Pain

Complex Regional Pain Syndrome – Diagnosis, Treatment

and Future Perspectives
S i gr i d G L F i sc h e r 1 a n d R o b e r t o S G M P e r e z 2

1. Physician and Researcher; 2. Associate Professor and Researcher, Department of Anaesthesiology, VU University Medical Center Amsterdam

Abstract
Complex regional pain syndrome (CRPS) is a pain syndrome of the extremities that can result in severe disability. CRPS is diagnosed
using diagnostic Budapest criteria based on signs and symptoms, whereby sensory, autonomic, vasomotor, motor and trophic
disturbances are assessed. Many pathophysiological mechanisms are proposed in the development and disease course of CRPS,
starting with exaggerated inflammation and resulting in vascular deregulation, central sensitisation and cortical reorganisation.
Treatment is based primarily on reducing inflammation by using medicinal anti-inflammatory therapy and increasing motor function
by physiotherapy. Furthermore, pain reduction, normalisation of vasomotor and motor function, and psychological interventions
might be needed. Future research should focus on the efficacy of anti-inflammatory therapy, effective rehabilitation programmes,
modulating neuropathic pain and cortical reorganisation.

Keywords
Complex regional pain syndrome, diagnosis, treatment, future perspectives

Disclosure: This work was performed as a part of Trauma Related Neuronal Dysfunction (TREND), a consortium that integrates research on epidemiology, assessment
technology, pharmacotherapeutics, biomarkers and genetics on complex regional pain syndrome. TREND is supported by a grant from the Dutch government (BSIK03016).
Roberto SGM Perez has received consultancy fees from Pfizer.
Received: 31 August 2011 Accepted: 30 September 2011 Citation: European Neurological Review, 2011;6(4):270–5 DOI:10.17925/ENR.2011.06.04.270
Correspondence: Sigrid GL Fischer, Department of Anaesthesiology, VU University Medical Center Amsterdam, 6F002, PO Box 7057, 1007 MB Amsterdam,
The Netherlands. E: s.fischer@vumc.nl

Complex regional pain syndrome (CRPS) is a painful disorder of the sudomotor and motortrophic disturbances. An adapted version of
extremities, characterised by sensory, autonomic, vasomotor, motor the latter criteria set has been validated internationally, resulting in
and trophic disturbances (see Figures 1 and 2). CRPS mostly occurs a diagnostic tool that combines good specificity with excellent
after a trauma, such as a fracture or an operation, but can also sensitivity for diagnosing CRPS: the Budapest criteria (see Table 1).9
develop without a preceding event. 1,2 In the Netherlands, These criteria have recently been adopted by the IASP as the
approximately 4,300 patients develop CRPS each year, whereby international standard for diagnosing CRPS.
females are affected three times more than males and the highest
incidence is found between the age of 61 and 70 years.3 To maximise the comparability of studies of CRPS and ensure
agreement between clinicians involved in diagnosing and treating
Diagnosing Complex Regional CRPS, a uniform and internationally accepted criteria set such as the
Pain Syndrome Budapest criteria is necessary. Uniform diagnosis and assessment
The diagnosis of CRPS is based on clinically observed signs and of CRPS could be further improved by identification of disease
symptoms reported by the patient. Additional laboratory or markers of CRPS Type 1 (CRPS-1) and development of objective
radiological assessments provide insufficient basis for diagnosing assessment tools.
CRPS, but should be used to exclude other pathologies (such as an
unresolved fracture or active infection). 4 Several sets of diagnostic Pathophysiologica l Mechanisms of Complex
criteria have been proposed over the past decades, some of which Regional Pain Syndrome
are still being used concurrently. The criteria of Veldman et al.5 are Neurogenic and immune-mediated inflammation, disproportional
based on the identification of a limited amount of signs and oxidative stress, autonomic dysfunction, vasomotor dysfunction,
symptoms, which are present predominantly in the acute phase increased neuronal excitation, central sensitisation, cortical
of CRPS. The International Association for the Study of Pain reorganisation and psychological predisposition have been proposed
(IASP)-Orlando criteria 6 allow for the diagnosis to be made almost as possible disease mechanisms for CRPS. This variety in
exclusively based on anamnestic information and appear to be more pathophysiological perspectives combined with possible simultaneous
sensitive than the Veldman et al. criteria. 7 More specific criteria have occurrence of different mechanisms in a single patient, might provide
been developed by Bruehl and Harden 8 requiring both anamnestic an explanation for the heterogeneity of phenotypes described in
and observed information regarding sensory, vasomotor, motor, CRPS literature in recent years.

