Neuroscience & Medicine, 2012, 3, 225-242 Published Online September 2012 ( 225
Systemic Complications of Complex Regional Pain
Robert J. Schwartzman
Department of Neurology, Drexel University College of Medicine, Philadelphia, USA.
Received July 18th, 2012; revised August 15th, 2012; accepted August 22nd, 2012
Complex Regional Pain Syndrome (CRPS) is a neuropathic pain disorder that is characterized by: 1) Severe pain be-
yond the area of injury; 2) Autonomic dysregulation; 3) Neuropathic edema; 4) A movement disorder, atrophy and dys-
trophy. It is most often caused by a fracture, soft-tissue injury or surgical procedure and is divided into Type I, in which
no nerve lesion is identified (classic reflex sympathetic dystrophy), and Type II where a specific nerve has been dam-
aged (causalgia). In addition to the periph eral manifestations, there are many internal medical complications whose eti-
ology is often not appreciated. This article will examine how CRPS affects the systems of: cognition; constitutional,
cardiac, and respiratory complications; systemic autonomic dysregulation; neurogenic edema; musculoskeletal, endo-
crine and dermatological manifestations; as well as urological and gastrointestinal function.
Keywords: Complex Regional Pai n Syndrome; CRPS; CR PS-1; C RPS-2; Chronic Pai n; Reflex Sym pathetic Dy strophy ;
1. Introduction
Complex Regional Pain Syndrome (CRPS) is a neuro-
pathic pain disorder that is characterized by: 1) Severe
pain beyond the area of injury; 2) Autonomic dysregula-
tion; 3) Neuropathic edema; 4) A movement disorder,
atrophy and dystrophy [1]. It is most often caused by a
fracture, soft-tissue injury or surgical procedure and is
divided into Type I, in which no n erve lesion is id entified
(classic reflex sympathetic dystrophy), and Type II
where a specific nerve has been damaged (causalgia).
Converging evidence suggests that CRPS-I is due to in-
jury and distal degeneration of axons and terminal twigs
of A-δ and C fibers [2]. Cluster analysis reveals that the
signs and symptoms in the syndrome comprise four dis-
tinct groups: 1) Abnormalities in pain processing (me-
chanical and thermal allodynia; hyperalgesia, and hyper-
pathia); 2) Temperature change and erythema, cyanosis
or mottling; 3) Neurogenic edema and sudomotor dys-
regulation; 4) A motor syndrome and trophic changes
[3-7]. There may be subtypes: 1) A limited syndrome
with predominant autonomic dysregulation; 2) A syn-
drome limited to one extremity that is characterized by
neuropathic pain with minimal autonomic dysregulation
and neurogenic edema; 3) A severe disorder that has
spread from the site or original injury, is long standing
and comprises all components of the syndrome [4]. The
present diagnostic criterion requires at least one symptom
in each of the four factors and one sign in at least two of
the four factors [7]. In general, early in the course of the
disease patients demonstrate prominent inflammatory
signs and symptoms that include neurogenic edema, ery-
thema and an increased temperature of the affected ex-
tremity while long standing patients suffer pain spread
and an apparent centralization of the process with con-
comitant severe generalized autonomic motor and trophic
changes of skin, nails, bone and muscle [1,8-11].
The epidemiology of the syndrome is uncertain . Many
patients diagnosed with fibromyalgia clearly have CRPS,
the pressure points being components of the brachial
plexus, the intercostobrachial (ICB) nerve and concomi-
tant L5-S1, injury [12,13]. The most representative popu-
lation-based study from the Netherlands revealed an in-
cidence of 40.4 females and 11.9 males per 100,000 per-
son-years at risk [14]. The variable incidence reported
are due to the cohorts studied, the time period in the
course of the disease in which they were studied and the
skill of the examiners [15-19].
The purpose of this article is to discuss the systemic
medical complications of CRPS. As Janig has pointed
out, with time CRPS centralizes to affect somatosensory,
autonomic and limbic components of the syndrome [20].
The immune component of neuropathic pain is now
viewed as pivotal to both in its initiation and mainte-
nance. Many of the features seen peripherally occur in
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Systemic Complications of Complex Regional Pain Syndrome
systemic organs.
2. Neuropsychological Deficits Associated
with CRPS
Severe neuropathic chronic pain is associated with poor
performance on neuropsychological tests that assess
working memory, language and executive function
[21-23]. Patients whose pain was due to a variety of un-
derlying medical conditions demonstrated decreased in-
formation processing speed [24].
Over 500 patients with severe CRPS (met all IASP
criteria [25]) underwent a battery of neuropsychological
tests that assesses executive systems function, naming/
lexical retrieval, memory and learning prior to treatment
with an outpatient ketamine protocol. The assessment
method is based on the work of Libon et al. [26]. Execu-
tive system function was measured by the digit span
subtest from the Wechsler Adult Intelligence Scale-III
(WAIS-III) [27]. The digits backward portion of the test
was used to evaluate working memory deficits [28,29].
Executive function was also evaluated by tests of letter
fluency which activate the left dorsolateral prefrontal
cortex in both young and older patients [30]. Naming
was assessed with the Boston Naming Test [31] and
lexical retrieval by a test of semantic fluency [32]. Con-
verging evidence supports category fluency tests as a
measure of lexical retrieval and semantic k nowledge that
activate the left temporal lobe [33,34]. Memory and
learning was evaluated by the California Verbal Learning
Test-II [35]. Delayed free recall and delayed recognition
discrimination index have been linked to parahippocam-
pal atrophy and the presence of anterograde amnesia [29].
Adjunctive tests administered with the above were the
McGill Pain Inventory [36] and the Beck Depression
Inventory-II [37]. The patterns of neuropsychological
impairment seen in this large cohort of CRPS patients
were determined by a statistical cluster algorithm which
demonstrated three distinct groups. Approximately 35%
of patients had no neuropsychological deficits, group I.
