REVIEW ARTICLE

Complex regional pain syndrome type I: a comprehensive

review
M. Bussa1, D. Guttilla1, M. Lucia2, A. Mascaro3 and S. Rinaldi4
1
O.U. of Anesthesia, Intensive Care and Pain Therapy of Sant’Antonio Abate Hospital, Casa Santa Erice, Trapani, Italy
2
O.U. of Anesthesia, Intensive Care and Pain Therapy of Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello, Palermo, Italy
3
Anaesthesiology, Intensive Care and Pain Therapy Department, Catholic University, Medical School, Rome, Italy
4
Plastic and Reconstructive Surgery Department, University ‘Sapienza’ of Rome, Rome, Italy

Correspondence Background: Complex regional pain syndrome type I (CRPS I),

M. Bussa, O.U. of Anesthesia, Intensive Care
and Pain Therapy of Sant’Antonio Abate
Hospital, Casa Santa Erice, C/da Duchessa 126,
91014 Castellammare del Golfo (TP), Trapani,
Italy
E-mail: martbuss@alice.it
Conflicts of interest
There are no conflicts of interest.
Submitted 25 November 2014; accepted 6
January 2015; submission 21 December 2013.
Citation
Bussa M, Guttilla D, Lucia M, Mascaro A,
Rinaldi S. Complex regional pain syndrome
type I: a comprehensive review. Acta
Anaesthesiologica Scandinavica 2015
doi: 10.1111/aas.12489
formerly known as reflex sympathetic dystrophy (RSD), is a
chronic painful disorder that usually develops after a minor injury
to a limb. This topical review gives a synopsis of CRPS I and dis-
cusses the current concepts of our understanding of CRPS I in
adults, the diagnosis, and treatment options based on the limited
evidence found in medical literature. CRPS I is a multifactorial
disorder. Possible pathophysiological mechanisms of CRPS I are
classic and neurogenic inflammation, and maladaptive neuroplas-
ticity. At the level of the central nervous system, it has been sug-
gested that an increased input from peripheral nociceptors alters
the central processing mechanisms.
Methods: A literature search was conducted using, as electronic
bibliographic database, Medline from 1980 until 2014.
Results: An early diagnosis and multidisciplinary treatment are
necessary to prevent permanent disability.
Conclusions: The pharmacological treatment of CRPS I is empiri-
cal and insufficiently effective. Further research is needed regard-
ing the therapeutic modalities discussed in the guidelines.
Physical therapy is widely recommended as a first-line treatment.
The efficacy of local anesthetic sympathetic blockade as treatment
for CRPS I is questionable.

Editorial comment: what this article tells us

Complex regional pain syndrome type 1 (CRPS I) can occur after an injury to a limb. This review
concludes that the mechanisms are complex and variable, and thus, no single treatment will likely
be sufficient. In the early phase, sympathetic blockade may be indicated, but a multidisciplinary
approach is required. There is also increasing evidence for spinal cord stimulation.

Complex regional pain syndrome type I (CRPS surgery to a limb.1–3 This topical review intends
I), previously known as reflex sympathetic dys- to describe epidemiology, major pathophysio-
trophy (RSD), is a chronic painful disorder char- logical mechanisms, diagnostic criteria, and in-
acterized by disabling pain, vasomotor and terventional and pharmacological therapies for
sudomotor changes, and motor disturbances. CRPS I. The purpose of this article was to con-
The trophic changes are not common. This dis- tribute to the dissemination of knowledge
order usually develops after a minor trauma or among clinicians of this painful condition, in
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd 685
 M. BUSSA ET AL.
virtue of the fact that a diagnostic delay may
have a negative impact on the prognosis and
therapeutic success.
Methods
A literature search was conducted using, as
electronic bibliographic database, Medline from
1980 until present. Evidence-based reviews,
from the Cochrane library, were also included
in this topical review. For each pathophysiolog-
ical mechanism, a separate search was con-
ducted in Medline, using the query ‘complex
regional pain syndrome type I’ combined with
one of the following queries: for autonomic ner-
vous system dysfunction was used ‘sympathetic
nervous system’ or ‘sympathetically maintained
pain’; for inflammation, ‘inflammation’, or ‘neu-
rogenic inflammation’, or ‘neuropeptide’, or
‘hypoxia’; for central sensitization, ‘hyperalge-
sia’, or ‘wind-up’, or ‘NMDA receptor’, or ‘glial
cells’; for brain plasticity, ‘cortical reorganiza-
tion’, or ‘referred sensations’, or ‘hemisensory
impairment’; for psychological factors, ‘psychol-
ogy’, or ‘psychiatric’, or ‘behavior‘. With the
purpose of overviewing the known risk factors,
the query ‘complex regional pain syndrome type
I’ was combined with the following terms:
‘incidence’, ‘prevalence’, and ‘genetic factors’.