270 © TOUCH BRIEFINGS 2011

EUROPEAN NEUROLOGICAL REVIEW 15
N e x
e - i A
u m d u
r e a t
o d t o
g i i n
e a v o
n t e m
i e i
c d S c
t
I I r D
n n e i
f f s s
l l s t
a a Excessive, non-self-limiting u
m m release of free oxygen r
m m radicals leading to
b
a a a
oxidative stress has been
t t n
proposed as a c
i i
o o pathophysiological e
n n mechanism underlying s
A trauma can easily result Especially during the CRPS. Studies based on Hyperactivity of the
in micro-injury of small early stages of the animal models have shown sympathetic nervous
nerve fibres, which in turn disease course, CRPS that infusion with free system has long been
triggers the release of signs and symptoms radical-inducing agents thought to be the primary
neuropeptides, such as resemble the classic results in features that pathophysiological
substance P (SP) and clinical presentation of resemble clinical signs of mechanism of CRPS-1,
calcitonin gene-related inflammation: rubor, calor, CRPS, such as swelling, resulting in increased
peptide (CGRP) in the dolor and functio laesa. impaired function, vasoconstriction,
periphery.10,11 This Increased levels of increased temperature, increased sweating and
excessive release of inflammatory markers and redness and increased trophic disturbances.
neuropeptides, called markers of mast cell pain sensitivity. 17 A role However, studies have
neurogenic inflammation, activity have been found in for increased oxidative shown lower levels of
induces vasodilatation and blister fluid (e.g. interleukin stress is also supported sympathetic
increases vascular [IL]-6, tumour necrosis by the observation of neurotransmitters in the
permeability, leading to factor [TNF]-α and tryptase) elevated levels of oxidative affected limb25–27 compared
plasma extravasation and and serum (IL-8, soluble markers in the serum and with the unaffected limb,
attraction of immune TNF receptors and SP) saliva of patients with indicating decreased
mediators to the site of obtained from the affected CRPS-1.18 Furthermore, sympathetic activity.
injury, resulting in an extremity of patients with leukocyte accumulation in Presumably, increased
inflammatory response. CRPS, compared with both the affected extremity has sensitivity of α-adrenergic
Neurogenic as well as the unaffected extremity been observed in patients receptors, probably resulting
immune-mediated and healthy with CRPS, probably from reduction of
inflammation contribute to controls. 10,13,14 resulting from increased sympathetic neural traffic,
the generation of pain, Indications for central vascular permeability owing would explain
whereby features of inflammatory activity can be to oxidative stress.19 Tissue
neuropathic sensitisation, found in increased pro- hypoxia, as shown by the
such as allodynia or inflammatory cytokines poor oxygenation of skin
hyperesthesia, are (IL-6) and decreased anti- in patients with CRPS,20
observed. In patients with inflammatory cytokines (IL-4 lends further support to
CRPS, elevated levels of and IL-10) in cerebrospinal this observation. The
CGRP have been found, fluid.15 Furthermore, efficacy of free radical
suggesting a contribution of markers of increased glial scavengers, such as
neurogenic inflammation to cell activation (glial dimethylsulfoxide and N-
the development and fibrillary acidic protein Acetylcysteine,21,22 in the
maintenance of in this [GFAP] and monocyte treatment of CRPS-1 and
condition.12 chemoattractant protein 1 the preventive effect of
[MCP1]) found in CRPS, vitamin C after fractures23,24
I might provide support for in the development of this
m neuronal-driven immune disease provide indirect
m activation.16 evidence for the oxidative
u stress hypothesis.
n
O