The second, group II, 42% of patients had mild
dysexecutive deficits. Group III, 22% of patients had
cognitive impairment that included poor performance on
tests of executive function, naming and memory. Both
affected CRPS groups II and III (65%) of patients) had
difficulty with repeating numbers backward. This func-
tion is thought to demonstrate higher-order mental ma-
nipulation that depends on working memory and visual
imagery mechanisms [26]. There is also evidence that
decreased output on letter fluency and poor performance
on a backwards digit span test are correlated with left
inferior frontal lobe pathology [34]. CRPS group III pa-
tients’ memory deficits suggest executive (retrieval)
rather than amnesic (encoding) dysfunction. The im-
provement of this group in the delayed recognition test
suggests impairment of frontal memory systems [38].
This detailed evaluation of over 500 patients suggests
that a wide network of cortical and subcortical anatomi-
cal nodes is involved in the illness and that a dysexecu-
tive syndrome is the primary deficit. A neurocognitive
study on nine patients prior to and following a ketamine
anesthesia protocol [39] by Koffler demonstrated im-
provement in brief auditory attention and processing
speed [40]. Levels of depression and extent (number of
limbs involved) or duration of illness is not a factor in
these cognitive changes.
Functional MRI (fMRI) studies in patients with CRPS-
I and II have given insights into cognitive function and
activity dependen t neuroplasticity in this illn ess. There is
clear alteration of the CRPS hand representation in the
primary somatosensory cortex (SI) cortex of the affected
versus unaffected side [41-44]. The side opposite the
affected hand is decreased or increased [44] in parallel
with the degree of mechanical hyperalgesia and pain in-
tensity [41,42] which reversed with recovery [42,43]. In
a recent study, patients with CRPS estimated their hand
size of the affected extremity to be larger when compared
to expanded or compressed schematic drawings of hands.
The overestimation correlated with disease duration, in-
creased two-point discrimination and neglect score [44].
In addition to tactile and proprioceptive deficits [45], a
significant proportion of CRPS patients feel as if their
hand is “foreign or strange” [46] or not belonging to their
body [47]. Studies with fMRI during electrical stimula-
tion of both index fingers revealed smaller signals in both
contralateral SI and secondary somatosensory cortices
(SII) that were associated with impaired 2-point dis-
crimination deficits. This suggests that patterns of corti-
cal reorganization in both SI and SII parallel impaired
tactile discrimination [48] and pain intensity. In addition
to plastic aberrations of the body schema in CRPS pa-
tients, increased activation of areas thought to process
affective components of pain, the cingulate gyrus and
frontal cortices have been demonstrated that may persist
after recovery [41,49]. A recent paper describes the
neuropsychological dissociation in which a CRPS patient
had preservation of object recognition and naming but
was unable to recognize object orientation (agnosia for
object orientation) [50]. This finding may be consistent
with a previous fMRI study that demonstrated aberrant
activation within the intraparietal sulcus (a multimodal
association area) and was associated with motor dysfunc-
tion [51]. The impaired spatial orientation demonstrated
by this patient suggests posterior parietal dysfunction.
The impaired cognitive function demonstrated by
these studies may also be associated with structural brain
changes demonstrated in other severe neuropathic pain
states and in CRPS patients maybe at least partially re-
versible [40,52]. Factors that also have to be considered
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Systemic Complications of Complex Regional Pain Syndrome 227
in the cognitive performance of patients with severe
neuropathic CRPS pain are medication, stress, and dis-
traction that detract from working memory [53,54]. A
recent experimental study on resolving postoperative
neuroinflammation and cognitive decline suggests a
mechanism for the neuropsychological deficits defined in
CRPS patients [55]. In C57BL/6J and other species of
mice, peripheral surgery was shown to cause disruption
of the blood brain barrier (BBB). The proposed mecha-
nism was release of tumor necrosis factor-alpha (TNF-α)
that facilitated the migration of macrophages into the
hippocampus by activation of nuclear factor kappa B
(NF-κB). This signaling pathway induces neuroinflam-
mation, microglial activation and release of proinflam-
matory cytokines. Activation of the alpha7 nAChR (ace-
tylcholine receptor) prevented the migration of mono-
cyte-derived macrophages into the CNS. Entry of leuko-
cyte like CD4 + T cells may be mediated by NF-κB am-
plification of interleukin-6 (IL-6) that is expressed in
cerebral endothelial cells and can lead to increased ex-
pression and accumulation of inflammatory cytokines.
This endothelial activation and breakdown of the BBB
may be initiated by peripheral nerve injury [5 6].
3. Constitutional Symptoms
CRPS-I and CRPS-II are systematic diseases which can
potentially affect any organ system [1,15]. Almost all
severely affected patients (those with more that one ex-
tremity involved) have complaints of lethargy, tiredness,
or weakness—the etiology of which is multifactorial.
Following injury mast cells, macrophages, leukocytes are
activated and recruited to the involved area [57]. As the
illness progresses proinflammatory cytokines increase in
the serum and cerebrospinal fluid (TNF-α and IL-6)
while anti-inflammatory cytokines Interleukin-4 (IL-4)
and Interleukin-10 (IL-10) decline [57-65]. Inflammatory
cytokines act both peripherally at th e site of injury and in
the CNS at multiple levels in the pain matrix [57]. In
patients with long-standing disease the percentage of
CD14+ and CD16+ monocyte/macrophage activity (pro-
inflammatory) in the serum increases although the total
monocyte count remains normal [66] and anti-inflam-
matory cytokines such as IL-10 decreases. Further evi-
dence for autoimmune mechanisms in the pathophysiol-
ogy of the constitutional symptoms noted in CRPS is
suggested by the finding that approximately 35% of pa-
tients have surface-binding autoantibodies against sym-
pathetic and mesenteric plexus neurons [67,68].