Abstracts were screened manually, and full-test
papers were considered if the abstract suggested
an experimental or observational study focused
on the pathogenesis of CRPS I or a review con-
cerning one or more pathogenetic mechanisms
or an association between CRPS I and risk fac-
tors. The research about the diagnostic criteria
was performed using the query ‘complex regio-
nal pain syndrome type I’ in combination with
‘diagnostic criteria’, or ‘diagnosis’, or ‘valida-
tion’. The research for therapeutic management
was conducted using the keyword ‘complex
regional pain syndrome type I’ in combination
with each treatment modality, for instance, anti-
convulsants, antidepressants, free radical scav-
engers, bisphosphonates, physical therapy,
occupational therapy, sympathetic blockade,
spinal cord stimulation, etc. Meta-analyses, sys-
tematic reviews, review articles, randomized
controlled trials, comparative cohort studies,
case series, and case reports were included. Full
copies were obtained for potentially relevant
686 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
papers. Recent guidelines were consulted. Only
articles written in English were included.
Terminology
The term RSD was proposed by Evans in 1946.1
In 1993, the International Association for the
Study of Pain (IASP) introduced the term
CRPS.2 A distinction is made between CRPS I
and CRPS II.3 CRPS I, formerly known as RSD,
develops after a minor trauma or a small nerve
injury. CRPS II, once known as causalgia, arises
after an injury to a large nerve. The biggest dif-
ference between CRPS I and CRPS II is a
demonstrable nerve injury in the latest, identi-
fied by electromyography (EMG) and nerve con-
duction velocity (NCV).
Epidemiology
CRPS I is more frequent in females than in males
(2,3:1–4:1).4,5 In adults, the upper limbs are
more often affected than the lower limbs. The
most common precipitating events leading to
CRPS I are fractures, contusions/sprains, and
surgery. In approximately 10% of cases,6 a pre-
cipitating event may not be identified. In a recent
prospective study of 596 patients with fractures,7
7% of the patients developed CRPS I and none
of the patients were free of symptoms at a 1-year
follow-up. Psychological factors and personality
traits have not been identified as factors that pre-
dispose an individual to develop CRPS
I.2,8,9,145,146 Gene technology has been used to
identify the genetic pattern of patients predis-
posed to the development of CRPS I.10 The fre-
quency of HLA-DQ1 is significantly increased in
patients affected by CRPS I.11 In addition, in
patients with CRPS I who progressed to multifo-
cal or generalized tonic dystonia, an association
with HLA-DR3 has been reported.12
Pathophysiological mechanisms of CRPS I
The pathophysiological mechanism of CRPS I
seems to be multifactorial. The mechanism con-
tributing to CRPS I differs from patient to patient,
and even in the same patient it changes over time.
There are a number of different mechanisms
accepted and documented in the literature.26
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697

Autonomic nervous system dysfunction
The involvement of the sympathetic nervous
system in the pathogenesis of CRPS I differs
from classic theory.13–20 The role of the sympa-
thetic nervous system in the development and
maintenance of symptomatology is not an exces-
sive sympathetic outflow to the skin, but rather
an increased sensitivity of blood vessels to cate-
cholamines and the development of the adrener-
gic sensitivity by nociceptive neurons.21–23 This
coupling between sympathetic post-ganglionic
neurons and afferent neurons is mediated by a-
adrenoceptors.21–24
Classic and neurogenic inflammation
CRPS I patients display significant increases in
pro-inflammatory cytokines (TNF-a, IL-1b, IL-2,
IL-6) locally, in the blood plasma, and in the
cerebrospinal fluid.25–33 It is postulated that the
systemic pro-inflammatory observed cytokine
profile may be a crucial factor in the pathogene-
sis of CRPS I.29 Moreover, the sympathetic-
afferent coupling may sensitize the nociceptive
primary afferents and lead to the release of neu-
ropeptides (Substance P and CGRP) from pepti-
dergic unmyelinated fibers.34,35 Neuropeptides
(SP and CGRP), antidromically released from
sensory terminals in the skin, evoke vasodila-
tion and protein extravasation in the tissue, and
the resulting signs (reddening, warming, and
edema) are called neurogenic inflammation.36–41
The important contribution of inflammation to
CRPS I is underlined by open-label studies on
treatments with infliximab (anti-TNF),42,43 tha-
lidomide,44 prednisone,45 and prednisolone.46,47
Central sensitization
The activity of nociceptive afferents will trigger
a central sensitization process, which will be
responsible for the development of allodynia
and hyperalgesia.48,49 Central sensitization may
play a crucial part in the pathogenesis of chronic
pain and is the driving factor for CRPS I.50–53
N-methyl D-aspartate (NMDA) receptors play a
critical role in central sensitization.54,55
The role of glia activation
Spinal cord glia activation plays a major role in
driving exaggerated pain states, including CRPS
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COMPLEX REGIONAL PAIN SYNDROME TYPE I
I.56,57 Activated glia drive the creation and
maintenance of allodynia and hyperalgesia.58
On activation, the glia release a number of sub-
stances that potentiate pain transmission by
neurons.58,59
Brain plasticity
This syndrome is considered a disease of the
central nervous system (CNS).60,61 The persis-
tent activity of nociceptive primary neurons gen-
erates plastic changes in the primary
somatosensory cortex (SI). Referred sensations
and hemisensory deficits in patients with CRPS
I provide evidence of central sensory reorganiza-
tion in such patients.62 These SI changes were
reversed following successful treatment and
recovery from CRPS I.63–65 Furthermore, adap-
tive cortical changes within the motor system
may occur in CRPS I.66–70
Clinical features
CRPS I progresses through successive stages
with an early, an intermediate, and a late stage.