16 EUROPEAN NEUROLOGICAL REVIEW

Figure 1: Patient with nia of
Complex Regional the Neuronal
Pain Syndrome Left Excitation
(Florid Clinical Type) Foot
and Central
of the Left Hand
Sensitisation
Clinical features displayed
in CRPS, such as allodynia,
hyperalgesia and wind-up,
have been related to the
process of central
sensitisation. 31 This process
is triggered by the release
of SP, CGRP and
glutamate after tissue
damage, which in turn
activate the normally
dormant N-methyl-D-
aspartic acid (NMDA)
receptor. 32
Elevated levels of
glutamate found in the
Characteristics of complex
regional pain syndrome: red serum and cerebrospinal
(vasomotor), swollen this phenomenon.28 The
(sudomotor) fluid of patients with CRPS
extent in which autonomic
a are suggestive of the
n disturbances are observed
d involvement of NMDA
can differ depending on the
receptor responses. 33
i stage of the disease
n
Central sensitisation might
course.29
c also influence the
r
e
a V
s a
e
d s
c
h u
a
i
l
r a
r
g
r
o D
w
t
y
h s
f
( u
t n
r
o c
p t
h
i i
c o
n
d
i An alternative hypothesis
s
t
for the vasomotor
u instability observed in
r
b patients with CRPS is
a
n based on endothelial
c dysfunction resulting in
e
) hypoxia, a decrease in nitric
.
oxide (NO) synthase and an
increase in endothelin-1. 30
Figure 2: This dysfunction leads to
Patient
clinical features, such as a
with
Complex cold affected extremity and
Regional discolouration (pale, blue
Pain
skin), and other features of
Syndr
ome CRPS associated with
and oxygen deprivation.
Dysto

EUROPEAN NEUROLOGICAL REVIEW 17

Table 1: Diagnostic Criteria for Complex Regional Pain and guidelines providing an evidence-based approach to treatment of
Syndrome (CRPS) Type 1
CRPS is presented in Tables 2 and 3.50–60

Budapest Clinical Diagnostic Criteria for CRPS Type 1

Pharmacological Treatment
1. Continuing pain, which is disproportionate to any inciting event
Analgesics
2. Must report at least one symptom in three out of four of the
Pain medication according to the WHO analgesic ladder has been
following categories:
• Sensory: reports of hyperesthesia and/or allodynia suggested in therapeutic guidelines, although evidence supporting
• Vasomotor: reports of temperature asymmetry and/or skin colour the efficacy of paracetamol and nonsteroidal anti-inflammatory drugs
changes and/or skin colour asymmetry (NSAIDS) is limited. Tramadol has been shown to be effective in
• Sudomotor/oedema: reports of oedema and/or sweating changes neuropathic pain disorders, therefore it can be considered for severe
and/or sweating asymmetry pain accompanying CRPS, although evidence for its effects in CRPS
• Motor/trophic: reports of decreased range of motion and/or motor
is lacking. 4,50,51,55,61–63
dysfunction (weakness, tremor or dystonia) and/or trophic changes
(hair, nail or skin)
3. Must display at least one sign at time of evaluation in two or more of Treating CRPS with strong opioids should only be considered as crisis
the following categories: management for a limited period of time.51,55 Furthermore, gabapentin
• Sensory: evidence of hyperalgesia (to pinprick) and/or allodynia (to has proven efficacy in CRPS-1;50,51,55,62,64 however, amitryptiline and
light touch and/or deep somatic pressure and/or joint movement) carbamazepine or newer tricyclic antidepressants (TCAs), such as
• Vasomotor: evidence of temperature asymmetry and/or skin colour duloxetine or venlafaxine, can also be considered, because of their
changes and/or asymmetry shown effectiveness in other neuropathic pain disorders. 50,55,62
• Sudomotor/oedema: evidence of oedema and/or sweating changes
and/or sweating asymmetry
Intravenous administration of the NMDA receptor antagonist
• Motor/trophic: evidence of decreased range of motion and/or motor
ketamine can be considered; however the full scope of its
dysfunction (weakness, tremor or dystonia) and/or trophic changes
(hair, nail or skin) therapeutical potential (including a risk–benefit assessment) has not
4. There is no other diagnosis that better explains the signs and symptoms yet been established. 50,60,65,66 Lidocaine patches have been proposed
for treatment of localised sensory deficits, such as allodynia in CRPS.67

spinal motor circuitry, resulting in movement disorders associated

Anti-inflammatory Therapy
with CRPS, such as dystonia, tremor or myoclonia.34
The free radical scavenger dimethyl sulfoxide (DMSO) has been shown
to be effective in patients who have had CRPS-1 for less than a year.58
Cortical Reorganisation
N-Acetylcysteine (NAC) shows comparable efficacy to DMSO, but
Pain and sensory disturbances in CRPS often spread from the location
proved superior to DMSO for primary cold CRPS in subgroup
of the initial trauma to a larger area, sometimes even to another
analyses.68 Vitamin C has established efficacy in the prevention of
extremity, which might indicate plastic changes of the central nervous
CRPS after wrist fractures.23,24 Furthermore, corticosteroids can provide
system owing to neurogenic inflammation.35 In patients with CRPS,
significant pain reduction in CRPS; however, there is no consensus on
reorganisation of the primary somatosensory cortex (S1) has been
the dosage or duration of treatment.50,58,62,63 Both types of intervention
observed, which correlated with the amount of pain and hyperalgesia
have so far only been evaluated in early-stage CRPS.51,55
experienced by the patients.36,37 Cerebral representation and motor
processing in the brain are also reported to be disturbed, possibly
leading to movement disorders in CRPS-1 and distorted visualised
Calcium-regulating Drugs
The use of bisphosphonates has been proposed as a treatment option
representation of the affected limb.38–41
for CRPS. Although limited support for their ability to reduce pain
(associated with bone loss) has been reported, additional research
Psychological Factors
with regard to their dosage, frequency and duration of treatment
Psychological disturbances have often been proposed to be
involved in complex conditions, such as chronic pain and CRPS. is required.21,50,53,55,56,62,69,70
However, little evidence has emerged to support this hypothesis.
No relation has been found between psychological dysfunction, Vasodilatory Medication
disease-related fear or personality and the development of For treatment of patients with CRPS and vasomotor disturbances,
CRPS. 42–44 One study reports that stressful life events are more α-1 adrenergic blockers, phenoxybenzamine and terazosin, or
common in patients with CRPS than in controls, 45 but other studies calcium influx blockers, such as nifedipine, can be considered.4,55,71
could not confirm this finding. 42,43,46,47 Once patients have developed No reduction in temperature asymmetry was found for NO-regulating
CRPS, pain-related fear and fear of re-injury are proposed to be risk medication (e.g. tadalafil or isosorbide dinitrate) in primary cold CRPS,
factors for a poor prognosis relating to pain reduction and although tadalafil is superior to placebo in reducing pain for this
functional improvement. 48,49 subgroup.72,73 Likewise, intravenous administration of ketanserine is
reported to reduce pain in CRPS.50,74
Treatment Options
Treatment of CRPS-1 is challenging, because of the variety of Spasmolytics
symptoms and the variable disease course exhibited by patients. A Movement disorders in CRPS-1, such as dystonia, myoclonia and
multimodal approach consisting of pharmacological treatment and tremor, might benefit from treatment with baclofen or
physiotherapy, sometimes in combination with invasive therapy or benzodiazepines. 4,50,63 Treatment with anti-cholinergics has not shown
psychological support, is required. An overview of systematic reviews to be beneficial for CRPS-related movement disorders over a longer
period of time.34

18 EUROPEAN NEUROLOGICAL REVIEW

Table 2: Systematic Reviews of Interventions for Complex Regional Pain Syndrome Type 1

Review Topic
Kingery, 199750 Oral corticosteroids, DMSO, calcitonin (intranasal and subcutaneous), regional blocks, intravenous
ketanserine and phentolamine, and epidural clonidine in CRPS compared with other neuropathic
pain disorders
Stanton-Hicks et al., 199851 NSAIDs, opioids, antidepressants, calcium blockers, corticosteroids, bisphosphonates, capsaicin, adrenergic
drugs, local anaesthetic blocks, neuromodulation, physical therapy, psychiatric and psychological measures,
and treatment of children with CRPS
Raja et al., 200252 Oral, topical and intravenous analgesics, bisphosphonates, free radical scavengers, corticosteroids, alpha
blockers, blockades, epidural and intrathecal therapies, physiotherapy, neuromodulation, psychotherapy
and invasive treatment options
Foroufanzar et al., 200253 Blocks, intravenous ketanserine, calcium-regulating drugs, free radical scavengers, corticosteroids,
complementary therapies and prevention of CRPS
Cepeda et al., 200254 Local anaesthetic sympathetic blockade
Harden, 200555 TCAs, anticonvulsants, anti-inflammatory drugs, opioids, clonidine, nifedipine, calcitonin, bisphosphonates,
adrenergic antagonists, topical treatments and local anaesthetic block therapies
Brunner et al., 200956 Bisphosphonates
Daly and Bialocerkowski, 200957 Physiotherapy
Fischer et al., 201058 Anti-inflammatory drugs
Perez et al., 200159 Anti-inflammatory drugs, free radical scavengers, beta blockers, calcitonin, stellate ganglion blocks,
intravenous treatment with lidocaine and ketanserine, clonidine and bisphosphonates
Collins et al., 201160 NMDA receptor antagonists
CRPS = complex regional pain syndrome; DMSO = dimethyl sulfoxide; NMDA = N-methyl-D-aspartic acid; NSAIDs = non-steroidal anti-inflammatory drugs; TCA = tricyclic antidepressant.

Table 3: Guideline s for the Treatment of Complex Regional Pain Syndrome Type 1

Treatment Guidelines Description

CBO Guidelines, Complex Regional Pain Dutch guidelines for CRPS considering analgesics, local and intravenous anaesthetics, anticonvulsants, Syndrome
type 1, 2006 antidepressants, capsaicin, free radical scavengers, oral muscle relaxants, local botulinum, intrathecal baclofen,
(www.cbo.nl/thema/Richtlijnen / corticosteroids, calcitonin, bisphosphonates, calcium channel blockers, invasive treatment, paramedical
Overzicht-richtlijnen/Overig) intervention, treatment options for children with CRPS and recommendations for the prevention of CRPS
AWMF: Leitlinien der Deutschen German guidelines for the treatment of CRPS considering bisphosphonates, calcitonin, corticosteroids, free radical
Gesellschaft für Neurologie, 2008 (German) scavengers, physio- and occupational therapy, analgesics, psychotherapy, blockades, spinal cord stimulation
(www.awmf.org/leitlinien / and intrathecal treatment
detail/ll/030-116.html)
RSDSA, Complex Regional Pain Syndrome American guidelines on the effects of anti-inflammatory drugs, anticonvulsants, neuromodulators, antidepressants,
Treatment Guidelines, 2010 anti-anxiolytics, opioids, NMDA receptor antagonists, anti-hypertensives and α-adrenergic antagonists, calcitonin,
(www.rsds.org/3/clinical_guidelines / bisphosphonates, topical treatment, psychological interventions and invasive interventions
index.html)
Van Eijs et al, 20114 Dutch guidelines for anaesthesiologists on physical therapy, psychological support, anti-inflammatory therapy,
analgesic therapy, vasodilatory therapy, spasmolytic therapy, regional blocks, intrathecal and epidural treatment
and neurostimulation
AWMF = Association of the Scientific Medical Societies in Germany; CBO = Central Accompaniment Organization; CRPS = complex regional pain syndrome; NMDA = N-methyl-D-aspartic acid;
RSDSA = Reflex Sympathetic Dystrophy Syndrome Association.
P with chronic CRPS; should not be considered
h however, the high in early stages of
y incidence and severity of CRPS.79 Studies of
s complications following intrathecal administration of
i
spinal cord stimulation baclofen show that patients
c
a warrant careful patient with CRPS dystonia can
l selection. 78 Spinal cord experience marked
stimulation improvement in pain and
T disability levels, paralleled
h by improvement in quality
e of life.80,81 However, as with
r other intrathecal
a
approaches, complications
p
y can be severe and,
An important modality for therefore, should be limited
treatment of CRPS is to patients who are
physical therapy directed refractory to conventional
at increasing control over therapy and be conducted
pain and improving by physicians with ample
skills.57,75 experience with intrathecal
Motor imagery and devices.81
mirror therapy have been
proven effective, both of P
s
which are applied to
y
counter disturbed cortical
c
motor processing, h
resulting in improvement o
of pain and l
function.41,76,77 o
Transcutaneous electrical g
i
nerve stimulation
c
(TENS) might be a
beneficial for treatment of l
pain in a subgroup of
patients and might T
therefore be a suitable r
adjunctive non-invasive e
therapy. However, a
t
evidence for the latter is
m
limited.4 e
n
I t
n Although studies with
v regard to psychological
a
interventions for CRPS are
s
i limited, treatment by a
v psychologist can be
e considered in cases where
disease burden is high or
T there is a discrepancy
r between noted pain
e behaviour and observed
a
signs and symptoms of
t
CRPS.63 Graded exposure is
m
e a promising therapy to
n reduce fear of pain and to
t regain functionality of the
Spinal cord stimulation affected extremity.49
with an implantable
generator can be
considered for patients
Future Perspectives interventions addressing sensory disturbances related to peripheral
In recent decades, much research effort has been directed to and central sensitisation, such as NMDA receptor antagonists86 and
unravelling the underlying mechanisms of CRPS, and improving the N-type calcium channel blocker ziconotide,87 are worthwhile
strategies for its prevention and treatment, alongside the unification targets for further research.
of diagnostic procedures. An important issue to be addressed is the
identification of prognostic factors for disease development, which Therapy directed at the stimulation of adaptive cortical reorganisation
could lead to a more targeted approach and therewith improve the involving brain-training programmes, such as mirror therapy76 and
prognosis of patients with CRPS. Prospective cohort studies on motor imagery, 77 merit implementation in daily practice. Continuing
the development of CRPS are necessary to gain a better this line of thought, a strong point can be made for increasing
understanding of prognostic factors related to disease onset and patients’ awareness and knowledge regarding mechanisms underlying
disease course.82 The recently developed CRPS severity score (CSS) the development of chronic pain and CRPS.88 Further research
as a derivation of the Budapest diagnostic criteria 83 might be helpful within the field of exercise and occupational therapy should be
in improving the systematic follow up of patients; however, validation focused on the distinction between pain and time-contingent
of this tool is ongoing. CRPS remains a clinical diagnosis, and the approaches. Positive initial results have been found for pain exposure
patient population is heterogeneous. Although it has been proposed physical therapy (PEPT), which is based on progressive-loading
that CRPS comprises different disease subtypes or stages of the exercises and desensitisation beyond the patients’ pain limits.89
disease, this has not led to further subcategorisation of the disease. 8 Cognitive behavioural aspects are taken into account, with the goal to
A targeted approach based on the identification of CRPS subtypes motivate patients to use the affected limb in daily activity despite
and specific mechanisms prevailing in an individual patient is experiencing pain. Likewise, for patients with CRPS with pain-related
therefore still warranted. fear, research is ongoing into the effects of graded exposure therapy
(GEXP), comprising provision of information about CRPS, observational
The many available treatment options suggest that the optimal learning and ‘flooding’ of feared movements and activities.
therapy for CRPS has not yet been identified. Given the
heterogeneous nature of CRPS, an optimal therapy seems unlikely; Repetitive transcranial magnetic stimulation (rTMS), whereby the
therefore, a mechanism-directed approach to treatment of CRPS motor cortex is stimulated to treat neuropathic pain, has been shown
appears preferable. With regard to interventions targeting to provide short-term pain relief in patients with CRPS-1.90 However,
inflammation, comparative studies of established interventions (e.g. issues related to placebo response and ways to prolong its efficacy
prednisolone and DMSO) and novel anti-inflammatory agents, such as need to be addressed.
intravenous administration of immunoglobulin, 84 should be
performed. Furthermore, alternative approaches, such as targeting For each of the interventions discussed in this article, long-term
the cholinergic anti-inflammatory pathway,85 whereby activating the studies of sufficient sample size, with specific attention to patient
parasympathetic nervous system to inhibit inflammatory activity and selection, timing and dosage of therapies, are required to establish
autonomic dysregulation in CRPS, could be pursued. Promising risks and benefits of each intervention for patients with CRPS. n

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