The body’s initial nonspecific immune activation fol-
lowing injury or infection is evident within hours and is
called the sickness response. It is initiated by immune
system to brain interactions that trigger a cascade of
nervous system reactions that include pain facilitation
As noted above, inflammatory cytokines are released
from activated immune cells at the site of injury. Inter-
leukin-1 (IL-1), IL-6 and TNF-α activate specialized
sensory structures, paraganglia, that synapse with sen-
sory vagal fibers [70-72]. Sickness-induced pain facilita-
tion can be blocked in experimental neuropathic pain
models by IL-1 receptor antagonists, TNF-α binding
protein or subdiaphragmatic vagotomy [73-77]. The se-
vere fatigue suffered by CRPS patients may result in part
from the sickness response circuitry [76]. Other contrib-
uting comorbidities are disruptions of sleep architecture,
hypothyroidism, secondary hypoadrenalism from a chro-
nic stress response, deconditioning and severe depress-
4. Cardiac Complications of CRPS
Approximately 2500 CRPS patients with disease dura-
tion of greater than 2 years and at least two-extremity
involvement have been evaluated at the Drexel Univer-
sity Pain Clinic. Five hundred had EKG and echocardio-
gram evaluation prior to sub-anesthetic ketamine treat-
ment. There were no specific EKG abnormalities other
than a higher than normal pulse rate ranging from 80 -
100 beats per minute. The ejection fraction was between
50% - 65% which did not differ from control male and
female controls. Approximately 10% of patients describ-
ed syncope or presyncope during the course of their ill-
ness [78]. Seventy four patients underwent head-up tilt
test (HUTT) to evaluate their complaints of syncope and
were compared to an age and gender-matched compara-
tor group and to literature standards of control patients
that underwent HUTT. The mean duration of CRPS of
the tested patients was 6.5 years whose average pain on a
Likert numeric scoring system was 7.7 (0 being no pain
and 10 being the worst pain imaginable). All patients
were extremely ill and had some spread of pain from the
original site of injury. Twenty nine patients (39%) had
generalized total body CRPS. Eight patients were not
able to complete a HUTT due to pain. Twenty eight
(42.4%) CRPS patients out of the sixty six tested had a
positive HUTT that could be classified as: 1) 17 (61%)
mixed response (heart rate decreased by greater that 10%
but does not decrease to less than 40 beats per minute for
greater than 10 seconds and the blood pressure fell prior
to heart rate; 2) 1 patient (4%) had cardioinhibition
without asystole in which blood pressure falls before
heart rate; 3) Two patients (7.1%) had a cardioinhibitory
response with asystole in which the blood pressure fell
prior to a decreased heart rate. Three patients (11%)
demonstrated a vasodepressor response in which the
heart rate does not fall greater than 10% from the maxi-
mum rate during tilt. The fall in blood pressure however
precipitates syncope [79]. The majority of CRPS patients
(23/28; 88%) required nitroglycerine provocation to in-
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Systemic Complications of Complex Regional Pain Syndrome
duce a positiv e HUTT. There was no correlatio n between
specific pain characteristics (dynamic or static mechani-
cal allodynia, hyperalgesia or hyperpathia) or duration of
illness with positive a head-up tilt test although it oc-
curred more frequently in younger patients. CRPS pa-
tients were 4.5 times more likely to have a positive
HUTT than age and gender-matched control subjects.
There was no significant difference in heart rate variabil-
ity between CRPS patients with or without a positive
HUTT. Fifty four percent of our HUTT-positive CRPS
patients were less than 40 years of age. Approximately
38% of the CRPS patients that completed the study had
at least one prior complaint of presyncope or syncope.
CRPS patients with involvement of the lower limbs are
more likely to have vasovagal syncope and positive or-
thostatic HUTT than those with upper extremity or total
body disease. Patients with CRPS have an enhanced pre-
disposition to neurocardiogenic syncope during head-up
tilt table testing compared to the vasovagal response of
historical controls of asymptomatic subjects [80-83]. In
children and adolescents with CRPS the tilt test demon-
strates orthostatic stability but a higher mean heart rate
with tilt than in control subjects [84]. Another recent
study of twenty age, sex and body-mass index-matched
control subjects demonstrated increased heart rate and
decreased heart rate variability in CRPS patients during
rest, mental and orthostatic stress. Baroreceptor sensitiv-
ity was maintained [85]. During a 60 degree tilt, CRPS
patients had a drop in cardiac output and an exaggerated
increase in total peripheral resistance. The autonomic
changes correlated with disease duration but not pain
intensity. The authors concluded that the increased heart
rate and decreased heart rate variability was due to a
generalized autonomic imbalance and increased their
susceptibility to sud den death [85]. Evid ence is emerging
that measures of reduced heart rate variability may be a
prognostic factor for cardiac arrhythmias [86].
Atypical chest pain is a common complaint of patients
with CRPS. Most of these patients have suffered a neu-
ropathic ICB nerve traction injury [13]. Atypical chest
pain often presents in young women who uncommonly
have coronary artery disease (CAD). If CAD is present,
they have a 7% higher risk of death than age matched
men [87]. Noninvasive cardiac screening tests that in-
clude stress EKG are less sensitive in female patients
[88]. This often leads to coronary arteriography in these
patients where the ICB nerve is generating the chest pain.
Approximately 25% of all coronary angiograms are
negative in the general popu lation and no positive stud ies
have been seen in our young patients with sensitized ICB
nerves from trauma or CRPS [89]. Most of our patients
with chest pain complained of anterior lateral and under
the breast pain and received extensive cardiac evalua-
tions that ended with negative catheter studies. The pa-
tients themselves did not think that their chest pain was
related to their CRPS. The majority of chest pain re-
ported by these patients (n = 35 in the Rasmussen study)
[13] was bilateral (66%), radiated to the jaw/head/neck
(concomitant cervical plexus C2-C4 involvement) [90]
and the brachial plexus distributions in the shoulder and
arm (46%). The majority of these patients that sought
care from their primary care physicians received an EKG
(79%) or were diagnosed with chest pain of unknown
origin (26%); costochondritis (21%); psychosomatic ill-
ness (21%); cardiac disease (16%); Gastroesophageal
reflux disease (GERD) (5%); hormonal disorders (11%)
and diseases of unknown etiology (26%).
In the CRPS patients, only 40% described their pain or
burning while most (60%) felt it as deep or aching. Ap-
proximately 65% of CRPS patients could elicit the chest
pain by elevating their arm and stretching the brachial
plexus that in turn would cause traction on the ICB nerve.