These clinical stages have been described by J.
J. Bonica.71 Recently, Bruehl described three
clinical pictures that do not represent three
sequential stages but rather three distinct sub-
types.72 The key features in CRPS I are sponta-
neous pain and stimulus-evoked pain,
vasomotor, sudomotor, and trophic changes.73
Pain can be sympathetically mediated (SMP) or
sympathetically independent (SIP).73–75 Charac-
teristically, the pain is disproportionate in
intensity to the initial event.35 Three distinct
vascular regulation patterns were identified
related to the duration of the disorder.76 Swell-
ing is a very common symptom in patients with
acute CRPS I.35,77 Trophic changes are not incor-
porated in the current IASP criteria.78 Initially,
the symptoms of CRPS I are localized to the site
of the lesion. During the course of the disease,
pain and other symptoms may spread. Maleki
identified three different patterns of spread in
CRPS I patients.79,80
Diagnosis
No specific diagnostic tests are available for
CRPS I.73 Diagnosis of CRPS I is based either on
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 M. BUSSA ET AL.
Table 1 Budapest clinical diagnostic criteria for complex regional
pain syndrome.
1. Continuing pain, which is disproportionate to any inciting event
2. Must report at least one symptom in three of the four
following categories
Sensory: Reports of hyperalgesia and/or allodynia
Vasomotor: Reports of temperature asymmetry, and/or
skin color changes, and/or skin color asymmetry
Sudomotor/edema: Reports of edema, and/or sweating
changes, and/or sweating asymmetry
Motor/Trophic: Reports of decreased range of motion,
and/or motor dysfunction (weakness, tremor, dystonia),
and/or trophic changes (hair, nail, skin)
3. Must display at least one sign* at time of evaluation in
two or more of the following categories
Sensory: Evidence of hyperalgesia (to pinprick) and/or
allodynia (to light touch, and/or deep somatic pressure,
and/or joint movement)
Vasomotor: Evidence of temperature asymmetry, and/or
skin color changes, and/or asymmetry
Sudomotor/Edema: Evidence of edema, and/or sweating
changes, and/or sweating asymmetry
Motor/Trophic: Evidence of decreased range of motion
and/or trophic changes (hair, nail, skin)
4. There is no other diagnosis that better explains the signs
and symptoms.
*A sign is counted only if it observed at the time of diagnosis.
the Orlando criteria,81,82,86 endorsed by the
International Association for the Study of Pain,
or a modified version called the Budapest crite-
ria83–85. The Budapest criteria have a greater
specificity and also include motor features of the
syndrome (Table 1).86 The occurrence of symp-
toms and signs in the distal part of an extremity,
outside the territory of the nerve is a hallmark of
this painful disorder. The disproportionate
degree of pain in relation to the intensity of the
inciting event is another distinguishing charac-
teristic.84,85 A careful clinical evaluation of signs
and symptoms remains the mainstay of CRPS I
diagnosis.82,87,88 The role of sympatholytic pro-
cedures in diagnosis of CRPS I have been mini-
mized by their low sensitivity and low
specificity and by the associated complications.2
Therefore, the phentolamine infusion test is pro-
posed.89 Phentolamine administration is less
invasive, has fewer potential side effects, and is
688
preferred by patients.90,91 Moreover, SMP is not
an essential requirement for the diagnosis of
CRPS I.3,35
Principles of therapy
Optimal management of CRPS I involves an
interdisciplinary approach to therapy focused on
functional restoration of the affected limb.92 The
main goals of the treatment are pain control,
physical rehabilitation, functional recovery of the
affected limb, and return to work. The drugs used
in therapy have not been demonstrated to signifi-
cantly change the overall course of the syndrome
and have been used primarily to help patients
progress with their rehabilitative program.93 The
selection of pain management modalities is
guided by the severity of pain and the presence
or absence of sympathetic dysfunction.73,94–96
Pharmacological treatment
Non-steroidal anti-inflammatory drugs. Few clinical
trials presented results supporting the use of
NSAIDs for neuropathic pain, and one study
showed no benefit in the treatment of CRPS I.
