in 38 cases with RSD statistically proved to be significantly higher compared with a control group of 18 cases (Blumberg 1988, see also Fig. 2). Other studies, using some other kind of thermal stimulation, report similar results (Bej & Schwartzman 1991, Cooke et al. 1993, Leriche 1923, Morsier 1947, Trostdorf 1956). These findings, which were made in skin with intact innervation, support the idea that RSD may be associated with an abnormal reflex pattern of skin sympathetic vasoconstrictor neurones. Direct evidence for this phenomenon, as could possibly be obtained by bilateral recordings of these neurones under such conditions, is missing in RSD. On the other hand, this interpretation of these results is consistent with experimental findings obtained in animals, which show that the reflex pattern in skin vasoconstrictor neurones may change after a nerve lesion (Blumberg & Jänig 1985, Jänig & Koltzenburg 1991). However, there is no indication that changes of SkT, as possibly caused by abnormal sympathetic activity, are related to the pain in RSD, since, for example, it is hard to see how diminished skin vasoconstriction upon cooling (see Fig. 2) may contribute to pain. 3.4.3. On the nature of the edema in RSD The edema seems to be a major symptom in RSD (Blumberg 1992, Blumberg & Jänig 1993, Davidoff et al. 1988, Evans 1946, Kurvers et al. 1995, Pak et al. 1970, Patman, Thompson & Persson 1973, Veldman et al. 1993), but it is uncertain, whether the edema should be described as an autonomic (sympathetic) symptom (Blumberg 1988, Blumberg & Jänig 1993, Kurvers et al. 1995), or as an inflammatory sign, for example (Veldman et al. 1993). The edema was measured in only a few studies, to see whether it could be diminished by sympatholytic strategies. In one study, the edema was reduced at the end of treatment, without showing acute effects (Davidoff et al. 1988). In an other study, which is part of an ongoing investigation at our institution, acute effects of various kinds of sympatholytic interventions on the edema in RSD could be demonstrated (Blumberg et al. 1994, see also Fig.1). On the other hand, treatment with corticoids also results in diminished edema in RSD, but no acute effects are reported (Christensen, Jensen & Neor 1982, Kozin et al. 1976). The mechanisms of the edema in RSD are unknown. With respect to the effect of sympatholytic interventions upon this symptom of RSD, a contribution of the sympathetic system may be assumed. This assumption is part of a hypothesis, which tries to explain this effect - and, at the same time, the nature of the pain in RSD, which will be discussed below (see: Section 6.). 4. SYMPATHETICALLY MAINTAINED PAIN SYNDROME 4.1. Case report 2 This 59 year old man suffered from steadily increasing paraesthesias for more than a year in his left arm, radiating from the side of the elbow to the fifth finger. There was no pain and no motor deficit in that hand. Since even light movements of the elbow caused these paraesthesias, a neurological investigation was performed, including electrophysiological measurements. Evidence for slight partial lesion of the ulnar nerve was found, probably caused by a tumor which was situated close to the ulnar sulcus. Because of this finding, a neurosurgical intervention was performed. Most of the tumor was be extirpated, and a neurinoma was diagnosed histologically. About eight days following that intervention, the patient for the first time noticed spontaneous pain at the ulnar part of the left hand. Inside the same area there developed pain upon brief light touch, but not on light constant touch. Since these symptoms did not disappear during the following two months, and could not be treated by analgesic oral drug treatment, the patient finally was referred to us under the suspicion of ulnar nerve neuralgia. Upon neurological investigation, the following findings were obtained in the left arm in comparison with the right arm: Tendon jerks at the upper extremities were regular and there was no motor deficit, including the muscles which were supplied by the left ulnar nerve. There was no edema and, on touch, no abnormality of sweating or of SkT, and the patient reported no change of SkT under environmental thermal load. He reported spontaneous burning pain, which was felt superficially within the zone of the left ulnar nerve, also affecting the ulnar part of the fourth finger. With about the same intensity, the pain was constantly present during the entire day, and was not influenced by elevating or hanging down the affected extremity (no orthostatic component). Within the area of the spontaneous pain, mechanical allodynia was present, accompanied by diminished sensation on touch (hypoaesthesia) and on pin prick (hypoalgesia). There was no hyperpathia. Measurements of SkT in all finger tips showed no systematic side differences. Under the ischemia test there was no pain relief. 