It has been demonstrated experimentally that nerve injury
over time induces pain markers on somatic mechanical
afferent nerves which then activate dorsal horn pain
transmission neurons [91]. The anatomy of the nerve
explains its radiations and how discharge in its territory
can easily be confused with coron ary artery pain . It arises
from the second intercostal nerve (T2) with variable con-
tributions from T3 and T4 nerve roots [92,93]. The ICB
nerve innervates the axilla, medial and anterior arm as
well as contributing to the innervation with the posterior
antebrachial cutaneous nerve. It innervates the anterior
chest wall by connections to the long thoracic nerve [92,
93] and on occasion innervates the pectoralis minor and
major muscles [93]. In thirty percent of patients the ICB
nerve is connected to the brachial plexus from the medial
cord [94]. T2 is the primary root of the ICB nerve and
connects to the brachial plexus 100% of the time, either
via the ICB nerve (80%) or from direct intrathoracic
connections in 20% of patients [95]. The nerve is very
frequently injured during breast surgery [96-98] which
may also cause CRPS.
5. Respiratory System
In the longitudina l study of 270 con secutiv e patien ts with
moderate to severe CRPS, shortness of breath was re-
ported in 42 (15.5%) [1]. Evaluation of these patients
revealed subsegmental atelectasis on chest x-ray in 33%,
low lung volume in 16.7% and only one patient (0.5%)
had evidence of chronic obstructive lung disease (COPD).
One patient had mild congestive heart failure. Hilar ade-
nopathy and small pleural effusions were noted in three
patients. Nine of the 42 patients underwent formal pul-
monary function tests. Five had restrictive lung disease
and two had mild restrictive lung disease. One patient
had normal studies.
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Systemic Complications of Complex Regional Pain Syndrome 229
In addition to these non-specific pulmonary abnor-
malities, many patients complain of not being able to
take a deep breath. Dystonia of the chest wall muscles is
common in severe long-standing patients but no epide-
miological studies have been done that would determine
its incidence and prevalence. Dystonia is a major com-
ponent of the movement disorder of CRPS [99-102].
That it can affect chest wall muscles causing restrictive
lung disease has only recently been recognized [103]. In
general, the presence of dystonia in CRPS patients is
associated with a younger age and longer duration of
disease [101]. The onset of dystonia is variable but may
precede other manifestations of the disease [99]. Another
cause of chest wall discomfort that prevents patients
from normal inspiration is irritation of the ICB nerve th at
often innervates pectoral and intercostal muscles [13].
Involvement of this nerve is most often confused with
cardiac pain if it occurs on the left side and gall bladder
disease if it is in the right chest wall.
6. Systemic Manifestations of Autonomic
Dysregulation in CRPS
Failure of a compensatory reflex-induced increase in
heart rate when blood pressure falls is a manifestation of
autonomic dysregulation which has both peripheral and
CNS comp onents [2 0]. The af fecte d extremitie s of CRPS
patients are most often warm early in the course of the
illness and then be come cold which sug gests a change in
activity of the vasoconstrictor neurons in the spinal inter
mediolateral column [104]. Clinical studies utilizing
whole body warming and cooling combined with respi-
ratory stimuli were utilized to evaluated CRPS patients
who suffered various durations of the illness [105,106].
Those patients with less than four months of disease had
a warm extremity and higher skin perfusion values than
the unaffected extremity. Norepinepherine concentration
from the affected extremity was decreased [106]. In those
patients with mean disease duration of 15 months had
either a warmer or cooler affected extremity that de-
pended on variable sympathetic activity. Patients with
cold affected extremities had disease duration of a mean
of 28 months and also demonstrated low norepinephrine
concentrations in the venous effluent from the affected
extremity [106]. In a significant portion of long standing
patients sympathetic vasoconstriction returns to normal
although the affected extremity is cold [106]. It has been
postulated that early in the illn ess there is central n ervous
system efferent autonomic dysregulation while over time
there may be increased density or sensitivity of blood
vessel noradrenergic receptors to circulating norepineph-
rine from the adrenal gland [107-110]. Earlier studies
utilizing laser Doppler fluxemetery found that the normal
reduction of skin blood flow from activation of the sym-
pathetic efferents by a Valsalva maneuver or cold presser
test was absent in CRPS patients. Sympathetic innerva-
tion of arterioles is the major innervation that controls
blood flow to capillaries in the extremities. Vasomotion,
the normal sympathetically mediated spontaneous wave-
like fluctuations in veins are also reduced or absent in
CRPS patients [110]. These earlier studies are supported
by another study that demonstrated sympathetically in-
duced vasoconstriction is reduced in early CRPS patients
which returns to normal over time [106,111,112]. That
sympathetic dysfunction maybe an early component of
any post-traumatic neuropathy was suggested by a ther-
mographic study of 200 inj uries suff ered b y 1000 recr u its
during basic training [113]. Immobilization of an injured
limb may also induce temperature changes in an injured
extremity and maybe a risk factor for the subsequent de-
velopment of CRPS [114,115]. Sudomotor dysfunction is
common in CRPS patients both early and late in the
course of illness. It usually manifests as an increased
resting sweat output of the affected extremity [116].
Sweat glands normally respond to cholinergic stimula-
tion but an adrenergic sweat response may occur in
CRPS-affected limbs following iontophoresis of an alpha-
adrenergic agonist [117]. This suggests that in CRPS
there is activation of systems that are not normally under
adrenergic control.
Anatomical connections of the sympathetic nervous
system innervation to afferent nociceptors occur after
experimental axotomy [118,119]. In the dorsal root gan-
glion (DRG) sympathetic fibers from blood vessels
sprout and form baskets around mechanoreceptors and
innervate thinly myelinated fibers. This is in response to
upregulation of p75 receptors that guide sympathetic
fibers and lymphocyte inhibitory factor (LIF) that in-
duces sympathetic nerve sprouting. There are other po-
tential mechanisms for the coupling of sympathetic ef-
ferents to nociceptive afferents that occur at the site of
injury [119]. Mechanosensitive sensory afferents and
nociceptive fibers express adrenoreceptors that may be
upregulated and activated following nerve injury. An
increased density of α-1 adrenergic receptors occurs in
the hyperalgesic skin of CRPS-I patients [119,120]. The
involvement of the sympathetic ne rvous system in CRPS
is further demonstrated by: 1) The response of early
CRPS patients to sympatholysis; 2) The demonstration of
acute antibodies to sympathetic ganglia; 3) Denervation
hypersensitivity of vascular smooth muscle (due to loss
or dysfunction of vasomotor neurons in the interme-
diolateral column); 4) Sensitization of mechanoreceptors
from the adrenal release of epinephrine; 5) Immune
sympathetic system interaction [67,121-123].