The use of COX-2 inhibitors does not seem
helpful in the treatment of CRPS I.147,148
Corticosteroids. There is good evidence supporting
a short course of oral corticosteroids in early
CRPS I.45,46,151 Long-term use of corticosteroids
has not proved to be effective.148 Little is
known as to the duration and dosage.149
Free radical scavengers. Dimethylsulfoxide
(DMSO) is a free radical scavenger, which dem-
onstrated a significant pain reduction when
applied in the form of a 50% cream for
2 months.115,116 In the Netherlands, free radical
scavengers such as DMSO and N-acetylcysteine
are widely applied in treatments of CRPS I.117
Vitamin C. High-dose vitamin C therapy is asso-
ciated with a lower risk of CRPS I after wrist
fractures.118 To prevent the occurrence of CRPS
I after wrist fractures, oral administration of
vitamin C is recommended.149
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Antiepileptic drugs. Gabapentin is one of the most
commonly prescribed analgesic drugs for neuro-
pathic pain, and in CRPS I patients specifi-
cally.93,97–99 There is no evidence that
anticonvulsants such as carbamazepine, pregab-
alin, and phenytoin are effective in reducing
pain in CRPS I patients.100,101,149
Antidepressants. Antidepressants are commonly
used in neuropathic pain.93 There is no evidence
that antidepressants are effective in reducing
pain in CRPS I patients.102–105,149
Opioids. Opioids, the gold standard for treatment
of acute pain, have not been studied in CRPS I
patients.106–110 There is not sufficient evidence
for the effects on pain of oral opioids in CRPS I
patients.149
Bisphosphonates. Bisphosphonates are effective in
the treatment of CRPS I as demonstrated by
multiple randomized controlled trials.111–
114,148,151
The Royal College of Physician’s
guidelines recommend a single I.V. infusion
(IVI) of 60 mg pamidronate during the first
6 months of symptoms.150
N-Methyl-D-Aspartate receptor blockers. Ketamine is
an anesthetic drug increasingly used, in suban-
esthetic doses, as an analgesic in patients with
neuropathic pain of various origins including
CRPS I.54,55,161–165 A recent meta-analysis of
therapeutics for neuropathic pain did not find
sufficient evidence to sustain a role for ketamine
or other NMDA antagonist.166
Rehabilitation
Physical therapy (PT) is widely recommended
as a first-line treatment for CRPS I.94,121 PT, and
to a lesser extent occupational therapy (OT),
were helpful in reducing pain and improving
active mobility in patients with CRPS I of less
than 1-year duration.122
Behavioral therapies
An approach to psychological treatment for
chronic pain is cognitive behavioral therapy
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COMPLEX REGIONAL PAIN SYNDROME TYPE I
(CBT) focused on controlling pain sensations,
pain-related thoughts, and negative emotions.
More recently, there is an increasing interest to
the acceptance and commitment therapy
(ACT).168 ACT is quite different from CBT in
that it teaches people how to accept and embrace
unpleasant thoughts and feelings rather than try-
ing to control or eliminate them. Patients with
CRPS I may benefit from the ACT.167
Interventional therapeutic techniques
Pain relief with drugs alone is often insufficient
in CRPS I patients. If no response to conven-
tional treatment (e.g., pharmacotherapy) is
observed within 12–16 weeks, an interventional
technique such as spinal cord stimulation (SCS)
should be used.123
Sympathetic blockade
Cepeda’s reviews120,143 question the efficacy of
local anesthetic sympathetic blockade as treat-
ment of CRPS I. Sympathetic blocks, repeated
over time, are beneficial in selected CRPS I
patients to facilitate participation in physiother-
apy, particularly when signs of continued
improvement are observed.25,144
Spinal cord stimulation
Spinal cord stimulation is efficacious in neuro-
pathic pain and in reducing pain in patients
with CRPS I.123–134 Recommendation of the use
of spinal cord stimulation in the early stages of
CRPS I as a strategy to prevent chronicity and
functional impairment is questionable.135,136
There is increasing evidence to demonstrate
that SCS is a cost-effective treatment for CRPS
I.137–139
Discussion
Complex regional pain syndrome type I is a
chronic painful disorder that usually evolves
after a mild or moderate trauma affecting the
limbs, without an obvious peripheral nerve
damage. The spontaneous onset of CRPS I is
rare. The CRPS I has a multifactorial pathogene-
sis. The complexity and diversity of the mecha-
nisms involved will be liable to the
heterogeneity of the clinical presentation and
689
 M. BUSSA ET AL.
may explain the difficulty of achieving an evi-
dence-based treatment of CRPS I. In fact, the
degree to which individual mechanisms contrib-
ute to CRPS I may differ from one patient to the
other and even within one patient over time.
Only articles written in English that were pub-
lished after 1980 were included in this topical
review. A Medline search was conducted for
each mechanism. Case reports and non-research
articles were excluded. Experimental or observa-
tional studies focused on the etiology or patho-
genesis of CRPS I and reviews that discussed
one or more pathogenetic mechanisms were
included. There is an open debate whether the
CRPS I can be considered a neuropathic pain
syndrome.152–155 Recently, CRPS I has also been
discussed as a new type of autoimmune syn-
drome, speculating that autoantibodies acting
against peripheral nervous system structures,
increasing central sensitization, may play a role
in its pathogenesis.156,157 The hypothesis that an
autoimmune mechanism could be involved in
the pathogenesis of CRPS I has been suggested
by the following findings: IgG antibodies trans-
ferred from a patient with CRPS I to a group of
mice (passive transfer) have induced a
significant depression of rearing behavior158;
moreover, treatment with intravenous immuno-
globulin reduces pain in patients with CRPS
I.159 However, considering the conspicuous cost
of therapies with intravenous immunoglobulin,
further research is needed to confirm this
assumption. We analyzed relevant articles for
the treatment of CRPS I, identified by searches
in the Cochrane Library and Medline; recent
guidelines were consulted. We performed the
selection process of the studies starting from the
titles and the abstracts. Studies were selected
based on their methodological strength (meta-
analyses, systematic reviews, randomized con-
trolled trials (RCTs), and controlled trials
(CTs)). If these studies were not available, com-
parative cohort studies, comparative patient-con-
trolled trials, or non-comparative trials were
used in the evaluations instead. Other important
inclusion criteria were: adequate size, adequate
follow-up, and adequate exclusion of selection
bias. The Medline research was extended to ref-
erences cited in case series and case reports.