4.1.1. Treatment and follow up Due to the combination of spontaneous pain and allodynia, strictly confined to the zone of a partially lesioned nerve (see Photo 5), SMP syndrome was assumed and a diagnostic ipsilateral stellate ganglion block was performed. Following the block, pain and allodynia were absent for a couple of days. Upon their return, a second block was done, which again relieved both symptoms. Thereafter, the patient was free of any pain sensation for the entire period of follow up (six months), with the sensory signs of the partial lesion of the ulnar nerve still being present. 4.2. Clinical picture of SMP syndrome - comparison with RSD In contrast with RSD, patients with SMP show a less complex clinical picture, its principal symptoms being spontaneous pain and (mechanical/cold) allodynia (Blumberg & Jänig, 1993, Frost et al. 1988, Leriche 1949, Loh & Nathan 1978, Meyer et al. 1992, Nathan 1947, Treede et al 1992, Wahren, Gordh & Torebjörk 1995). For the most part these symptoms are found in the zone of a partially lesioned nerve or nerve root; this spatial relationship seems to be the key feature of the SMP syndrome. The spontaneous pain in SMP is mostly felt superficially, does not show an orthostatic component, and, according to preliminary results (Blumberg, Hoffmann, unpublished observations), is not suppressed by the ischemia test, all these characteristics being in contrast with those of the pain in RSD. Motor symptoms, if at all present, can be explained by lesions of motor axons. Consistent signs of sympathetic hyperactivity are not found in SMP and autonomic changes, which may be present inside the lesioned area (Frost et al 1988), can be related to denervation and reinnervation of sympathetic effector organs. In Table II, the main clinical features of SMP are compared with those of RSD. The distinct differentiation made between these conditions, clinically may not always be found, since there may be transient states between them, in the extreme case leading to causalgia (see: Section 5.). 4.3. Effect of sympatholytic strategies in SMP Sympatholytic strategies should, by definition, relieve pain in SMP. Consequently, if applied for diagnostic reasons, sympathetic blocks should yield positive results, as has been reported for the test with local anaesthetics (applied to paravertebral ganglia) and for the intravenous phentolamine test (Treede et al 1992, Raja et al. 1991), as well as for the guanethidine block (Torebjörk et al. 1995, Wahren, Gordh & Torebjörk, 1995). The phentolamine test is reported not to produce signs of a sympathetic block in patients suspected as having SMP (nor in RSD, Arnér 1991), but nevertheless induces pain relief in some patients (Meyer et al 1992, Raja et al. 1991). Thus, in terms of quality control, the efficacy of the test to block alpha adrenergic receptors remains uncertain, at least for the site of neurovascular transmission. For the non- responders of such studies, this offers the possibility that the doses of the drug applied may have been insufficient to interrupt the possible sympathetic- sensory coupling in these cases. Thus, it seems hard to conclude that these non- responders did have sympathetically independent pain (SIP), as has been stated (Meyer et al 1992, Treede et al 1992). Individuals with suspected SMP, who fail to respond to conventional sympathetic blocks, should not be diagnosed as having SIP, if the blocks are incomplete, as judged by SkT (Treede et al 1992). Regarding the diagnosis of SIP as a consequence of a negative response upon guanethidine block (Torebjörk et al. 1995, Wahren, Gordh & Torebjörk 1995), one also has to consider the possibility that such a (distal) regional block does not reach more proximal areas, as recently has been pointed out (Wall 1995). According to the findings as obtained in animal experiments, such proximal areas like the dorsal root ganglion, for example, may be the site of sympathetic- sensory coupling following nerve lesion (Wall& Devor 1983, Devor, Jänig & Michaelis 1994). The problem of placebo responses during sympatholytic interventions was not touched on here, but will be in other chapters of this volume. 5. CAUSALGIA - A COMBINATION OF RSD AND SMP? With respect to the clinical picture of patients who are described as suffering from causalgia and who respond to sympathetic blocks (for ref. see Bonica 1990), there are two main characteristics: They have a partial nerve lesion, which acutely is followed by pain within the zone of the lesioned nerve. The pain syndrome of these cases consists of spontaneous pain and of pain upon light touch, now called allodynia. In addition, also occurring acutely or somewhat later in the course of the disorder, they often develop symptoms outside the territory of the lesioned nerve. These symptoms, for example, consist of diffuse pain and distally generalized swelling, changes of skin blood flow and sweating, and motor impairments. 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