The autonomic manifestations of CPRS are frequently
misdiagnosed as Raynaud’s phenomena (particularly if
the affected extremity is minimally painful), fibromyal-
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Systemic Complications of Complex Regional Pain Syndrome
gia and vascular insufficiency. This occurs in the setting
of a cold blue extremity, with mottling and livedo reticu-
laris and neurogenic edema. The erythematous warm
extremity is often thought to be infected.
7. Inflammation/Neurogenic Edema
In a longitudinal study of ov er 600 patien ts with CRPS of
at least one year’s duration, 75% were positive for neu-
rogenic edema. In those with long standing disease, 90%
were positive. The swelling correlated with disease dura-
tion and may be generalized and massive [1]. There is
often sustained diuresis at the initiation of ketamine
therapy. The averag e weight loss of moderate to severely
affected CRPS patients when the edema is mobilized is
between 10 and 12 pounds. Diuretics are often adminis-
tered for the edema and are ineffective. Frequently af-
fected body parts are concomitantly erythematous as well
as swollen. If these signs are present in a painful lower
extremity, patients are misdiagnosed as suffering from
thrombophlebitis. There are often severe dystrophic skin,
nail and integument changes in the affected lower ex-
tremities that in association with erythema and increased
temperature suggest infection.
At the site of injury an “inf lammatory soup” develops.
It originates from the blood or inflammatory cells that
include: inflammatory cytokines (IL-1, IL-6 and TNF-α,
prostaglandins (PGE2), serotonin (5-hydroxy-trypta-
mine), bradykinin, epinephrine, lipoxygenase, neuro-
trophic factors (nerve growth factor (NGF), brain derived
neurotrophic factor (BDNF)), neurotrophin-3 (NT-3) and
nucleotide transmitters su ch as adenosine [12 4,125]. This
microenvironment blurs the distinction between inflam-
matory or purely neuropathic pain in CRPS. The effect of
these cytokines, neutrophilic factors, small molecules
and enzymes is to directly activate the terminal mem-
branes of C and A-δ nociceptors or to decrease their fir-
ing threshold. This effect is mediated by activation of
phosphokinase A (PKA) and phosphokinase C (PKC)
which phosphorylate tetrodotoxin (TTX) resistant sen-
sory neurons and specific sodium channels [126]. In ad-
dition, cytokines TNF-α, Interleukin-1 beta (IL-1β) and
IL-6 release calcitonin gene related peptide into the skin.
Retrogradely transported NGF has also been shown to
regulate gene expression (new receptors and proteins)
and biosynthesis in neonatal rat sensory neurons [127,
128]. The activation of these C and A-δ terminal twigs
induces an axon reflex that releases the vasoactive neu-
ropeptides substance-P, calcitonin gene related peptide
(CGRP) and neurokinin A which causes vasodilation and
protein extravasation. The associated neurogenic in-
flammation causes erythema, increased temperature and
edema [129]. The majority of the neurogenic inflamma-
tion, edema and augmented flare response in CRPS pa-
tients are caused by substance-P and CGRP [130-134].
Substance-P has also been demonstrated to stimulate skin
keratinocytes to express cytokines in the affected ex-
tremities of CRPS patients [135,136]. Further evidence
for the involvement of inflammatory cytokines in neuro-
inflammation and edema in the affected extremities of
CRPS patients is: 1) Increased concentration of TNF-α
and IL-6 in skin blister fluid from fracture sites in the
CRPS affected limb [58,59]; 2) Serum concentrations of
soluble TNF receptors and TNF-α receptors, IL-1 and
interleukin-8 (IL-8) are elevated in early CRPS (mean of
3 months) while the anti-inflammatory cytokines IL-4,
IL-10 and transforming growth factor beta-1 (TGFβ-1)
are decreased [62,131]. A contrary study found that blis-
ter fluid and serum cytokine concentrations were not
linked to disease duration or clinical signs other than
mechanical hyperalgesia [62,137,138]. An aberrant in-
flammatory response to tissue injury inducing erythema,
warmth and neurogenic edema appears to be an impor-
tant aspect of CRPS. In addition to pain relief, these in-
flammatory changes respond dramatically to N-Methyl-
D-aspartate (NMDA) blockade by ketamine protocols
[139]. The erythema and neurogenic edema seen on both
early and long standing CRPS patients is often mistaken
for thrombophlebitis or infection when it occurs in the
lower extremities. Unfortunately, the grossly edematous
and poorly perfused lower extremities often do get in-
8. Musculoskeletal System
The musculoskeletal system is profoundly affected in
almost all patients with CRPS. Weakness was reported in
approximately 70% of patients in a longitudinal study [1].
In addition to weakness, patients suffer atrophy in mus-
cles that maybe normally exercised. This is apparent par-
ticularly in intrinsic hand and foot muscles as well as the
gastrocnemius muscles. Occasionally a specific compo-
nent of muscle will be atrophied in a muscle that does no t
appear to be involved with the illness. Evaluation of
muscle from the amputated limbs of 14 severe end-stage
CRPS patients revealed fatty degeneration, Type I and II
fiber atrophy and evidence of degeneration with reinner-
vation. There was no difference in the pathology between
arm or legs and no correlation with duration of illness
[140]. Under hypoxic conditions elevated levels of reac-
tive oxygen species are produced which act as second
messengers that activate hypoxia inducible factors (HIPs)
that help to maintain ATP levels [141]. Magnetic reso-
nance spectroscopy has demonstrated that muscle in
CRPS patients is hypoxic [142] which causes failure to
maintain a normal redox state and that in turn will in-
crease reactive oxygen species (ROS) production and cell
injury [143]. Mitochondrial dysfunction has been dem-
onstrated in severe late stage patients in limbs prior to
amputation [144]. Biochemical analysis suggests that
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Systemic Complications of Complex Regional Pain Syndrome 231
decreased activity of mitochondrial succinate dehydro-
genase (complex II) is causative of mitochondrial energy
production failure and free radical production [145].
ROS cause carbonylation of mitochondrial proteins
which signifies oxidative damage [146]. These observa-
tions of oxidative damage in muscle support previous
observations of free radical damage as a pathologic
mechanism in CRPS [147-149]. Eight children with mi-
tochondrial disease and probable CRPS have been de-
scribed which also lends further support to a role of dys-
functional mitochondria as a possible mechanism of the
muscle dysfunction that occurs in CRPS patients [150].
Bone and joint pain are suffered by a majority of
CRPS patients. X-rays of the affected extremities dem-
onstrate bone lakes (intracortical excavation) associated
with periarticular, trabecular and periosteal demineraliza-
tion and bone resorption [151]. These changes are
thought to be the resu lt of osteoclastic activatio n possibly
from nociceptor release of substance P [152]. During
bone resorption, activated osteoclasts reduce pH enough
to depolarize pain afferents which densely innervate bone
[151]. Magnetic resonance imaging often reveals bone
marrow edema and triple phase bone scans demonstrate
pooling in the late phase [151,153] in 30% to 50% of
patients. Pathologic fractures are very common in
CRPS-I patients. A frequent fracture occurs in the 5th
metatarsal bone. Most patients suffer fractures during
their usual activities or with minimal trauma. Experi-
mental evidence demonstrates that bone formation and
maintenance are critically dependent on an intact small
fiber innervation which is dysfunctional in CRPS-I pa-
tients [2,154-156]. These fractures are difficult to heal
which may also be a reflection of dysfunction of bone
9. Endocrine System
All patients with moderate to severe CRPS experience
stress due to pain itself and the disruption of work, per-
sonal relationships and activities of da ily living. In a lon-
gitudinal study of 270 patients, 69% described severe
tiredness and unusual fatigue. Disproportionate unex-
plained fatigue may be due to congestive heart failure,
hepatic and renal failure, decreased systemic ox ygen ation
(anemia or COPD), endocrine dysfunction (hypothyroid-
ism, adrenal insufficiency), depression or inflammatory
cytokine mediated illness (malignancy, human immuno-
deficiency, HIV, Epstein-Barr and other viral infections)
and medications including narcotics. Twenty six patients
with severe fatigue and total body CRPS underwent
evaluation of their hypothalamic pituitary axis. Twenty
three were females and 3 were males whose median age
was 44 years (mean 43 years, range 20 to 64 years). No
patient had anemia, congestive heart failure, COPD, re-
nal or hepatic failure, HIV, malignancy or recent infec-
tion. No patient had active major depression or had a
history of recent steroid use. Low baseline cortisol levels
were noted in ten of the twenty six patients—one of
whom had a low TSH level. The adrenocorticotrophic
hormone (ACTH) stimulation test was administered to
patients with low baseline cortisol levels. All ten patients
with low cortisol levels responded with a significant in-
crease in serum cortisol within one hour. This implies
normal adrenal gland function but an impaired hypo-
thalamo-pituitary-adrenal [157] axis demonstrating terti-
ary adrenal insufficiency. In this ongoing study [158]
approximately 38% of severe CRPS patients have a low
serum cortisol level.
Experimental studies have demonstrated that systemic
corticosterone suppressed the late phase of the formalin
test which implies a role in control of central sensitiza-
tion [159,160] or inhibition of inflammatory mediators
[161]. Further support that glucocorticoids mediate cen-
tral effects in neuropathic pain is derived from models in
which the development and maintenance of mechanical
hyperalgesia and allodynia following nerve injury is de-
creased following systemic administration of be- tame-
thasone [162]. Glucocorticoids may decrease pain by
several mechanisms: 1) Suppression of intracellular cas-
cades mediated by phospholipase A2 [163]; 2) De-
creasing ectopic discharge from experimental neuromas;
3) Blocking neurotransmission in C fibers [164,165]; 4)
Decreasing microglial activation [166]. Approximately
40% of CRPS patients have low cortisol levels which can
be a component of their sustained pain.
Approximately one third of moderate to severe CRPS
patients suffer hypothyroidism [1]. The effect of this
deficit is not known other than that noted in Sudek’s at-
rophy. Hyperparathyroid function and bone metabolism
has not been reported .
The role of the HPA in chronic stress is well docu-
mented [167,168]. The above data that demonstrates low
cortisol levels in a significant portion of CRPS patients
with normal adrenal function after cosyntropin stimula-
tion supports failure of the HPA axis in the illness.
A great percentage of patients with severe CRPS are
treated with large doses of strong opiods. A recent study
has demonstrated pituitary dysfunction in all of its axes
with hypofunction of: 1) The hypothalamic-pituitary-go-
nadal axis; 2) Hyperfunction of the HPA axis; 3) Higher
prolactin levels. Cessation of narcotics can reverse the
endocrine dysfuncti o n [ 16 9].
10. Dermatologic Manifestations of CRPS
In a longitudinal study of the natural history of CRPS
71% of patients reported skin color changes within 5
years that increased to 81% after 15 years. This was usu-
ally a combination of erythema, mottling, livedo reticu-
laris and cyanosis [1]. Swelling was noted in 75% of pa-
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Systemic Complications of Complex Regional Pain Syndrome
tients by the first year and in 90% of patients after 15
years [1]. A peculiar finding noted in several patients
was the “ligature sign”, as if the patient had tied a liga-
ture around the edematous extremity that persisted even
as edema decreased during treatment. Approximately
20% of patients report a slightly raised morbilliform rash.
The most common lesion seen is a well circumscribed 1 -
3 mm punched out ulcer-like lesion that is preceded by a
pruritic skin lesio n resembling an insect bite. Within 2 to
3 days, the center of the lesion is excavated and its cir-
cumference is raised. The pruritis ends at this stage. The
lesion heals with an atrophic thin center and clearly ery-
thematous margins. In an early publication, two of nine
patients suffered recurrent bullae in their chronically
edematous legs [170]. Ultrastructural evaluation of bi-
opsy material from a bullous lesion in one patient re-
vealed abnormalities in basement membrane and an-
choring fibrils. In some areas the basement membrane
did not contain any anchoring fibrils and segments of
basement membrane revealed decreased electron density
and focal disruption. Two patients demonstrated lesions
similar to pigmented purpura. These patients had the
acute onset of marked erythema in their chronically
edematous leg. Biopsy revealed lymphocytes and histio-
cytes surrounding blood vessels with extravasted eryth-
rocytes that most closely resembled Schamberg’s disease
[171]. After approximately two years, the skin of the
affected extremity becomes atrophic, smooth and often
dry. Brittleness, ridging and thinning of the nails occurs
concomitantly. Verrucous changes often seen in patients
with venous stasis do occur in addition to cellulitis and
ulceration. A subset of these patients slough large areas
of skin. Patients with bullae and evidence of disruption
of collagenous anchoring fibrils had normal dermoepi-
dermal immunofluorescence. The bullous eruption seen
in these patients is similar to that described in diabetic
patients with n e ur o pat hy [1 72 -1 7 4] .
There has been extensive pathologic study of the am-
putated limbs of 8 CRPS patients which revealed severe
muscle atrophy and severely thickened capillaries as well
as ultrastructural quantification of C fiber degeneration
[149]. Two further anatomical studies of skin from am-
putated CRPS-I limbs revealed loss of endothelial integ-
rity, blood vessel hypertrophy and reduced epidermal
sweat gland and vascular small nerve fiber innervation.
Altered neuropeptide profiles were noted in surviving
small nociceptive fiber afferents that innervated hair fol-
licles, superficial arterioles and sweat glands [175,176].
However, a recent study of much less severely affected
patients found alterations of small fiber skin innervation
in only 20% of CRPS-I patients. There were no patient
signs or symptoms or stage of disease that predicted epi-
dermal nerve density [177,178]. In this study there was
no consistent reduction in sweat gland nerve fiber density.
An abnormal dense small-fiber innervation around hair
follicles has also been described in CRPS-I patients
The trophic effects of CRPS-I are noted in skin, mus-
cle, bone (Sudek’s atrophy) and joints. The skin and in-
tegument atrophy is often particularly apparent in inter-
phalangeal joints of the hand and the dorsum of the foot
and lower leg in conjunction with brawny edema. The
nails become thickened, ridged, grow too rapidly and
split. Early in the course of the illness when it is often
sympathetically maintained, hair becomes thicker, curly
and grows more rapidly. As the disease progresses it is
lost [114]. Experimental axotomy of cutaneous nerves
decreases keratinocyte mitosis and results in epidermal
thinning and hair loss [179,180].
The distal extremities and particularly the finger tips
are pivotal for thermo-regulation affected by arterioven-
ous shunts [2]. The sympathetic innervation of these ar-
terioles normally tonically constricts their smooth muscle
which occludes the arteriovenous shunt (AVS). During
the progression of CRPS-I there maybe nervi vasulorum
degeneration (small fibers) which would allow blood to
bypass nutritive capillaries and thus cau se hypoxia of the
perfused tissue (loss of skin, connective tissue and mus-
cle). This mechanism has been suggested as a cause of
the atrophy seen in th e muscles of CRPS patients [2,142].
Sweating abnormalities are seen in approximately 3 0%
of patients. In a large study of well characterized CRPS-I
patients, 22% had increased resting sweat output, 7%
decreased and in 71% it was normal [181]. Patients are
often unaware of sweating abnormalities which fluc-
tuate with emotional state and environmental stimuli.
Denervated sweat glands that do not respond to neu-
rologic stimuli may respond to circulating norepineph-
rine although their usual ligand is acetylcholine [117].
The Gardner Diamond syndrome is common in CRPS
patients. Patients experience spontaneous bruising which
often occurs months following an initial trauma [182].
The bruising occurs in areas that were not injured. The
suggested mechanism is an autoimmune reaction against
a component of the patient’s erythrocytes. Coagulation
parameters are normal and skin biopsy reveals nonspe-
cific changes. Possible antigens that elicit this autoim-
mune response are thought to be phosphatidyl serine—a
phosphoglyceride of the red blood cell membrane [183-
185]. Occasionally, deep muscle tissue is the site of
erythrocyte extravasation. As noted earlier, the inflame-
matory response resulting in ne urogenic edema may be a
mechanism for red blood extravasation in CRPS [186,
11. Urological System
Urological symptoms and signs are seen in approxima-
tely 25% of CRPS patients [1]. In a study of 20 consecu-
tive CRPS patients who were referred to an academic
urology service, the main complaints were frequency,
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Systemic Complications of Complex Regional Pain Syndrome 233
urgency or urinary incontinence. The mean age of these
patients was 43 ± 10 years and the duration of urological
symptom was almost 5 years [188]. No patient had void-
ing problems prior to the onset of CRPS. Endoscopic
evaluation of these patients was normal as was cytology.
Renal ultrasound cleared upper tract pathology such as
hydronephrosis, nephrolithisasis or tumor. Detrusor hy-
perreflexia was found in 8 patients, detrusor areflexia in
8 patients and sensory urgency in 3. Detrusor hyperre-
flexia with detrusor external sphincter dysnergia was
documented in 1 patient. Four of the patients (women)
had stress incontinence. The mean cystometric bladder
capacity was 417 ± 182 ml. Complex regional pain has
been diagnosed in the penis one year following transure-
thral prostatectomy [189]. Pelvic and perineal pain is also
seen in CRPS patients particularly if both lower extremi-
ties are affected [114,190].
12. Gastrointestinal System
In the prospective study of 270 patients who were evalu-
ated prior to ketamine infusion [1], constipation was re-
ported most frequently (113 patients, 41%). Common
other symptoms were nausea (63 patients, 23.3%), vom-
iting (31 patients, 11.5%), complaints of intermittent di-
arrhea (18.5%) and indigestion (18.5%). Irritable bowel
syndrome was diagnosed in 46 patients (17%) since on-
set of CRPS.
Dysphagia was frequently noted (47 patients, 17.4%)
and has been thoroughly evaluated in over 20 patients.
Patients typically describe a feeling of food being stuck
in their throat. All patients were evaluated by an ENT
and swallowing specialist. They underwent a compre-
hensive head and neck examination that included fi-
ber-optic nasopharyngoscopy. The patients’ swallowing
function was evaluated with water, thickened juice (nec-
tar, honey) and solids (cottage cheese). The swallowing
parameters assessed were: 1) Bolus formation; 2) Initia-
tion; 3) Delay; 4) Residual; 5) Clearance; 6) Spasm; 7)
GERD. All patients had difficulty with bolus formation
and control. They were slow to initiate swallow and had
a significant delay with the bolus which collected at the
valleculae for a prolonged period of time. Deglutition
demonstrated poor clearance from the hypopharynx with
multiple involuntary swallows. Laryngeal penetration
and frank aspiration did not occur. The dysphagia ex-
perienced by these patients appears to be multifactorial.
Inability to init iate movement of pharyngeal musculature
causes poor bolus formation with consequent segmenta-
tion. Patients also appear to have diminished sensation of
the bolus that leads to pooling within the vallecula, a
delayed swallow and significant residual within the piri-
form sinus and poor pharyngeal clearance. GERD is
common in the CRPS population (73%). As noted, stress
of many types is noted in these patients [191] and multi-
ple medications may contribute to GERD specifically
and dysphagia generally.
Gastroparesis is a major problem in almost all long-
standing patients that have suffered more than 5 years
with CRPS. In general, these patients have multi-limb
disease; the lower extremities are affected to a greater
extent than the upper and urological symptoms are con-
comitant. The most frequent complaint is early satiety
and bloating. Severe constipation, diarrhea and irritable
bowel symptomatology are present in 90% of these pa-
Pain from CRPS involvement on the right side is fre-
quently mistaken for gall bladder disease leading to op-
eration [13]. Although the pain emanates from the axilla
and radiates to the anterior chest wall, lateral chest wall
(gall bladder region) and may also be felt at the tip of th e
scapula, its most troubling feature maybe ep igastric pain.
This is most often diagnosed as GERD. Approximately
5% of our severe patients have had their gall bladder
removed for pain caused by the ICB nerve on the right
Central sensitization syndrome (CSS), a pathophysi-
ologic component of CRPS, is though t to be important in
irritable bowel syndrome (IBS) and functional dyspepsia
[192]. A closely related syndrome, fibromyalgia (FB),
has been related to the metabolic syndrome in women
[193]. FB is also associated with functional bowel disor-
ders and cyclic vomiting syndrome (CVS) [194]. In a
study of 18 adult patients with CVS, it was demonstrated
that the strongest associations were FB and CRPS [195].
A recent study identified 8 children in seven families
who suffered CRPS-I and also had additional gastroin-
testinal (GI) dysmotility and cyclic vomiting. All 7 chil-
dren met the Nijmegen (2002) diagnostic criteria for mi-
tochondrial disease and 6 of the 7 probands had probable
maternal inheritance [150]. GI disorders are common in
CRPS and detailed physiolog ic studies are in progress.
There is accumulating evidence that thinly myelinated
A-δ and unmyelinated C fibers are involved in the so-
matic manifestations of CRPS [2]. They may also in-
volve internal organs such as the GI tract. Early evidence
suggests gastroparesis is a component of the clinical
manifestations of early satiety, bloating, nausea and
vomiting reported by approximately 5% of patients [1].
Nociceptive C and A-δ axons innervate blood vessels
and their neuroeffector secretions can marginalize im-
munocytes into the intestinal wall. Lymphocyte, mono-
cytes, and mast cells thus recruited may trigger a
neuro-immune cycle of inflammation and vasogenic
edema of the intestinal wall similar to their somatic ef-
fects [2]. Small fiber involvement and resulting gas-
troparesis are well documented in diabetics who have
small fiber neuropathy [196]. Circulating systemic in-
flammatory cytokines have also been demonstrated to
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Systemic Complications of Complex Regional Pain Syndrome
cause gut edema [197].
13. Conclusion
Almost all organ systems are involved during the course
of CRPS. Major progress has been accomplished in un-
derstanding its mechanisms as regard to pain [187,198]
but little is known abou t its pleiotropic effects on internal
organs which are frequently very perplexing to those that
care for these patients.
14. Acknowledgements
The author would like to acknowledge the support given
to research over the years by the Tilly Family Foundation
for the Study of Complex Regional Pain Syndrome and
the Emily Sunstein Foundation for the Study of Neuro-
pathic Pain.
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Abbreviation List
Complex Regional Pain Syndrome (CRPS)
intercostobrachial (ICB)
Wechsler Adult Intelligence Scale-III (WAIS-III)
functional MRI (fMRI)
primary somatosensory cort ex (SI)
secondary somatosensory cortices (SII)
blood brain barrier (BBB)
tumor necrosis factor-alpha (TNF-α)
nuclear factor kappa B (NF-κB)
nAChR (acetylcholine receptor)
interleukin-6 (IL-6)
interleukin-10 (IL-10)
interleukin-1 (IL-1)
head-up tilt test (HUTT)
coronary artery disease (CAD)
Gastroesophageal reflux disease (GERD)
second intercostal nerve (T2)
chronic obstructive lung disease (COPD)
dorsal root gangl i on (DRG )
lymphocyte inhibitory factor (LIF)
prostaglandins ( PG E 2)
neurotrophi c fa ct ors ( ner ve gr owth factor (NGF)
brain derived neur o t rophic factor (BDNF)
neurotrophin-3 (NT-3)
phosphokinase A (PKA)
phosphokinase C (PKC)
tetrodotoxin (TTX)
interleukin-1 beta (IL-1β)
calcitoni n g ene rela t e d peptid e (C GR P)
interleukin-8 (IL-8)
transforming growth factor beta-1 (TGFβ-1)
N-Methyl-D-aspartate (NMDA)
hypoxia inducible factors (HIPs)
reactive oxygen species (ROS)
adrenocorti c ot r op hi c ho rmone (ACT H )
arteriovenous sh unt (AVS)
central sensitization syndrome (CSS)
irritable bowel sy ndrome (IBS )
fibromyalgia (FB)
cyclic vomiting syndrome (CVS)
gastrointestinal (GI)