Studies were excluded if they were (1) not pub-
lished in full article format; (2) conducted in
690 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
pediatric samples or in adult samples where the
CRPS I onset was during childhood; and (3)
published in languages other than English. For
this research analysis, we did not take into
account studies which did not describe the
methods utilized to obtain data. There are still
many unanswered questions regarding the best
treatment modality. The Royal College of Physi-
cians (RCP) in the United Kingdom has recently
published guidelines for diagnosis, referral, and
management of CRPS in the context of primary
and secondary care.150,151 As pain is the most
common symptom in CRPS I, commencing early
treatment with optimized simple analgesia and
NSAIDs, and even a short course of steroids
may be effective, particularly in the early stages.
The RCP guidelines recommend introducing
medication for neuropathic pain as early as pos-
sible if simple analgesia is ineffective. Prompt
diagnosis and early treatment is required to
avoid secondary physical problems related to
disuse of the affected limb and the psychologi-
cal consequences of living with undiagnosed
chronic pain. Physiotherapy and/or occupational
therapy should be initiated immediately when
CRPS I is suspected. The activation of NMDA
receptors plays a crucial role in the central sen-
sitization and therefore, in the chronicization of
pain in CRPS I patients. Ketamine (an NMDA
antagonist) was administered intravenously, at
low doses, significantly reducing CRPS I pain,
in two small RCTs, without functional improve-
ment. However, the analgesic effect is not per-
sistent after treatment discontinuation and the
long-term effects of repeated intravenous doses
of ketamine are poorly understood.160 The use
of oral ketamine, ketamine at anesthetic doses
(ketamine coma), and ketamine combined with
nerve block are included in the ‘Experimental
Research’ section of guidelines for CPR, stating,
however, the insufficient evidence for their effi-
cacy.150 As it has been suggested that CRPS I is
due to an exaggerated inflammatory response,
topical antioxidants/free radical scavengers were
studied in a few RCTs. Although the proofs
regarding the efficacy of local free radical scav-
engers are weak, the Dutch guidelines recom-
mend their use when signs of inflammation
(heat, redness, and swelling), frequent in acute
CRPS I, appear.149 They also recommend the
prescription of vitamin C, 500 mg dosage per
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697

day for 50 days, with the aim to prevent the
onset of CRPS I after fractures. Epidural spinal
cord stimulation (SCS) reduces central sensitiza-
tion. SCS is reserved as a last resort in those
chronic cases where patients do not respond to
other treatment modalities.119,151 In base of the
identified literature and the extent of the evi-
dence found for therapeutic interventions for
CRPS I, we can conclude that further research is
needed for each of the modalities discussed in
these guidelines. This specifically includes treat-
ment approaches recommended in the guide-
lines based on expert opinions, such as the use
of tricyclic antidepressants.149
Summary
CRPS I is a poorly understood condition, which
tends to occur after an injury to a limb. CRPS I
is associated with a particularly poor quality of
life and large healthcare and societal costs. Early
diagnosis and a multidisciplinary approach to
management of CRPS I increase the likelihood
of obtaining an optimal outcome. It is worth-
while to mention here the use of palmitoyle-
thanolamide (PEA)140,141 due to its control of
the neurogenic inflammation, of the mast cell
degranulation, and of the activation of microglia.
If pain, edema, or motor dysfunction do not
regress immediately, local anesthetic sympa-
thetic blockade should be employed.142 SCS
must be executed if symptoms still persist after
3–4 months. Prolonged misdiagnosis and lack of
treatment may result in chronic disability.73
References
1. Dommerholt J. Complex regional pain sindrome 1:
history, diagnostic criteria and etiology. J Bodyw
Mov Ther 2002; 8: 167–77.
2. Raja SN, Grabow TS. Complex regional pain
sindrome I (Reflex Sympathetic Dystrophy).
Anesthesiology 2002; 96: 1254–60.
3. Stanton-Hicks M, Janig W, Hassembusch S,
Haddox JD, Boas R, Wilson P. Reflex sympathetic
dystrophy: changing concepts and taxonomy. Pain
1995; 63: 127–33.
4. Allen G, Galer BS, Schwartz L. Epidemiology of
complex regional pain syndrome: a retrospective
chart review of 134 patients. Pain 1999; 80: 539–
44.
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
COMPLEX REGIONAL PAIN SYNDROME TYPE I
5. Sandroni P, Benrud-Larson LM, McClelland RL,
Low PA. Complex regional pain syndrome type I:
incidence and prevalence in Olmsted county, a
population-based study. Pain 2003; 103: 199–207.
6. de Mos M, de Bruijn AGJ, Huygen FJPM,
Dieleman JP. The incidence of complex regional
pain syndrome: a population-based study. Pain
2006; 129: 12–20.
7. Beerthuizen A, Stronks DL, Van’t Spijker A, Yaksh
A, Hanraets BM, Klein J, Huygen FJ. Demografic
and medical parameters in the development of
complex regional pain syndrome type I:
prospective study on 596 patients with a fracture.
Pain 2012; 153: 1187–92.
8. Lohnberg JA, Altmaier EM. A review of
psychosocial factors in complex regional pain
syndrome. J Clin Psychol Med Settings 2013; 20:
247–54.
9. Beerthuizen A, Van’t Spijker AM, Huygen FJ,
Klein J, de Wit R. Is there an association between
psychological factors and the complex regional
pain syndrome type I (CRPS1) in adults? A
systematic review. Pain 2009; 145: 52–59.
10. Mailis A, Wode J. Profile of Caucasian women
with possible genetic predisposition to reflex
sympathetic: a pilot study. Clin J Pain 1994; 10:
210–7.
11. Kemler MA, van de Vussue AC, van den Berg-
Loonem EM, Barendse GA, van Kleef M, Weber
WE. HLA-DQ1 associated with reflex sympathetic
dystrophy. Neurology 1999; 53: 1350–1.
12. Van de Beek WJ, Roep BO, van der Slik AR,
Giphart MJ, van Hilten BJ. Susceptibility loci for
complex regional pain syndrome. Pain 2003; 103:
93–7.
13. van der Laan L, Goris RJ. Reflex sympathetic
dystrophy. Hand Clin 1997; 13: 373–85.
14. Kurvers HA. Reflex sympathetic dystrophy: facts
and hypotheses. Vasc Med 1998; 3: 207–14.
15. Pham T, Lafforgue P. Reflex sympathetic syndrome
and neuromediators. Joint Bone Spine 2003; 70:
12–7.
16. Casale R, Elam M. Normal sympathetic nerve
activity in a reflex sympathetic dystrophy with
marked skin vasoconstriction. J Auton Nerv Syst
1992; 41: 215–20.
17. Casale R, Buonocore M. Intraneural recordings do
not support the hypothesis of an abnormal
sympathetic nerve activity in reflex sympathetic
dystrophy. Funct Neurol 1993; 6: 79–84.
18. Drummond PD. Mechanism of complex regional
pain syndrome: no longer excessive sympathetic
outflow? Lancet 2001; 358: 168–70.
691
 M. BUSSA ET AL.
19. Elam M. Is reflex sympathetic dystrophy a valid
concept? Behav Brain Sci 1997; 20: 447–8.
20. Drummond P, Finch PM, Smythe GA. Reflex
sympathetic dystrophy: the significance of
differing plasma catecholamine concentrations in
affected and unaffected limbs. Brain 1991; 114:
2025–36.
21. Janig W, Levine JD, Michaelis M. Interactions of
sympathetic and primary afferent neurons
following nerve injury and tissue trauma. Prog
Brain Res 1996; 113: 161–84.
22. Shi TS, Winzer-Serhan U, Leslie F, Hokfelt T.
Distribution and regulation of a2 –adrenoceptors in
rat dorsal root ganglia. Pain 2000; 84: 319–30.
23. Drummond P, Skipworth S, Finch PM. alpha 1-
adrenoceptors in normal and hyperalgesic human
skin. Clin Sci 1996; 91: 73–7.
24. Ali Z, Raja SN, Wesselmann U, Fuchs PN, Meyer
RA, Campbell JN. Intradermal injection of
norepinefrina evokes pain in patients with
sympathetically maintained pain. Pain 2000; 88:
161–8.
25. de Mos M, Sturkenboom MC, Huygen FJ. Current
understandings on complex regional pain
syndrome. Pain Pract 2009; 9: 86–9.
26. Shah A, Kirchner JS. Complex regional pain
syndrome. Foot Ankle Clin N Am 2011; 16:
351–66.
27. Huygen FJ, De Bruijn AG, De Bruin MT,
Groeneweg JG, Klein J, Zijlstra FJ. Evidence for
local inflammation in complex regional pain
syndrome type I. Mediators Inflamm 2002; 11:
47–51.
28. Alexander GM, van Rijn MA, van Hilten JJ,
Perreault MJ, Schwartzman RJ. Changes in
cerebrospinal fluid levels of pro-inflammatory
cytokines in CRPS. Pain 2005; 116: 213–9.
29. Uceyler N, Eberle T, Rolke R, Birklein F, Sommer
C. Differential expression patterns of cytokines in
complex regional pain syndrome. Pain 2007; 132:
195–205.
30. Parkitny L, McAuley JH, Di Pietro F, Stanton R,
O’Connell NE, Marinus J, van Hilten JJ, Moseley
GL. Inflammation in complex regional pain
syndrome: a systematic review and meta-analysis.
Neurology 2013; 80: 106–17.
31. Bruehl S. An update on the pathophysiology of
complex regional pain syndrome. Anesthesiology
2010; 113: 713–25.
32. Tan EC, Oyen WJ, Goris RJ. Leukocytes in
complex regional pain syndrome type I.
Inflammation 2005; 29: 182–6.
692 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
33. Okudan B, Celik C. Determination of
inflammation of reflex sympathetic dystrophy at
early stages with Tc-99 m HIG scintigraphy:
preliminary results. Rheumatol Inter 2006; 26:
404–8.
34. Marinus J, Moseley L, Birklein F, Baron R,
Maihofner C, Kingery WS, van Hilten JJ. Clinical
features and pathophysiology of complex regional
pain syndrome. Lancet Neurol 2011; 10: 637–48.
35. Janig W, Baron R. Complex regional pain
syndrome: mystery explained? Lancet 2003; 2:
687–97.
36. Leis S, Weber M, Schmelz M, Birklein F.
Facilitated neurogenic inflammation in unaffected
limbs of patients with complex regional pain
syndrome. Neurosci Lett 2004; 359: 163–6.
37. de Mos M, Huygen FJ, Stricker BH, Dieleman JP,
Sturkenboom MC. The association between ACE
inhibitors and the complex regional pain
syndrome: suggestions for a neuro-inflammatory
pathogenesis of CRPS. Pain 2009; 142: 218–24.
38. Birklein F, Schelmz M, Schiffer S, Wiber M. The
important role of neuropeptides in complex
regional pain syndrome. Neurology 2001; 57:
2179–84.
39. Schinkel C, Gaertner A, Zaspel J, Zedler S, Faist
E, Schuermann M. Inflammatory mediators are
altered in the acute phase of posttraumatic
complex regional pain syndrome. Clin J Pain
2006; 22: 235–9.
40. Birklein F, Schmelz M. Neuropeptides, neurogenic
inflammation and complex regional pain syndrome
(CRPS). Neurosci Lett 2008; 437: 199–202.
41. Taha R, Blaise G. Is complex regional pain
syndrome an inflammatory process? Theories and
therapeutic implications. Can J Anaesth 2007; 54:
249–53.
42. Huygen FJ, Niehof S, Zijlstra FJ, van Hagen PM,
van Daele PL. Successful treatment of CRPS 1 with
anti-TNF. J Pain Symptom Manage 2004; 27: 101–3.
43. Bernateck M, Rolke R, Birklein F, Treede RD,
Fink M, Karst M. Successful intravenous regional
block with low-dose tumor necrosis factor-alfa
antibody infliximab for treatment of complex
regional pain syndrome 1. Anesth Analg 2007;
105: 1148–51.
44. Schwartzman RJ, Chevlen E, Bengtson K.
Thalidomide has activity in treating complex
regional pain syndrome. Arch Inter Med 2003;
163: 1487–8.
45. Christensen K, Jensen EM, Noer I. The reflex
dystrophy syndrome response to treatment with
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697

systemic corticosteroids. Acta Chir Scand 1982;
148: 653–5.
46. Kalita J, Vajpayee A, Misra UK. Comparison of
prednisolone with piroxicam in complex regional
pain syndrome following stroke: a randomized
controlled trial. QJM 2006; 99: 89–95.
47. Munts AG, van de Plass AA, Ferrari MD, Teepe-
Twiss IM, Marinus J, van Hilten JJ. Efficacy and
safety of a single intrathecal methylprednisolone
bolus in chronic complex regional pain syndrome.
Eur J Pain 2010; 14: 523–8.
48. Schattschneider J, Hartung K, Stengel M, Ludwig
J, Binder A, Wasner G, Baron R. Endothelial
dysfunction in cold type complex regional pain
syndrome. Neurology 2006; 67: 673–5.
49. Ji RR, Kohno T, Moore KA, Woolf CJ. Central
sensitization and LTP: do pain and memory share
similar mechanisms? Trends Neurosci 2003; 26:
696–705.
50. Goebel A. Complex regional pain syndrome in
adults. Rheumatology 2011; 50: 1739–50.
51. Woolf CJ. Windup and central sensitization are
not equivalent. Pain 1996; 66: 105–8.
52. Eide PK. Wind-up and the NMDA receptor
complex from a clinical perspective. Eur J Pain
2000; 4: 5–17.
53. Sieweke N, Birklein F, Riedl B, Neundorfer B,
Handwerker HO. Patterns of hyperalgesia in
complex regional pain syndrome. Pain 1999; 80:
171–7.
54. Sigtermans MJ, Wan Hilten JJ, Bauer MC, Arbous
MS, Marinus J, Sarton EY, Dahan A. Ketamine
produces effective and long-term pain relief in
patients with complex regional pain syndrome
type I. Pain 2009; 145: 304–311.
55. Schwartzman RJ, Alexander GM, Grothusen JR,
Paylor T, Reichenberger E, Perreault M.
Outpatient intravenous ketamine for the
treatment of complex regional pain syndrome: a
double-blind placebo controlled study. Pain
2009; 147: 107–15.
56. Watkins LR, Milligan ED, Maier SF. Glial
activation: a driving force for pathological pain.
Trends Neurosci 2001; 24: 450–5.
57. Milligan ED, Watkins LR. Pathological and
protective roles of glia in chronic pain. Nature
2009; 10: 23–36.
58. Watkins LR, Maier SF. Glia: a novel drug
discovery target for clinical pain. Nature 2003; 2:
973–85.
59. Alexander GM, Perreault MJ, Reichenberg ER,
Schwartzam RJ. Changes in immune and glial
markers in the CSF of patients with complex
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
COMPLEX REGIONAL PAIN SYNDROME TYPE I
regional pain syndrome. Brain Behav Imm 2007;
21: 668–676.
60. Janig W, Baron R. Complex regional pain
syndrome is a disease of the central nervous
system. Clin Auton Res 2002; 12: 150–64.
61. Maihofner C, Handwerker HO, Neundorfer B,
Birklein F. Patterns of cortical reorganization in
complex regional pain syndrome. Neurology 2003;
61: 1707–15.
62. Maihofner C, Handwerker HO, Neundorfer B,
Birklein F. Cortical reorganization during recovery
from complex regional pain syndrome. Neurology
2004; 63: 693–701.
63. McCabe CS, Haigh RC, Halligan PW, Blake DR.
Referred sensations in patients with complex
regional syndrome type I. Rheumatology 2003; 42:
1067–73.
64. Rommel O, Gehling M, Dertwinkel R, Witscher K,
Zenz M, Malin JP, Janig W. Hemisensory
impairment in patients with complex regional
pain syndrome. Pain 1999; 80: 95–101.
65. Rommel O, Malin JP, Zenz M, Janig W.
Quantitative sensory testing, neurophysiological
and psychological examination in patients with
complex regional pain syndrome and hemisensory
deficits. Pain 2001; 93: 279–93.
66. Maihofner C, Baron R, Decol R, Binder A, Birklein
F, Deuschl G, Handwerker HO, Schattschneider J.
The motor system shows adaptive changes in
complex regional pain syndrome. Brain 2007; 130:
2671–87.
67. Schwenkreis P, Janssen F, Rommel O, Pleger B,
V€olker B, Hosbach I, Dertwinkel R, Maier C,
Tegenthoff M. Bilateral motor cortex
disinhibition in complex regional pain syndrome
(CRPS) type I of the hand. Neurology 2003; 61:
515–9.
68. Moseley GL. Why do people with complex
regional pain syndrome take longer to recognize
their affected hand? Neurology 2004; 62: 2182–6.
69. Moseley GL. Graded motor imagery for pathologic
pain. Neurology 2006; 67: 2129–34.
70. Moseley GL. Is successful rehabilitation of
complex regional pain syndrome due to sustained
attention to the affected limb? A randomised
clinical trial. Pain 2005; 114: 54–61.
71. Bonica JJ. The management of pain, 1st edn.
Philadelphia, PA: Lea & Fabiger, 1953.
72. Bruehl S, Harden RN, Galer BS, Saltz S, Backonja
M, Stanton-Hicks M. Complex regional pain
syndrome: are there distinct subtypes and
sequential stages of the syndrome? Pain 2002; 95:
119–24.
693
 M. BUSSA ET AL.
73. Albazaz R, Wong YT, Homer-Vanniasinkam S.
Complex regional pain syndrome: a review. Ann
Vasc Surg 2008; 22: 297–306.
74. Galer BS, Butler S, Jensen MP. Case reports and
hypothesis: a neglect-Like syndrome may be
responsible for the motor disturbance in reflex
sympathetic dystrophy (Complex regional pain
syndrome-I). J Pain Symptom Manage 1995; 5:
385–91.
75. Galer BS, Jensen M. Neglect-like symptoms in
complex regional pain syndrome: results of a self-
administered survey. J Pain Symptom Manage
1999; 3: 213–7.
76. Wasner G, Schattschneider J, Heckmann K, Maier
C, Baron R. Vascular abnormalities in reflex
sympathetic dystrophy (CRPS I): mechanisms and
diagnostic value. Brain 2001; 124: 587–99.
77. Blumberg H, Hoffman U, Mohadjer M, Scheremet
R. Clinical phenomenology and mechanisms of
reflex sympathetic dystrophy: emphasis on edema.
In: Gebhart GF, Hammond DL, Jensen TS eds.
Proceedings of the 7th World Congress in Pain.
Research and management 1994, vol. 2. Seattle:
IASP Press, 455–81.
78. Birklein F, Riedl B, Sieweke N, Weber M,
Neundorfer B. Neurological findings in complex
regional pain syndrome- analysis of 145 cases.
Acta Neurol Scand 2000; 101: 262–9.
79. Maleki J, LeBel AA, Bennett GJ, Schwartzman RJ.
Patterns of spreads in complex regional pain
syndrome, type I (reflex sympathetic dystrophy).
Pain 2000; 88: 259–66.
80. Van Der Laan LVeldaman PMGoris RJ. Severe
complications of reflex sympathetic dystrophy
(CRPS1). Arch Phys Med Rehabil 1998; 79: 424–9.
81. Harden RN, Bruehl SP. Diagnosis of complex
regional syndrome. Signs, symptoms and new
empirically derived diagnostic criteria. Clin J Pain
2006; 22: 415–9.
82. Galer BS, Bruehl S, Harden RN. IASP diagnostic
criteria for complex regional pain syndrome: a
preliminary empirical validation study. Clin J Pain
1998; 14: 211–9.
83. Bruehl S, Harden RN, Galer BS, Saltz S, Bertram
M, