complex regional pain syndromes

Review

Complex regional pain syndrome ± diagnostic, mechanisms, CNSinvolvement and therapy

G Wasner*,1, J Schattschneider1, A Binder1 and R Baron1

1Klinik fuÈr Neurologie, UniversitaÈtsklinikum Kiel, 24105 Kiel, Germany

Complex regional pain syndromes (CRPS, formerly re¯ex sympathetic dystrophy andcausalgia) are neuropathic pain conditions of one extremity developing inadequately after atrauma. The initiating trauma a�ects primarily the extremity, but can also be a central lesion(e.g., spinal cord injury, stroke). CRPS is clinically characterized by sensory, autonomic andmotor disturbances. Pathophysiologically there is evidence for functional changes within thecentral nervous system and for involvement of peripheral in¯ammatory processes. Thesympathetic nervous system plays a key role in maintaining pain and autonomic dysfunctionin the a�ected extremity. After a primary central lesion, secondary peripheral changes in theparetic extremity are suggested to be important in initiating a CRPS. Though there is nodiagnostic gold standard, careful clinical evaluation and additional test procedures should leadto an adequate diagnosis. An early diagnosis and an interdisciplinary approach are importantfor optimal and successful treatment.Spinal Cord (2003) 41, 61 ± 75. doi:10.1038/sj.sc.3101404

Keywords: complex regional pain syndrome; re¯ex sympathetic dystrophy; sympathetic; centralnervous system; in¯ammation; treatment

Introduction

Complex regional pain syndromes (CRPS, formerlyre¯ex sympathetic dystrophy and causalgia) areneuropathic pain disorders developing as a dispropor-tionate consequence of painful trauma or a nerve lesiona�ecting the limbs, or a bone fracture, or as aconsequence of a remote process like stroke, spinalcord injury and myocardial infarction.1 Clinicalfeatures that occur in a distal generalized distributionare spontaneous pain, allodynia, hyperalgesia, auto-nomic and motor dysfunction. In 1872 the AmericanCivil War physician, Weir Mitchell, was the ®rst whodescribe a pain syndrome, named causalgia, developingin the distal extremity following traumatic partial nerveinjury. The a�ected extremity was characterized bysensory and trophic symptoms spreading beyond theinnervation territory of the injured peripheral nerve.Early in the last century Paul Sudeck described similarsymptoms in an extremity pain syndrome thatdeveloped after distal bone fractures without a�ectingany peripheral nerve. Based on the experience thatpatients with Sudeck's syndrome obtained dramaticpain relief by sympathetic block, the term re¯ex

sympathetic dystropy was introduced by Evans in1946 to accommodate the suggested pathophysiologicalrole of the sympathetic nervous system. Following thegrowing evidence from recent years that sympatheti-cally maintained pain (SMP) is still an importantsymptom, but not obligatorily necessary for thediagnosis of these disorders, a new terminology wasintroduced based entirely on elements of history,symptoms and ®ndings on clinical examination, withno implied pathophysiological mechanism.2 Accordingto the International Association for the Study of Pain(IASP) `Classi®cation of Chronic Pain', re¯ex sympa-thetic dystrophy and causalgia are now called complexregional pain syndromes (CRPS). In CRPS type I(re¯ex sympathetic dystrophy), minor injuries to a limbor lesions in remote body areas precede the onset ofsymptoms. CRPS type II (causalgia) develops afterinjury to a major peripheral nerve.3 Recent investi-gations of autonomic, motor and somatosensoryabnormalities indicate that the whole picture of CRPSis considered to be a neurological disorder involvingthe central nervous system as well as a peripheralneurogenic in¯ammatory process.4 However, the gen-eral awareness of CRPS is still poor, because onaverage thirty months pass by until patients areadmitted to a pain center for adequate therapy.5

*Correspondence: G Wasner, Klinik fuÈ r Neurologie, Christian-Albrechts-UniversitaÈ t Kiel, Niemannsweg 147, 24105 Kiel, Germany

Spinal Cord (2003) 41, 61 ± 75ã 2003 International Spinal Cord Society All rights reserved 1362 ± 4393/03 $25.00

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Clinical picture of complex regional pain syndromes

CRPS type I (re¯ex sympathetic dystrophy)Noxious events, including minor trauma (eg sprains,bruises, soft tissue trauma, frostbite or skin lesions),bone fracture or surgery of the a�ected extremity oftendetermine the onset of CRPS I. Occasionally thedisease develops after other medical events such asshoulder trauma, myocardial infarction or a lesion ofthe central nervous system. A peripheral nerve lesion isnot detectable,6 although one histopathological studydemonstrated damage of small a�erent ®bers in CRPSafter leg amputation.7 The clinical picture of CRPS I ischaracterized by sensory, autonomic, trophic andmotor abnormalities, as well as sometimes in¯amma-tory symptoms (Figure 1).8 ± 12

Sensory symptoms These include a burning sponta-neous pain felt in the distal part of the a�ectedextremity.13 Characteristically, the pain is dispropor-tionate in intensity to the inciting event. The painusually increases when the extremity is in a dependentposition. Stimulus-evoked pains are a striking clinicalfeature; they include mechanical and thermal allodyniaand/or hyperalgesia. These sensory abnormalities oftenappear early, are most pronounced distally, and haveno consistent spatial relationship to individual nerveterritories or to the site of the inciting lesion.14 ± 16

Typically the pain can be elicited by movements andpressure at the joints, even if these are not directlya�ected by the inciting lesion. In addition, somatosen-sory de®cits may be present.17,18

Autonomic abnormalities These include swelling andchanges of sweating and skin blood ¯ow (Figure 1).19 ± 25

At normal room temperature the skin temperature ofthe limbs shows an inconstant side di�erence in about30 ± 80% of the patients, ie the a�ected extremity is

either warmer or colder. In the acute stages of CRPS Ithe a�ected limb is more often warmer than thecontralateral limb. It is likely that there is anin¯ammatory component of CRPS I in the acutephase that contributes to pain and skin warming.Sweating abnormalities are present in nearly all CRPSI patients. Either hypohidrosis or, more frequently,hyperhidrosis is present.19,23,26 The acute distal swellingof the a�ected limb depends very critically onaggravating stimuli. Since it often diminishes aftersympathetic blocks, it is likely that it is maintained bysympathetic activity.11

Trophic changes Trophic changes such as abnormalnail growth, increased or decreased hair growth, ®brosis,thin glossy skin and osteoporosis may be present,particularly in chronic stages. Restrictions of passivemovement are often present in long-standing cases andmay be related to both functional motor disturbancesand trophic changes of joints and tendons.

Motor symptoms Weakness of all muscles of thea�ected distal extremity are often present.27 Smallaccurate movements are characteristically impaired.11

Nerve conduction and electromyography studies arenormal, except in patients in very chronic andadvanced stages. Therefore, the peripheral motorneuron and the neuromuscular junction are unlikelyto contribute to the motor dysfunction. About half ofthe patients have a postural or action tremor thatrepresents an increased physiological tremor.28 Inabout 10% of cases dystonia of the a�ected hand orfoot develops.29,30

An important feature of CRPS I is that the severityof symptoms is disproportionate to the severity oftrauma, with a tendency to generalize in the a�ecteddistal limb but not to be con®ned to the innervationzone of an individual nerve. Thus, all symptoms ofCRPS I may occur irrespective of the type of thepreceding lesion.31 Furthermore, the site of the lesionat the limb does not determine the location ofsymptoms.32

CRPS type II (Causalgia)CRPS II develops in the distal extremity followingtraumatic partial peripheral nerve lesion. In the earliestsystematic description of causalgia, Weir Mitchellnoted that in addition to spontaneous pain, patientsreported exquisite hypersensitivity of the skin to lightmechanical stimulation.33,34 Furthermore, movement,loud noises or strong emotions might trigger their pain.Distal extremity swelling, smoothness and mottling ofthe skin, and in some cases, acute arthritis was present.In most cases the limb was cold and sweaty. Thesensory and trophic abnormalities spread beyond theinnervation territory of the injured peripheral nerveand showed a distally generalized distribution. Since allsymptoms show many similarities to those of CRPS I,this syndrome is now called CRPS II.

Figure 1 Patient with acute CRPS. The patient developedCRPS of the left hand after a radial fracture. Markedswelling two weeks after the initial trauma. Adapted from 169,with permission

Pain in CRPSG Wasner et al

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Post-traumatic neuralgiaIt is important to recognize that in many post-traumatic neuropathy patients the pain is locatedlargely within the innervation territory of the injurednerve.35 Although these patients often describe theirpain as burning, they exhibit a less complex clinicalpicture than patients with causalgia, and do not showmarked swelling or a tendency for progressive spreadof symptoms. The cardinal symptoms are spontaneousburning pain, hyperalgesia and mechanical and espe-cially cold allodynia. These sensory symptoms arecon®ned to the territory of the a�ected peripheralnerve although allodynia may extend beyond theborder of nerve territories to a certain degree.Spontaneous and evoked pain are felt super®ciallyand not deep inside the extremity, and the intensity ofboth is not dependent on the position of the extremity.Following the IASP classi®cation it is possible to usethe name `neuralgia' for this type of neuropathic pain(pain within the innervation territory of a lesionednerve, eg post-traumatic neuralgia). However, thede®nition of CRPS II includes the statement thatsymptoms may also be limited to the territory of asingle peripheral nerve.3 Therefore, the term CRPS IIprovides space to include these localized post-traumaticneuropathies. An inherent weakness of this de®nitionof CRPS II is that di�erent syndromes with di�erentunderlying mechanisms are obviously included.

Despite the described symptoms one has to beaware of other clinical entities that demonstrate asimilar clinical picture to CRPS, eg neuropathy.36,37

Recent validation of the current IASP de®nition forCRPS indicated that modi®cations of the diagnosticcriteria have to be performed in the near future toimprove speci®city and sensitivity.38

CRPS after stroke and spinal cord injury

Stroke Interestingly, CRPS may also develop aftercentral lesions. Gellman et al. reported that 12% ofbrain-injured patients complained about symptoms ofre¯ex sympathetic dystrophy.39 The incidence forCRPS in the a�ected paretic upper extremity afterstroke ranges between 1.5 and 61%.40 ± 43 One reasonfor this large variation of data is probably that manysymptoms of CRPS are also found in stroke patients.Motor abnormalities like paresis, somatotensory ab-normalities and neglect, are typical features in strokepatients. Furthermore, skin temperature of the pareticextremity decreases in more than 50% of the patientsafter stroke.44,45 Disuse might be an important factorfor these cold hands.46 The development of unilateralsweating abnormalities after stroke led to the hypoth-esis that autonomic disturbances in stroke and CRPSmight share a common central pathophysiology.47 Painis also a frequent symptom after a central lesion.Central pain, eg after thalamic lesions, has a burningcharacteristic and is often associated with allodynia.Furthermore, peripheral traumatic injury of the

shoulder led to painful extremities after stroke, asdemonstrated by shoulder joint capsules taken atautopsy.48 Important risk factors for development ofsuch a peripheral shoulder ± hand syndrome aresubluxation, paresis of the shoulder girdle, moderatespasticity and visual de®cits for the paretic extremity.The peripheral lesion might initiate a self-perpetuatingvicious cycle of pain followed by the full picture ofCRPS in some patients (Figure 2).48 Similarly, inbrain-injured patients associated extremity injuryappears to be at a signi®cantly higher risk ofdeveloping CRPS.39

Spinal cord injury Although chronic pain is a frequentsymptom in patients with spinal cord injury, theassociation with CRPS seems to be relatively rare withan estimated incidence of about 5 ± 10%.49 ± 52 In aretrospective study of 125 patients with re¯ex sympa-thetic dystrophy only two patients had previous neckinjury.53 CRPS appears within a few months followinginjury, and most often a�ects unilaterally one upperextremity in tetraplegia patients, whereas bilateralinvolvement or CRPS at the lower extremity haverarely been reported.54 ± 57 Similar to stroke, morepatients seem to have some features of CRPS withoutdeveloping the complete syndrome.58 An importantpredisposing factor is a medullary gunshot wound,although it only represents 10% of the etiology ofspinal cord injury.54 The association of CRPS intetraplegia with limb trauma and shoulder pain may

Figure 2 Hypothesis on the development of CRPS afterstroke a�ecting the upper extremity. Stroke de®cits due to thecentral infarction may lead to secondary peripheral lesionsthat might initiate a self-perpetuating vicious cycle of painfollowed by the full picture of CRPS in a minority ofpatients. Many symptoms in a majority of stroke patientsthat are due to the central lesion are at least partially alsofound in CRPS (bold type). Risk factors for development ofpainful shoulder-hand syndrome are italicized


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indicate that peripheral mechanisms are involved ininitiating CRPS, similar to that decribed instroke.48,50,54 CRPS may be one cause of contracturesin patients with spinal cord injury.59

CRPS and sympathetically maintained pain

The former term `re¯ex sympathetic dystrophy' forCRPS was based on the experience that sympatholy-tic procedures relieved pain in many patients.However, it became clear in recent years that paindepending on sympathetic activity is not necessary forthe diagnosis of CRPS, because not all patientsrespond to sympatholytic procedures. Furthermore, itis not speci®c, because other neuropathic painconditions might bene®t from sympathetic blocks(Figure 3). Therefore, the term sympatheticallymaintained pain was re-de®ned: Neuropathic painpatients presenting with similar clinical signs andsymptoms, can be divided into two groups by thenegative or positive e�ect of selective sympatheticblockade or antagonism of alpha adrenoceptormechanisms.60,61 The pain component that is relievedby speci®c sympatholytic procedures is considered`sympathetically maintained pain' (SMP). Thus, SMPis now de®ned to be a symptom or the underlyingmechanism in a subset of patients with neuropathicdisorders and not a clinical entity. The positive e�ectof a sympathetic blockade is not essential for thediagnosis. On the other hand, the only possibility todi�erentiate between SMP and `sympathetically in-dependent pain' (SIP) is the e�cacy of a correctlyapplied sympatholytic intervention.2

Pathophysiological mechanisms in CRPS

Although the entire pathophysiology of CRPS is notresolved, evidence from human experimentation andanimal studies illuminate many aspects of the under-lying pathophysiological mechanisms.

The sympathetic nervous systemThe clinical picture of autonomic dysfunction withchanges in skin blood ¯ow, temperature and sweating,as well as the symptom of sympathetically maintainedpain, suggests that the sympathetic nervous system isinvolved in the pathophysiology of CRPS. Physiologi-cally, sympathetic preganglionic neurons, which areinvolved in regulation of e�ector cells in somatictissues, project to the paravertebral ganglia of thesympathetic trunk and synapse with postganglionicneurons that innervate the e�ector cells. Thesepreganglionic sympathetic neurons are under centralcontrol, and the pattern of ongoing and re¯exdischarges is characteristic for each type of sympatheticpathway, eg skin vasoconstrictor, muscle vasoconstric-tor and sudomotor neurons, and varies according tothe innervated target cells.62,63 Under normal condi-tions sympathetic activity does not interact with thenociceptive neurons in the periphery.64,65

Autonomic disturbances A partial nerve lesion is theimportant preceding event in CRPS II. Therefore, ithas generally been assumed that abnormalities in skinblood ¯ow within the territory of the lesioned nerve aredue to peripheral impairment of sympathetic functionand sympathetic denervation. During the ®rst weeksafter transection of vasoconstrictor ®bers, vasodilata-tion is present within the denervated area. Later thevasculature may develop increased sensitivity tocirculating catecholamines, probably due to upregula-tion of adrenoceptors.66 Similar observations wererecently described in the chronic nerve constrictioninjury model in rats.67,68 The skin on the lesioned sidewas abnormally warm for about the ®rst post-operativeweek and then evolved to a chronically cold status. Thelate-stage cold skin was present despite a completeabsence of ¯uorescence for norepinephrine. Thus, inthis animal model, the skin is cold due to denervationsupersensitivity of adrenoceptors rather than excessivesympathetic vasoconstrictor activity.

Sympathetic denervation and denervation hypersen-sitivity cannot completely account for vasomotor andsudomotor abnormalities in CRPS. First of all, inCRPS I there is no overt nerve lesion.69 Furthermore,in CRPS II the autonomic symptoms spread beyondthe territory of the lesioned nerve.

Studies on skin blood ¯ow and temperature inCRPS I demonstrated that the warmer a�ectedextremity in the acute stage of the disease (56months) is due to a functional inhibition of cutaneoussympathetic vasoconstrictor activity, leading to cuta-neous vasodilatation.24,25 Consistently, direct measure-

Figure 3 Neuropathic pain conditions with the facultativesymptom of sympathetically maintained pain (SMP). CRPSpatients have the highest incidence of an SMP followed bypatients su�ering from acute herpes zoster or postherpeticneuralgia, phantom limb pain and polyneuropathy (PNP)


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ments of norepinephrine levels from the venouse�uent above the area of pain show a reduction inthe a�ected extremity.24,25,70,71 These data support theidea that CRPS I is associated with disturbedsympathetic re¯ex patterns in the a�ected extre-mity.20,22 The locus of pathophysiological changesunderlying such disturbed re¯ex activity must be in thecentral nervous system. Abnormalities in centralautonomic control are consistent with experimental®ndings in animals, which show that the re¯ex patternin single cutaneous vasoconstrictor neurons maychange after peripheral nerve injury.64,72

Measurements of skin temperature and blood ¯owover time demonstrated a change according to theduration of CRPS.21 In more advanced stages (46months), there is an increased number of patients inwhom skin temperature and blood ¯ow in the a�ectedlimb are decreased.25 There is evidence that cutaneoussympathetic vasoconstrictor activity returns with theduration of the disease.24

The initial functional inhibition of vasoconstrictoractivity in the acute stage might have led to secondaryend-organ supersensitivity (decentralization supersensi-tivity) in the absence of structural damage to sympa-thetic ®bers.62,66,69,73 Such supersensitivity could lead toincreased vasoconstriction and reduced skin tempera-ture, even though sympathetic postganglionic neuronactivity is reduced. In fact, alpha-adrenoceptor densityhas been reported to be increased in skin biopsies ofpatients with CRPS.74,75 Accordingly, the few micro-neurographic studies of small sympathetic nervefascicles that have been performed so far in patientswith chronic CRPS with cold a�ected limbs showed thatthe average skin sympathetic activity was not di�erentbetween the a�ected and contralateral side.76,77

Further important signs of sympathetic dysfunctionin CRPS are unilateral sweating abnormalities.78

Quantitative measurements of sudomotor activityshow enhanced sweat production in the disturbedlimb in the acute and chronic stage of the disease inmany CRPS patients.23,26 This unilateral hyperhidrosisindicates enhanced sympathetic sudomotor activity.

In conclusion, the combination of increased sudo-motor and decreased cutaneous sympathetic vasocon-strictor out¯ow is a well known centrally regulatedthermoregulatory function to keep body core tempera-ture constant in di�erent environments. However,under physiological conditions all extremities areinvolved. Therefore, the unilateral activation ofsudomotor and inhibition of cutaneous sympatheticvasoconstrictor neurons indicates a centrally locatedthermoregulatory dysfunction in CRPS.

Sympathetically maintained pain Under physiologicalconditions there is no interaction between the sympa-thetic and the a�erent nociceptive system; stimulation ofthe sympathetic trunk does not induce any activity ina�erent neurons.65,79 However, under pathophysiologi-cal conditions the situation dramatically changes.80

Neurophysiological and neuroanatomical experiments

in animals show that a pathologic coupling of sympa-thetic and a�erent activity may follow a mechanicallyinduced peripheral nerve lesion. This may take placebetween sympathetic ®bers and regenerating or intactnociceptive C-®bers in the periphery, or betweensympathetic vasoconstrictor ®bers and a�erent somatawithin the dorsal root ganglion.81 The interaction ischemically via noradrenaline from sympathetic endingsand adrenoreceptors that are expressed on a�erentneurons under pathophysiological conditions (Figure4A). Accordingly, mRNA for alpha2A-adrenoceptors isup-regulated in DRG neurons after nerve lesion.82

Clinical studies in humans support the idea thatnociceptors develop catecholamine sensitivity aftercomplete or partial nerve lesions. After limb amputa-tion, injection of epinephrine around a stump neuromais reported to be intensely painful.83,84

Furthermore, intraoperative stimulation of thesympathetic chain induces an increase of spontaneouspain in patients with CRPS II but not in patients withhyperhidrosis.85,86 In CRPS and post-traumatic neur-algias, intracutaneous application of norepinephrineinto a symptomatic area rekindled spontaneous painand dynamic mechanical hyperalgesia that had beenrelieved by sympathetic blockade, supporting the idea

Figure 4 In¯uence of sympathetic activity and catechola-mines on primary a�erent neurons (PAN). (A) After nervetransection a sympathetic-a�erent interaction occurs in theneuroma and in the dorsal root ganglion. It is mediated bynorepinephrine (NA) released from sympathetic postganglio-nic neurons (SPGN) and a-adrenoreceptors expressed at theplasma membrane of a�erent neurons. PGN, preganglionicneuron. (B) After tissue in¯ammation intact but sensitizedprimary a�erents acquire norepinephrine sensitivity. Norepi-nephrine is not acting directly on a�erents but induces therelease of prostaglandins (PG) from sympathetic terminalsthat sensitize the a�erents. In accordance, bradykinin andnerve growth factor (NGF) induced nociceptor sensitizationis also mediated by the release of prostaglandins fromsympathetic postganglionic neurons. Adapted from 169, withpermission


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that noradrenergic sensitivity of human nociceptors ispresent after a partial nerve lesion.87 Also, inpostherpetic neuralgia, spontaneous pain and mechan-ical hyperalgesia are enhanced after injection ofepinephrine or phenylephrine.88 A potential criticismof the above mentioned studies, where pain wasrekindled with exogenous adrenergic agonists, is thatthe doses of norepinephrine (NE) used were muchhigher than are likely to exist in vivo. Therefore, thealgesic e�ects of peripheral administration of NE inphysiologically relevant doses was compared inpatients with SMP and normal subjects.89 IntradermalNE, in physiologically relevant doses, was demon-strated to evoke greater pain in the a�ected regions ofpatients with SMP, than in the contralateral una�ectedlimb, and in control subjects. In accordance with this,spontaneous pain and dynamic as well as punctatemechanical hyperalgesia was augmented in patientswith CRPS I when sympathetic cutaneous vasocon-strictor neurons were activated physiologically bythermoregulatory and respiratory stress.90,91 Interest-ingly, this applies also to acute CRPS patients whodemonstrate a functional inhibition of cutaneoussympathetic vasoconstrictor activity in the a�ectedextremity (see above). This is not necessarily aparadox, because a reduced sympathetic activity mightbe su�cient to maintain the pain, in particular iffunctional a-adrenoceptors at the membrane of intacta�erent ®bers are up-regulated acutely. Furthermore,animal experiments have demonstrated that thesympathetic in¯uence on in¯ammatory processes doesnot depend on sympathetic activity itself, but on theanatomical integrity of postganglionic ®bers.92

Peripheral in¯ammationPaul Sudeck postulated an exaggerated in¯ammatoryresponse as an important pathophysiological mechan-ism in CRPS.6

Indeed, some of the clinical features of CRPS,particularly in its early phase, could be explained byan in¯ammatory process.93 ± 95 Consistent with thisidea, corticosteroids are often successfully used inacute CRPS.96

There is increasing evidence that a localizedneurogenic in¯ammation might be involved in thegeneration of acute edema, vasodilatation and in-creased sweating. Scintigraphic investigations withradiolabelled immunoglobulins show extensive plasmaextravasation in patients with acute CRPS I.10

Analysis of joint ¯uid and synovial biopsies in CRPSpatients have shown an increase in protein concentra-tion, synovial hypervascularity, and neutrophil in®l-tration.97 ± 99 Furthermore, synovial e�usion isenhanced in a�ected joints as measured with MRI.100

In acute untreated CRPS I patients protein extravasa-tion elicited by strong transcutaneous electricalstimulation was only provoked on the a�ectedextremity as compared with the normal side, indicatingthat substance P might be involved.101

As further support of a neurogenic in¯ammatoryprocess, serum concentrations of calcitonin gene-relatedpeptide were elevated in CRPS patients as a marker forneurogenic in¯ammation.102 Venous blood samples ofthe a�ected extremity showed increased cytocine levelsof interleukin-6 and tumor necrosis-alpha as evidencefor a local in¯ammation.103 The production of nitricoxide in peripheral blood monocytes was signi®cantlyincreased after stimulation with interferon-gamma inpatients compared with controls.104

Thus the weight of evidence indicates that in¯am-matory processes are involved in the pathogenesis ofearly CRPS. However, the exact mechanisms of theinitiation and maintenance of these in¯ammatoryreactions are still far from clear. The central issue iswhether there is a sympathetic as well as anin¯ammatory component and whether the sympatheticnervous system may contribute to the early in¯amma-tory state. Animal studies have demonstrated that thesympathetic nervous system can in¯uence the intensityof an in¯ammatory process,105,106 and studies indicatethat sympatholytic procedures can ameliorate bothpain and in¯ammation in humans (Figure 4B).107

However, this concept has yet to be proven in patientswith CRPS.

The central nervous systemAutonomic disturbances indicate a centrally locatedthermoregulatory dysfunction in CRPS (see Thesympathetic nervous system). Also other symptoms ofCRPS I favour a central origin of the disorder, or atleast a substantial role of central pathways. Impair-ment of muscle strength involving all muscles of thea�ected distal extremity that is not due to pain,oedema or severance of peripheral nerves is likely tobe the result of a centrally mediated impulse abnorm-ality in the motorneurone pool. Furthermore, patientscomplain about a neglect-like syndrome responsible forsevere motor dysfunctions.108,109 In about 50% of thepatients an increased physiological tremor is found thatis due to central changes.28 Kinematic analysis of theupper extremity in CRPS revealed motor de®citsprobably due to impaired integration of visual andsensory a�erent inputs to the partietal cortex.110

Based on numerous animal experimental ®ndings,spontaneous pain and various forms of hyperalgesia atthe distal extremity16,111 are thought to be generatedby processes of peripheral and central sensitization(for review see112). Clinical and quantitative sensorytesting of the nociceptive system demonstrated hemi-sensory impairment and hyperalgesia that frequentlyextends far beyond the area a�ected by spontaneouspain, indicating changes in central a�erent processingthat have been recently demonstrated by functionalimaging studies.16 ± 18,113 ± 115 Furthermore, it is sug-gested that prefrontal networks are involved in SMPin CRPS patients.116 In one chronic CRPS patientsymptoms resolved after a traumatic cerebral contu-sion in the left temporal lobe.117


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All these data indicate that alterations of the centralnervous system play an important role in CRPS.However, it is not clear, whether these are primaryabnormalities in the disease or whether they arechanges secondary to the pain.

Genetic considerationsThe observation that many patients su�ered fromsimilar peripheral extremity trauma that is followed, inonly a few by a CRPS, raises the question whethergenetic factors are involved in the pathophysiology.Two studies revealed di�erences between CRPSpatients and healthy controls in the human leukocyteantigen class II molecules encoded by genes of thehuman major histocompatibility complex on chromo-some 6.118 ± 120 The investigation of the innate cytokinepro®le in CRPS patients to determine a possible role ofthe immune system in the disease pathophysiologyfailed to show any signi®cant results.121 The clinicalrelevance of these ®ndings is not clear. The evidence ofa facilitated neurogenic in¯ammation and an increasedserum level of the neurogenic in¯ammatory peptidecalcitonin gene-related peptide, even in the non-a�ectedextremity, might indicate phenotypic di�erences be-tween CRPS patients and controls.101,102

Psychology of CRPS

Most patients with CRPS exhibit a signi®cant amountof psychological distress symptoms, with depressionand anxiety being most common. Many patientsbecome overwhelmed by the pain and associatedsymptoms. Without adequate psychosocial supportthe patients may develop maladaptive coping skills.These observations in connection with normal neuro-physiological test results in CRPS I led to thehypothesis that CRPS is primarily a psychogenicdisorder.122,123 However, well designed studies andcomprehensive reviews of the available literature havesuggested that psychological symptoms are the resultand not the cause of CRPS.124 ± 127

Diagnosis of CRPS and additional diagnostic tests

For the present the diagnosis of CRPS is based on theclinical criteria described above. Procedures shouldstart with taking a detailed medical history consideringan initiating trauma and any history of sensory,autonomic and motor disturbances. One shouldexplicitly ask for the development, time course,distribution and characteristics of pain. A generalneurological examination is needed. Detection of anyswelling, sweating, trophic, temperature and motorabnormality in the disturbed area is important. Musclestrength of the a�ected limb, as well as characteristicsand distribution of somatosensory abnormalities,should be investigated in detail. One should test ifthe pain can be elicited by movements and pressure atthe joints. Such an approach, according to the

standardized diagnostic criteria for CRPS, is importantin order to provide an accurate and completedescription of patients' characteristics.128

Furthermore, many tests and procedures arevaluable diagnostic tools that can add information tocon®rm the diagnostic impression about autonomic,sensory and motor function and dysfunction.

Bone scintigraphyBone scintigraphy can provide information aboutvascular bone changes,129 but it should be noted thatbone scintigraphy is only positive for signi®cant changesduring the subacute period (up to 1 year). Especially,pathological uptake in the metacarpophalangeal jointsand metacarpal bones in phase three of the three-phasebone scintigram are described as highly sensitive andspeci®c for CRPS (Figure 5).130 It is therefore oftenapplied to di�erentiate CRPS from other pain causesafter central lesion.39 However, there is no known goldstandard against which to compare this test.

Plain radiographsThese could be used to evaluate the status ofmineralization, but are only positive in chronic stages.

Quantitative sensory testing (QST)Psychophysical testing of thermal and thermal painthresholds can provide information about the functionor dysfunction of unmyelinated and small myelinateda�erent ®bers that project into the spinothalamictracts. QST can also analyse the functional status oflarge myelinated ®bers projecting to the dorsal columnsby vibratory threshold testing.14,15,78,131,132 However,there seems to be no sensory pro®le that is character-istic for CRPS.

Figure 5 Three-phase bone scan in acute CRPS. In phasethree a di�use increase in tracer-uptake is found around thedistal joints of the disturbed extremity. Adapted from 170, withpermission


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Autonomic functionThis can be tested by a variety of new and emergingmethods. These are infrared thermometry, laserDoppler ¯owmetry,20,22,133 infrared thermogra-phy134,135 and a quantitative sudomotor axon re¯extest (QSART).19,23,26 Skin temperature di�erences maybe helpful for diagnosis of CRPS. These typicaltemperature side di�erences are no static descriptorsbut comprise dynamic changes critically depending onenvironmental temperature and are most prominent ata high to medium level of sympathetic vasoconstrictoractivity (Figure 6).25,136 Under resting conditionssensitivity of skin temperature asymmetries was only32% compared with healthy controls. However,during experimental alteration of sympathetic activityby whole-body cooling and warming with a thermalsuit, temperature di�erences between both sidesincreased dynamically in CRPS patients but not in

controls, so that the sensitivity increased up to 76%.A skin temperature asymmetry of more than 2.28Chad a speci®city of 93% compared with patientssu�ering from painful limbs of other origin (Figure6).136 Autonomic testing with the QSART can provideinformation about the function of sudomotor re¯exloops. Swelling can be quanti®ed by measuring waterdisplacement.

Di�erential diagnosis of CRPS

The current CRPS diagnostic criteria are adequatelysensitive (ie, rarely miss a case of actual CRPS).However, both internal and external validationresearch suggests that CRPS is currently overdiag-nosed, despite the discrepancy that it is oftenrecognized too late by general practitioners.5,36,38

Probable reasons are that there is no test available as

Figure 6 Characteristics of interside skin temperature di�erences during controlled alterations in sympathetic activity in CRPS.Controlled alterations of cutaneous sympathetic activity (whole-body cooling and warming) were applied by means of a thermalsuit. The subject was lying in a suit supplied by tubes, in which running water of 128C and 508C, respectively was used to cool(increase of sympathetic activity) or warm (inhibition of sympathetic activity) the whole body. The skin temperature of the®ngers of both hands was monitored. (A) Temperature of the right and left hand in a healthy subject (C) A�ected and healthyextremity in a CRPS patient. Side di�erences in skin temperature of the ®ngers of both hands in the healthy control subject (B)and in the CRPS patient (D) during controlled alterations of sympathetic activity. The arrow indicates beginning of whole-bodywarming. Maximal skin temperature di�erences during whole-body warming are indicated by the vertical dotted lines. Adaptedfrom 136, with permission


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a gold standard and many other clinical entities areincluded under the umbrella of CRPS.8,37 Therefore,one should always search for the full picture of CRPS,including all clinical criteria and the typical medicalhistory described above. In case of doubt other diseasesthat may cause neuropathic pain should be excluded.Furthermore, one should be aware of disorders causingpain and unilateral vascular changes such as in¯amma-tion or infections (eg, rheumatism, ulceration) andunilateral vascular occlusive diseases. Di�erentialdiagnostic problems might also be due to repetitivearti®cial occlusion of the blood supply to one limb asin a malingering or factitious disorder that needs adetailed psychological exploration.

Therapeutic options for CRPS

Lack of understanding of the underlying pathophysio-logical abnormalities and lack of objective diagnosticcriteria resulted in inherent di�culties of conductingclinical trials with therapeutic modalities. Therefore,only few evidence-based treatment regimens for CRPSare available so far. In fact, three literature reviews ofoutcome studies ®nd discouragingly little consistentinformation regarding the pharmacological agents andmethods for treatment of CRPS.137,138 In the absenceof more speci®c information about pathophysiologicalmechanisms and treatment of CRPS one has to rely onoutcomes from treatment studies for other neuropathicpain syndromes. Furthermore, the still hypotheticalmechanism-based treatment concept has to be trans-ferred from ideas derived from animal experiments onperipheral nerve lesions to the situation in CRPSpatients. Therefore, the following treatment optionsshould be considered as a recommendation based onclinical evidence.

General rulesTreatment of CRPS requires a multidisciplinaryapproach including neurologists, anesthesiologists,orthopedic specialists, physiotherapists and psycholo-gists. Treatment should be immediate, and mostimportantly directed toward restoration of full functionof the extremity. The general principles of pharmaco-logical treatment are the individualization of therapyand the titration of a given pharmacological agent,depending on the e�ect on one hand and side e�ects onthe other. `No-response' should not be accepted until asu�cient period of time has passed to judge the e�cacyof the drug. Destructive surgery of the peripheral orcentral a�erent nervous system in cases of CRPSalways implies further dea�erentation and therebyprovides an increased risk for a persistent dea�erenta-tion type of pain.

Pharmacological therapyNonsteroidal anti-in¯ammatory drugs (NSAIDs) havenot been demonstrated to have signi®cant analgesic

e�ect in treatment of CRPS, however, NSAIDs couldbe used for relief of mild to moderate pain.

Opioids strongly inhibit central nociceptive neuronsmainly through interaction with m-receptors. Opioidsare clearly e�ective in postoperative, in¯ammatory andcancer pain. The use of opioids in CRPS has not beenstudied. In other neuropathic pain syndromes intrave-nous morphine is clearly analgesic when compared toplacebo.139 However, there are no long-term studies oforal opioids in the treatment of neuropathic pain,CRPS included. Even without solid scienti®c evidencethe expert opinion of pain clinicians is that opioidscould be, and should be, used as a part of acomprehensive pain treatment program. Given thatsome patients with neuropathic pain may obtainconsiderable pain relief, opioids should be tested earlyin the course of CRPS, and a trial of opioids shouldnot be delayed to the `last resort' status. Administra-tion of opioids requires speci®c treatment programsfor patients with a history of chemical dependence andcaution in patients with pulmonary disease. Prophy-lactic treatment of common side-e�ects, notablynausea or constipation, can improve patients' com-pliance.

Tricyclic antidepressants (TCA) are the best studiedgroup of pharmacological agents in neuropathic painand they have shown an analgesic e�ect. TCA inhibitre-uptake of monoaminergic transmitters. There issolid evidence that the re-uptake blocker of serotoninand noradrenaline amitriptyline and the selectivenoradrenaline blocker desipramine produce pain reliefin diabetic or postherpetic neuropathy.140 ± 142 Themean dose that is often su�cient for pain reduction(eg amitriptyline 75 ± 150 mg/day) is smaller thandoses necessary to achieve anti-depressant e�ects.Onset of the analgesic e�ect occurs within 1 ± 2 weeksand peaks around 4 ± 6 weeks.141 Improvement ofsleep, mood and anxiety can further add to the painrelieving action.

Sodium blocking agents, the type Ib anti-arrhythmicdrugs lidocaine, mexiletine and tocainide, and theanticonvulsant carbamazepine have an e�ect onsodium channels and potentially relieve neuropathicpain.139,143 Intraveneous lidocaine was e�ective inCRPS.144 Care needs to be taken when administeringthese compounds. Contra-indications include electro-cardiac abnormalities, reduced left ventricular functionand coronary heart disease.

GABA-agonists such as baclofen, valproic acid,vigabatrine and benzodiazepines interacting withGABAergic transmission have been reported toalleviate di�erent neuropathic pain conditions. Thegeneral clinical impression is that such drugs do notprovide substantial pain relief, except for baclofen intrigeminal neuralgia. Some agents may have a place inthe treatment of painful muscle spasms.

The action of the drug gabapentin is not completelyresolved, but probably includes an inhibition ofcalcium channels. In one study, gabapentin had apromising e�ect on CRPS.145


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Glucocorticoids taken orally are the category ofagents that has clearly demonstrated e�cacy incontrolled trials.96 There is no evidence that otherimmune-modulating therapies, notably intravenousimmunoglobulins or immunosuppressive drugs have aplace in the treatment of CRPS.

Transdermal application of the a2-adrenoceptoragonist clonidine, which is thought to prevent therelease of catecholamines by a presynaptic action, maybe helpful when small areas of hyperalgesia arepresent.146,147

Clinically available compounds that are demon-strated to have NMDA receptor blocking propertiesinclude ketamine, dextromethorphane and memantine.They o�er new options for treatment of CRPS pain,but studies which will help clinicians to fully utilizethese agents are not available.

Subcutaneous calcitonin only had a mild e�ect onspontaneous pain.148 Intravenous bisphosphonates(alendronate, clodronate), however, showed a signi®-cant improvement in pain, swelling and move-ments.149,150

Interventional therapy at the sympathetic nervoussystemInterruption of the sympathetic nerve supply to thea�ected extremity has been used to treat CRPS formany years. Proof of the e�ectiveness of sympatheticblockade, however, is scanty.137,151 Some authors evendiscard the concept that the sympathetic nervoussystem is actively involved in the generation ofpain.122,152 They claim that interventions that blocksympathetic activity lack speci®city, and argue that thetechniques and results of sympathetic blockade haverarely been adequately evaluated and are in most casesnot placebo-controlled.

Currently, two therapeutical techniques to blocksympathetic nerves are used: (1) injections of a localanaesthetic around sympathetic paravertebral gangliathat project to the a�ected body part (sympatheticganglion blocks); and (2) regional intravenous applica-tion of guanethidine, bretylium or reserpine (which alldeplete noradrenaline in the postganglionic axon) toan isolated extremity blocked with a tourniquet(intravenous regional sympatholysis, IVRS).

Although sympatholytic therapy can frequentlyresult in substantial or even complete pain relief,blockade of the sympathetic activity is ine�ective insome patients. Nonetheless, with all of the short-comings there is a compelling historical and basic andclinical science evidence that it is important that anadequate sympatholytic trial by a quali®ed clinicianshould be performed in an attempt to di�erentiatebetween SMP and SIP. In the presence of a signi®cantsympathetic component, treatment strategies towardsthe sympathetic therapy could be considered. Besidethe pain, other symptoms may improve after sympa-thetic blocks.

There are many uncontrolled surveys in theliterature reviewing the e�ect of sympathetic interven-tions in CRPS and post-traumatic neuralgias. InCRPS, about 85% of the patients report a positiveacute e�ect, but fewer patients experience long-termrelief (60% in sympathetic block and 30% inintravenous regional sympatholysis). In post-traumaticneuralgias the sympatholytic interventions are clearlyless e�ective. One controlled study in patients withCRPS I has shown that sympathetic blockade withlocal anaesthetic has the same immediate e�ect onpain as a control injection with saline.153 However,after 24 hours patients in the local anaesthetic groupwere much better, indicating that non-speci®c e�ectsare important initially and that evaluating the e�cacyof sympatholytic interventions is best done after oneday. Interestingly, one prospective study showed thatperioperative stellate ganglion blocks in patients with ahistory of CRPS can signi®cantly reduce the recur-rence rate of this disease.154 Controlled studies usingguanethidine IVRS did not show a bene®ciale�ect.155 ± 157

In our view, there is a desperate need for controlledstudies that assess the acute as well as the long-terme�ect of sympathetic blockade on pain and otherCRPS symptoms, in particular motor function. Wellperformed sympathetic ganglion blocks should beperformed rather than IVRS.

Stimulation techniques and spinal drugs applicationTranscutaneous electrical nerve stimulation (TENS)may be e�ective in some cases and has minimal sidee�ects. Epidural spinal cord stimulation (SCS) hasshown e�cacy in one randomized study in selectedchronic CRPS patients158,159 and may be a promisingtreatment for this group of patients. Interestingly, thesepatients had undergone previous unsuccessful surgicalsympathectomy. The pain relieving e�ect was notassociated with peripheral vasodilatation suggestingthat central disinhibition processes are involved.160

Sensory detection threshold were not e�ected by thestimulation.161 Other stimulation techniques, ie periph-eral nerve stimulation with implanted electrodes, anddeep brain stimulation (sensory thalamus and mediallemniscus), have been reported to be e�ective inselected cases of CRPS.162

Also in selected patients with severe refractoryCRPS, epidural administration of clonidine or theNMDA-antagonist ketamine induced analgesia asso-ciated with marked side-e�ects like sedation andhypotension.163,164 Intrathecal baclofen demonstrateda positive outcome for CRPS patients with severedystonia.165

Physical therapyClinical experience and two prospective studies indicatethat physiotherapy is of utmost importance to achieverecovery of function and rehabilitation.166 ± 168 At the


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acute stage of CRPS when the patients still su�er fromsevere pain, it is mostly impossible to carry outintensive active therapy. Painful interventions and inparticular aggressive physical therapy at this stageleads to deterioration. Therefore, immobilization andcareful contralateral physical therapy should be theacute treatment of choice. Later, when pain subsides,passive physical therapy, active isometric followed byactive isotonic training should be performed incombination with sensory desensitization programs.

Acknowledgements

This work was supported by the Deutsche Forschungsge-meinschaft (DFG Ba 1921/1-1) and the BMBF Network`Neuropathic Pain'.

References

1 Wasner G, Backonja MM, Baron R. TraumaticNeuralgias: Complex Regional Pain Syndromes (Re¯exSympathetic Dystrophy and Causalgia): Clinical Char-acteristics, Pathophysiological Mechanisms and Ther-apy. Neurol Clin 1998; 16: 851 ± 868.

2 Stanton-Hicks M, JaÈ nig W, Hassenbusch S, Haddox JD,Boas R, Wilson P. Re¯ex sympathetic dystrophy:changing concepts and taxonomy. Pain 1995; 63: 127 ±133.

3 Merskey H, Bogduk N. Classi®cation of chronic pain:descriptions of chronic pain syndromes and de®nition ofterms. Seattle: IASP Press, 1995.

4 Harden RN, Baron R, JaÈ nig W. Complex regional painsyndrome, Vol. 22, Progress in Pain Research andManagement. Seattle: IASP Press, 2001.

5 Allen G, Galer BS, Schwartz L. Epidemiology ofcomplex regional pain syndrome: a retrospective chartreview of 134 patients. Pain 1999; 80: 539 ± 544.

6 Sudeck P. UÈ ber die akute (trophoneurotische) Knoche-natrophie nach EntzuÈ ndungen und Traumen der Ex-tremitaÈ ten. Deut Med Wschr 1902; 28: 336 ± 342.

7 van der Laan L et al. Complex regional pain syndrometype I (RSD): pathology of skeletal muscle andperipheral nerve. Neurology 1998; 51: 20 ± 25.

8 Schott GD. Re¯ex sympathetic dystrophy. J NeurolNeurosurg Psychiatry 2001; 71: 291 ± 295.

9 Schwartzman RJ, McLellan TL. Re¯ex sympatheticdystrophy. A review. Arch Neurol 1987; 44: 555 ± 561.

10 Oyen WJ et al. Re¯ex sympathetic dystrophy of thehand: an excessive in¯ammatory response? Pain 1993;55: 151 ± 157.

11 Blumberg H, JaÈ nig W. Clinical manifestation of re¯exsympathetic dystrophy and sympathetically maintainedpain. In: Wall and Melzack (eds). Textbook of Pain.Edinburgh: Churchill Livingstone, 1994; pp 685 ± 697.

12 Veldman PHJM. Clinical aspects of re¯ex sympatheticdystrophy. Thesis, Nijmegen, 1995.

13 Galer BS, Jensen MP. Development and preliminaryvalidation of a pain measure speci®c to neuropathicpain: the Neuropathic Pain Scale. Neurology 1997; 48:332 ± 338.

14 Price DD, Bennett GJ, Ra®i A. Psychophysical ob-servations on patients with neuropathic pain relieved bya sympathetic block. Pain 1989; 36: 273 ± 288.

15 Price DD, Long S, Huitt C. Sensory testing ofpathophysiological mechanisms of pain in patients withre¯ex sympathetic dystrophy. Pain 1992; 49: 163 ± 173.

16 Sieweke N et al. Patterns of hyperalgesia in complexregional pain syndrome. Pain 1999; 80: 171 ± 177.

17 Rommel O, Malin JP, Zenz M, JaÈ nig W. Quantitativesensory testing, neurophysiological and psychologicalexamination in patients with complex regional painsyndrome and hemisensory de®cits. Pain 2001; 93: 279 ±293.

18 Rommel O et al. Hemisensory impairment in patientswith complex regional pain syndrome. Pain 1999; 80:95 ± 101.

19 Chelimsky TC et al. Value of autonomic testing in re¯exsympathetic dystrophy.Mayo Clin Proc 1995; 70: 1029 ±1040.

20 Baron R, Maier C. Re¯ex sympathetic dystrophy: skinblood ¯ow, sympathetic vasoconstrictor re¯exes andpain before and after surgical sympathectomy. Pain1996; 67: 317 ± 326.

21 Wasner G, Drummond P, Birklein F, Baron R. The roleof the sympathetic nervous system in autonomicdisturbances and `sympathetically maintained pain' inCRPS. In: Harden RN, Baron R, JaÈ nig W (eds).Progress in Pain Research and Management, Vol. 22,Complex regional pain syndrome. Seattle: IASP Press,2001; pp 89 ± 118.

22 Birklein F, Riedl B, NeundoÈ rfer B, Handwerker HO.Sympathetic vasoconstrictor re¯ex pattern in patientswith complex regional pain syndrome. Pain 1998; 75:93 ± 100.

23 Birklein F et al. Sudomotor function in sympatheticre¯ex dystrophy. Pain 1997; 69: 49 ± 54.

24 Wasner G, Heckmann K, Maier C, Baron R. Vascularabnormalities in acute re¯ex sympathetic dystrophy(CRPS I): complete inhibition of sympathetic nerveactivity with recovery. Arch Neurol 1999; 56: 613 ± 620.

25 Wasner G et al. Vascular abnormalities in re¯exsympathetic dystrophy (CRPS I): mechanisms anddiagnostic value. Brain 2001; 124: 587 ± 599.

26 Low PA et al. Laboratory ®ndings in re¯ex sympatheticdystrophy: a preliminary report. Clin J Pain 1994; 10:235 ± 239.

27 Schwartzman RJ, Kerrigan J. The movement disorderof re¯ex sympathetic dystrophy. Neurology 1990; 40:57 ± 61.

28 Deuschl G, Blumberg H, LuÈ cking CH. Tremor in re¯exsympathetic dystrophy. Arch Neurol 1991; 48: 1247 ±1252.

29 Bhatia KP, Bhatt MH, Marsden CD. The causalgia-dystonia syndrome. Brain 1993; 116: 843 ± 851.

30 Marsden CD et al. Muscle spasms associated withSudeck's atrophy after injury. Br Med J (Clin Res Ed)1984; 288: 173 ± 176.

31 Evans JA. Re¯ex sympathetic dystrophy. Surg ClinNorth Am 1946; 26: 435 ± 448.

32 Pak TJ, Martin GM, Magness JL, Kavanaugh GJ.Re¯ex sympathetic dystrophy. Review of 140 cases.Minn Med 1970; 53: 507 ± 512.

33 Mitchell SW. Injuries of Nerves and their Consequences.New York: Dover, 1865.


71

Spinal Cord

34 Richards RL. Causalgia. A centennial review. ArchNeurol 1967; 16: 339 ± 350.

35 Baron R, JaÈ nig W. Pain syndromes with causalparticipation of the sympathetic nervous system. Anaes-thesist 1998; 47: 4 ± 23.

36 Harden RN et al. Complex regional pain syndrome: arethe IASP diagnostic criteria valid and su�cientlycomprehensive? Pain 1999; 83: 211 ± 219.

37 Galer BS, Bruehl S, Harden RN. IASP diagnosticcriteria for complex regional pain syndrome: a pre-liminary empirical validation study. InternationalAssociation for the Study of Pain. Clin J Pain 1998;14: 48 ± 54.

38 Bruehl S et al. External validation of IASP diagnosticcriteria for Complex Regional Pain Syndrome andproposed research diagnostic criteria. InternationalAssociation for the Study of Pain. Pain 1999; 81: 147 ±154.

39 Gellman H et al. Re¯ex sympathetic dystrophy in brain-injured patients. Pain 1992; 51: 307 ± 311.

40 Chalsen GG et al. Prevalence of the shoulder-hand painsyndrome in an in-patient stroke rehabilitation popula-tion: a quantitative cross-sectional study. J NeurolRehab 1987; 1: 137 ± 141.

41 Petchkrua W, Weiss DJ, Patel RR. Reassessment of theincidence of complex regional pain syndrome type 1following stroke. Neurorehabil Neural Repair 2000; 14:59 ± 63.

42 Daviet JC et al. Clinical factors in the prognosis ofcomplex regional pain syndrome type I after stroke: aprospective study. Am J Phys Med Rehabil 2002; 81:34 ± 39.

43 Davis SW, Petrillo CR, Eichberg RD, Chu DS.Shoulder-hand syndrome in a hemiplegic population: a5-year retrospective study. Arch Phys Med Rehabil 1977;58: 353 ± 356.

44 Wanklyn P, Forster A, Young J, Mulley G. Prevalenceand associated features of the cold hemiplegic arm.Stroke 1995; 26: 1867 ± 1870.

45 Korpelainen JT, Sotaniemi KA, Myllyla VV. Asymme-trical skin temperature in ischemic stroke. Stroke 1995;26: 1543 ± 1547.

46 Butler SH. Disuse and CRPS. In: Harden RN, Baron R,JaÈ nig W (eds). Progress in Pain Research and Manage-ment, Vol. 22, Complex regional pain syndrome. Seattle:IASP Press, 2001; pp 141 ± 150.

47 Riedl B et al. Autonomic failure after stroke ± is itindicative for pathophysiology of complex regional painsyndrome? Acta Neurol Scand 2001; 103: 27 ± 34.

48 Braus DF, Krauss JK, Strobel J. The shoulder-handsyndrome after stroke: a prospective clinical trial. AnnNeurol 1994; 36: 728 ± 733.

49 Fenollosa P et al. Chronic pain in the spinal cordinjured: statistical approach and pharmacological treat-ment. Paraplegia 1993; 31: 722 ± 729.

50 Waring WP, Maynard FM. Shoulder pain in acutetraumatic quadriplegia. Paraplegia 1991; 29: 37 ± 42.

51 Andrews LG, Armitage KJ. Sudeck's atrophy intraumatic quadriplegia. Paraplegia 1971; 9: 159 ± 165.

52 Gellman H et al. Re¯ex sympathetic dystrophy incervical spinal cord injury patients. Clin Orthop 1988;233: 126 ± 131.

53 Subbarao J, Stillwell GK. Re¯ex sympathetic dystrophysyndrome of the upper extremity: analysis of totaloutcome of management of 125 cases. Arch Phys MedRehabil 1981; 62: 549 ± 554.

54 Gallien P et al. The re¯ex sympathetic dystrophysyndrome in patients who have had a spinal cord injury.Paraplegia 1995; 33: 715 ± 720.

55 Philip PA, Philip M, Monga TN. Re¯ex sympatheticdystrophy in central cord syndrome: case report andreview of the literature. Paraplegia 1990; 28: 48 ± 54.

56 Lefkoe TP, Cardenas DD. Re¯ex sympathetic dystro-phy of the lower extremity in tetraplegia: case report.Spinal Cord 1996; 34: 239 ± 242.

57 Cremer SA, Maynard F, Davido� G. The re¯exsympathetic dystrophy syndrome associated with trau-matic myelopathy: report of 5 cases. Pain 1989; 37: 187 ±192.

58 Aisen PS, Aisen ML. Shoulder-hand syndrome incervical spinal cord injury. Paraplegia 1994; 32: 588 ±592.

59 Dalyan M, Sherman A, Cardenas DD. Factorsassociated with contractures in acute spinal cord injury.Spinal Cord 1998; 36: 405 ± 408.

60 ArneÂ r S. Intravenous phentolamine test: diagnostic andprognostic use in re¯ex sympathetic dystrophy. Pain1991; 46: 17 ± 22.

61 Raja SN, Treede RD, Davis KD, Campbell JN.Systemic alpha-adrenergic blockade with phentolamine:a diagnostic test for sympathetically maintained pain.Anesthesiology 1991; 74: 691 ± 698.

62 JaÈ nig W, McLachlan EM. Neurobiology of theautonomic nervous system. In: Mathias CJ, BannisterSir R (eds). Autonomic failure ± a textbook of clinicaldisorders of the autonomic nervous system. 4th edn.Oxford: Oxford University Press, 1999; pp 3 ± 15.

63 JaÈ nig W, HaÈ bler HJ. Organization of the autonomicnervous system: structure and function. In: Vinken PJ,Bruyn GW (eds). Handbook of Clinical Neurology ± TheAutonomic Nervous System, Part I: Normal Functions.Amsterdam: Elsevier Science Publishers, 1999; pp 1 ± 52.

64 JaÈ nig W, Koltzenburg M. Sympathetic re¯ex activityand neuroe�ector transmission change after chronicnerve lesions. In: Bond MR, Charlton EJ, Woolf CJ(eds). Proceedings of the VIth World Congress on Pain.Amsterdam: Elsevier Science Publishers, 1991; pp 365 ±371.

65 Baron R et al. E�ect of sympathetic activity oncapsaicin-evoked pain, hyperalgesia, and vasodilata-tion. Neurology 1999; 52: 923 ± 932.

66 Fleming WW, Westfall DP. Adaptive supersensitivity.In: Trendelenburg U, Weiner N (eds). Handbook ofExperimental Pharmacology, Vol. 90/I, Catecholamines.New York: Springer Verlag, 1988; pp 509 ± 559.

67 Kurvers HA et al. Skin blood ¯ow abnormalities in a ratmodel of neuropathic pain: result of decreased sympa-thetic vasoconstrictor out¯ow? J Auton Nerv Syst 1997;63: 19 ± 29.

68 Wakisaka S, Kajander KC, Bennett GJ. Abnormal skintemperature and abnormal sympathetic vasomotorinnervation in an experimental painful peripheralneuropathy. Pain 1991; 46: 299 ± 313.

69 Goldstein DS, Tack C, Li ST. Sympathetic innervationand function in re¯ex sympathetic dystrophy. AnnNeurol 2000; 48: 49 ± 59.

70 Drummond PD, Finch PM, Smythe GA. Re¯exsympathetic dystrophy: the signi®cance of di�eringplasma catecholamine concentrations in a�ected anduna�ected limbs. Brain 1991; 114: 2025 ± 2036.


72

Spinal Cord

71 Harden RN et al. Norepinephrine and epinephrinelevels in a�ected versus una�ected limbs in sympathe-tically maintained pain. Clin J Pain 1994; 10: 324 ± 330.

72 Blumberg H, JaÈ nig W. Re¯ex patterns in postganglionicvasoconstrictor neurons following chronic nerve lesions.J Auton Nerv Syst 1985; 14: 157 ± 180.

73 Bossut DF, Shea VK, Perl ER. Sympathetectomyinduces adrenergic excitability of cutaneous C-®bernociceptors. J Neurophysiol 1996; 75: 514 ± 517.

74 Drummond PD, Skipworth S, Finch PM. alpha 1-adrenoceptors in normal and hyperalgesic human skin.Clin Sci (Colch) 1996; 91: 73 ± 77.

75 Arnold JM et al. Increased venous alpha-adrenoceptorresponsiveness in patients with re¯ex sympatheticdystrophy. Ann Intern Med 1993; 118: 619 ± 621.

76 Casale R, Elam M. Normal sympathetic nerve activityin a re¯ex sympathetic dystrophy with marked skinvasoconstriction. J Auton Nerv Syst 1992; 41: 215 ± 219.

77 TorebjoÈ rk E. Clinical and neurophysiological observa-tions relating to pathophysiological mechanisms ofre¯ex sympathetic dystrophy. In: Stanton-Hicks M,JaÈ nig W, Boas RA (eds). Re¯ex sympathetic dystrophy.Boston, Dordrecht, London: Kluwer, 1989; pp 71 ± 80.

78 Birklein F et al. Neurological ®ndings in complexregional pain syndromes ± analysis of 145 cases. ActaNeurol Scand 2000; 101: 262 ± 269.

79 Elam M, Olausson B, Skarphedinsson JO, Wallin BG.Does sympathetic nerve discharge a�ect the ®ring ofpolymodal C-®bre a�erents in humans? Brain 1999; 122:2237 ± 2244.

80 JaÈ nig W, Levine JD, Michaelis M. Interactions ofsympathetic and primary a�erent neurons followingnerve injury and tissue trauma. Prog Brain Res 1996;113: 161 ± 184.

81 McLachlan EM, JaÈ nig W, Devor M, Michaelis M.Peripheral nerve injury triggers noradrenergic sproutingwithin dorsal root ganglia. Nature 1993; 363: 543 ± 546.

82 Shi TS, Winzer-Serhan U, Leslie F, Hokfelt T.Distribution and regulation of alpha(2)-adrenoceptorsin rat dorsal root ganglia. Pain 2000; 84: 319 ± 330.

83 Chabal C, Jacobson L, Russell LC, Burchiel KJ. Painresponse to perineuromal injection of normal saline,epinephrine, and lidocaine in humans. Pain 1992; 49: 9 ±12.

84 Raja SN, Abatzis V, Frank SM. Role of a-adrenocep-tors in neuroma pain in amputees. Anesthesiology 1998;89: A1083.

85 Walker AE, Nulsen F. Electrical stimulation of theupper thoracic portion of the sympathetic chain in man.Arch Neurol Psychiatr 1948; 59: 559 ± 560.

86 White JC, Sweet WH. Pain and the neurosurgeon.Illinois: Charles C. Thomas Spring®eld, 1969.

87 TorebjoÈ rk E et al. Noradrenaline-evoked pain inneuralgia. Pain 1995; 63: 11 ± 20.

88 Choi B, Rowbotham MC. E�ect of adrenergic receptoractivation on post-herpetic neuralgia pain and sensorydisturbances. Pain 1997; 69: 55 ± 63.

89 Ali Z et al. Intradermal injection of norepinephrineevokes pain in patients with sympathetically maintainedpain. Pain 2000; 88: 161 ± 168.

90 Baron R et al. Relation between sympathetic vasocon-strictor activity and pain and hyperalgesia in complexregional pain syndromes: a case-control study. Lancet2002; 359: 1655 ± 1660.

91 Drummond PD, Finch PM, Skipworth S, Blockey P.Pain increases during sympathetic arousal in patientswith complex regional pain syndrome. Neurology 2001;57: 1296 ± 1303.

92 Green PG, JaÈ nig W, Levine JD. Negative feedbackneuroendocrine control of in¯ammatory response in therat is dependent on the sympathetic postganglionicneuron. J Neurosci 1997; 17: 3234 ± 3238.

93 Leitha T et al. Five phase bone scintigraphy supportsthe pathophysiological concept of a subclinical in¯am-matory process in re¯ex sympathetic dystrophy. Q JNucl Med 1996; 40: 188 ± 193.

94 Calder JS, Holten I, McAllister RM. Evidence forimmune system involvement in re¯ex sympatheticdystrophy. J Hand Surg [Br] 1998; 23: 147 ± 150.

95 van der Laan L, Goris RJ. Re¯ex sympatheticdystrophy. An exaggerated regional in¯ammatoryresponse? Hand Clin 1997; 13: 373 ± 385.

96 Christensen K, Jensen EM, Noer I. The re¯ex dystrophysyndrome response to treatment with systemic corticos-teroids. Acta Chir Scand 1982; 148: 653 ± 655.

97 Renier JC et al. The joint in algodystrophy. Joint ¯uid,synovium, cartilage. Rev Rhum Mal Osteoartic 1983; 50:255 ± 260.

98 Kozin F, McCarty DJ, Sims J, Genant H. The re¯exsympathetic dystrophy syndrome. I. Clinical andhistologic studies: evidence for bilaterality, response tocorticosteroids and articular involvement. Am J Med1976; 60: 321 ± 331.

99 Hannington-Ki� JG. Relief of Sudeck's atrophy byregional intravenous guanethidine. Lancet 1977; 1:1132 ± 1133.

100 Graif M et al. Synovial e�usion in re¯ex sympatheticdystrophy: an additional sign for diagnosis and staging.Skeletal Radiol 1998; 27: 262 ± 265.

101 Weber M, Birklein F, Neundorfer B, Schmelz M.Facilitated neurogenic in¯ammation in complex regio-nal pain syndrome. Pain 2001; 91: 251 ± 257.

102 Birklein F, Schmelz M, Schifter S, Weber M. Theimportant role of neuropeptides in complex regionalpain syndrome. Neurology 2001; 57: 2179 ± 2184.

103 Huygen FJ et al. Evidence for local in¯ammation incomplex regional pain syndrome type 1. MediatorsIn¯amm 2002; 11: 47 ± 51.

104 Hartrick CT. Increased production of nitric oxidestimulated by interferon-gamma from peripheral bloodmonocytes in patients with complex regional painsyndrome. Neurosci Lett 2002; 323: 75 ± 77.

105 Levine JD, Taiwo YO, Collins SD, Tam JK. Noradrena-line hyperalgesia is mediated through interaction withsympathetic postganglionic neurone terminals ratherthan activation of primary a�erent nociceptors. Nature1986; 323: 158 ± 160.

106 Perl ER. Cutaneous polymodal receptors: characteris-tics and plasticity. Prog Brain Res 1996; 113: 21 ± 37.

107 Levine JD et al. Clinical response to regional intrave-nous guanethidine in patients with rheumatoid arthritis.J Rheumatol 1986; 13: 1040 ± 1043.

108 Galer BS, Butler S, Jensen MP. Case reports andhypothesis: a neglect-like syndrome may be responsiblefor the motor disturbance in re¯ex sympatheticdystrophy (Complex Regional Pain Syndrome-1). JPain Symptom Manage 1995; 10: 385 ± 391.


73

Spinal Cord

109 Galer BS, Jensen M. Neglect-like symptoms in complexregional pain syndrome: results of a self-administeredsurvey. J Pain Symptom Manage 1999; 18: 213 ± 217.

110 Schattschneider J, Wenzelburger R, Deuschl G, BaronR. Kinematic analysis of the upper extremity in CRPS.In: Harden RN, Baron R, JaÈ nig W (eds). Progress inPain Research and Management, Vol. 22, Complexregional pain syndrome. Seattle: IASP Press, 2001; pp119 ± 128.

111 Maleki J, LeBel AA, Bennett GJ, Schwartzman RJ.Patterns of spread in complex regional pain syndrome,type I (re¯ex sympathetic dystrophy). Pain 2000; 88:259 ± 266.

112 Woolf CJ, Mannion RJ. Neuropathic pain: aetiology,symptoms, mechanisms, and management. Lancet 1999;353: 1959 ± 1964.

113 Juottonen K et al. Altered central sensorimotorprocessing in patients with complex regional painsyndrome. Pain 2002; 98: 315 ± 323.

114 Thimineur M et al. Central nervous system abnormal-ities in complex regional pain syndrome (CRPS): clinicaland quantitative evidence of medullary dysfunction.Clin J Pain 1998; 14: 256 ± 267.

115 Fukumoto M et al. Contralateral thalamic perfusion inpatients with re¯ex sympathetic dystrophy syndrome.Lancet 1999; 354: 1790 ± 1791.

116 Apkarian AV, Thomas PS, Krauss BR, Szeverenyi NM.Prefrontal cortical hyperactivity in patients withsympathetically mediated chronic pain. Neurosci Lett2001; 311: 193 ± 197.

117 Shibata M et al. A case of re¯ex sympathetic dystrophy(complex regional pain syndrome, type I) resolved bycerebral contusion. Pain 1999; 79: 313 ± 315.

118 Mailis A, Wade J. Pro®le of Caucasian women withpossible genetic predisposition to re¯ex sympatheticdystrophy: a pilot study. Clin J Pain 1994; 10: 210 ± 217.

119 Kemler MA et al. HLA-DQ1 associated with re¯exsympathetic dystrophy. Neurology 1999; 53: 1350 ±1351.

120 Mailis A, Wade JA. Genetic considerations in CRPS.In: Harden RN, Baron R, JaÈ nig W (eds). Progress inPain Research and Management, Vol. 22, Complexregional pain syndrome. Seattle: IASP Press, 2001; pp227 ± 238.

121 van de Beek WJ, Remarque EJ, Westendorp RG, vanHilten JJ. Innate cytokine pro®le in patients withcomplex regional pain syndrome is normal. Pain 2001;91: 259 ± 261.

122 Ochoa JL. Truths, errors, and lies around `re¯exsympathetic dystrophy' and `complex regional painsyndrome'. J Neurol 1999; 246: 875 ± 879.

123 Verdugo RJ, Ochoa JL. Abnormal movements incomplex regional pain syndrome: assessment of theirnature. Muscle Nerve 2000; 23: 198 ± 205.

124 Ciccone DS, Bandilla EB, Wu W. Psychologicaldysfunction in patients with re¯ex sympathetic dystro-phy. Pain 1997; 71: 323 ± 333.

125 Van Houdenhove B et al. Etiopathogenesis of re¯exsympathetic dystrophy: a review and biopsychosocialhypothesis. Clin J Pain 1992; 8: 300 ± 306.

126 van der Laan L, van Spaendonck K, Horstink MW,Goris RJ. The Symptom Checklist-90 Revised ques-tionnaire: no psychological pro®les in complex regionalpain syndrome-dystonia. J Pain Symptom Manage 1999;17: 357 ± 362.

127 Geertzen JH et al. Stressful life events and psychologicaldysfunction in Complex Regional Pain Syndrome type I.Clin J Pain 1998; 14: 143 ± 147.

128 van de Beek WJ et al. Diagnostic criteria used in studiesof re¯ex sympathetic dystrophy. Neurology 2002; 58:522 ± 526.

129 Kozin F et al. Bone scintigraphy in the re¯exsympathetic dystrophy syndrome. Radiology 1981; 138:437 ± 443.

130 Zyluk A. The usefulness of quantitative evaluation ofthree-phase scintigraphy in the diagnosis of post-traumatic re¯ex sympathetic dystrophy. J Hand Surg[Br] 1999; 24: 16 ± 21.

131 Wahren LK, Torebjork E, Nystrom B. Quantitativesensory testing before and after regional guanethidineblock in patients with neuralgia in the hand. Pain 1991;46: 23 ± 30.

132 Wahren LK, Torebjork E. Quantitative sensory tests inpatients with neuralgia 11 to 25 years after injury. Pain1992; 48: 237 ± 244.

133 SchuÈ rmann M et al. Assessment of peripheral sympa-thetic nervous function for diagnosing early post-traumatic complex regional pain syndrome type I. Pain1999; 80: 149 ± 159.

134 Gulevich SJ et al. Stress infrared telethermography isuseful in the diagnosis of complex regional painsyndrome, type I (formerly re¯ex sympathetic dystro-phy). Clin J Pain 1997; 13: 50 ± 59.

135 Bruehl S, Lubenow TR, Nath H, Ivankovich O.Validation of thermography in the diagnosis of re¯exsympathetic dystrophy. Clin J Pain 1996; 12: 316 ± 325.

136 Wasner G, Schattschneider J, Maier C, Baron R. Skintemperature side di�erences ± a diagnostic tool forCRPS? Pain 2002; 98: 19 ± 26.

137 Kingery WS. A critical review of controlled clinicaltrials for peripheral neuropathic pain and complexregional pain syndromes. Pain 1997; 73: 123 ± 139.

138 Perez RS, Kwakkel G, Zuurmond WW, de Lange JJ.Treatment of re¯ex sympathetic dystrophy (CRPS type1): a research synthesis of 21 randomized clinical trials. JPain Symptom Manage 2001; 21: 511 ± 526.

139 Rowbotham MC, Reisner-Keller LA, Fields HL. Bothintravenous lidocaine and morphine reduce the pain ofpostherpetic neuralgia. Neurology 1991; 41: 1024 ± 1028.

140 Watson CP et al. Amitriptyline versus placebo inpostherpetic neuralgia. Neurology 1982; 32: 671 ± 673.

141 Max MB. Treatment of post-herpetic neuralgia: anti-depressants. Ann Neurol 1994; 35 Suppl: S50 ± 53.

142 MaxMB et al. E�ects of desipramine, amitriptyline, and¯uoxetine on pain in diabetic neuropathy. N Engl J Med1992; 326: 1250 ± 1256.

143 Dejgard A, Petersen P, Kastrup J. Mexiletine fortreatment of chronic painful diabetic neuropathy.Lancet 1988; 1: 9 ± 11.

144 Wallace MS et al. Concentration-e�ect relationship ofintravenous lidocaine on the allodynia of complexregional pain syndrome types I and II. Anesthesiology2000; 92: 75 ± 83.

145 Mellick GA, Mellicy LB, Mellick LB. Gabapentin in themanagement of re¯ex sympathetic dystrophy. J PainSymptom Manage 1995; 10: 265 ± 266.

146 Davis KD et al. Topical application of clonidine relieveshyperalgesia in patients with sympathetically main-tained pain. Pain 1991; 47: 309 ± 317.


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Spinal Cord

147 Byas-Smith MG, Max MB, Muir J, Kingman A.Transdermal clonidine compared to placebo in painfuldiabetic neuropathy using a two-stage `enriched enroll-ment' design. Pain 1995; 60: 267 ± 274.

148 Gobelet C, Waldburger M, Meier JL. The e�ect ofadding calcitonin to physical treatment on re¯exsympathetic dystrophy. Pain 1992; 48: 171 ± 175.

149 Adami S et al. Bisphosphonate therapy of re¯exsympathetic dystrophy syndrome. Ann Rheum Dis1997; 56: 201 ± 204.

150 Varenna M et al. Intravenous clodronate in thetreatment of re¯ex sympathetic dystrophy syndrome.A randomized, double blind, placebo controlled study. JRheumatol 2000; 27: 1477 ± 1483.

151 Schott GD. Interrupting the sympathetic out¯ow incausalgia and re¯ex sympathetic dystrophy. Bmj 1998;316: 792 ± 793.

152 Verdugo RJ, Ochoa JL. `Sympathetically maintainedpain.' I. Phentolamine block questions the concept.Neurology 1994; 44: 1003 ± 1010.

153 Price DD, Long S, Wilsey B, Ra®i A. Analysis of peakmagnitude and duration of analgesia produced by localanesthetics injected into sympathetic ganglia of complexregional syndrome patients. Clin J Pain 1998; 14: 216 ±226.

154 Reuben SS, Rosenthal EA, Steinberg RB. Surgery onthe a�ected upper extremity of patients with a history ofcomplex regional pain syndrome: a retrospective studyof 100 patients. J Hand Surg [Am] 2000; 25: 1147 ± 1151.

155 Blanchard J et al. Intravenous regional sympatholysis: adouble-blind comparison of guanethidine, reserpine,and normal saline. J Pain Symptom Manage 1990; 5:357 ± 361.

156 Jadad AR, Carroll D, Glynn CJ, McQuay HJ.Intravenous regional sympathetic blockade for painrelief in re¯ex sympathetic dystrophy: a systematicreview and a randomized, double-blind crossover study.J Pain Symptom Manage 1995; 10: 13 ± 20.

157 Ramamurthy S, Ho�man J. Intravenous regionalguanethidine in the treatment of re¯ex sympatheticdystrophy/causalgia: a randomized, double-blind study.Guanethidine Study Group. Anesth Analg 1995; 81:718 ± 723.

158 Kumar K, Nath RK, Toth C. Spinal cord stimulation ise�ective in the management of re¯ex sympatheticdystrophy. Neurosurgery 1997; 40: 503 ± 508; discussion508 ± 509.

159 Kemler MA et al. Spinal cord stimulation in patientswith chronic re¯ex sympathetic dystrophy. N Engl JMed 2000; 343: 618 ± 624.

160 Kemler MA, Barendse GA, van Kleef M, Egbrink MG.Pain relief in complex regional pain syndrome due tospinal cord stimulation does not depend on vasodila-tion. Anesthesiology 2000; 92: 1653 ± 1660.

161 Kemler MA et al. Impact of spinal cord stimulation onsensory characteristics in complex regional pain syn-drome type I: a randomized trial. Anesthesiology 2001;95: 72 ± 80.

162 Hassenbusch SJ et al. Long-term results of peripheralnerve stimulation for re¯ex sympathetic dystrophy. JNeurosurg 1996; 84: 415 ± 423.

163 Rauck RL et al. Epidural clonidine treatment forrefractory re¯ex sympathetic dystrophy. Anesthesiology1993; 79: 1163 ± 1169.

164 Takahashi H et al. The NMDA-receptor antagonistketamine abolishes neuropathic pain after epiduraladministration in a clinical case. Pain 1998; 75: 391 ±394.

165 van Hilten BJ et al. Intrathecal baclofen for thetreatment of dystonia in patients with re¯ex sympatheticdystrophy. N Engl J Med 2000; 343: 625 ± 630.

166 Lee BH et al. Physical therapy and cognitive-behavioraltreatment for complex regional pain syndromes. JPediatr 2002; 141: 135 ± 140.

167 Sherry DD et al. Short- and long-term outcomes ofchildren with complex regional pain syndrome type Itreated with exercise therapy. Clin J Pain 1999; 15: 218 ±223.

168 Oerlemans HM, Oostendorp RA, de Boo T, Goris RJ.Pain and reduced mobility in complex regional painsyndrome I: outcome of a prospective randomisedcontrolled clinical trial of adjuvant physical therapyversus occupational therapy. Pain 1999; 83: 77 ± 83.

169 Baron R, Levine JD, Fields HL. Causalgia and re¯exsympathetic dystrophy: does the sympathetic nervoussystem contribute to the pain?. Muscle Nerve 1999; 22:678 ± 695.

170 Baron R, Binder A, Ullrich W, Maier C. Komplexeregionale Schmerzsyndrome. Nervenarzt 2002; 73: 305 ±320.


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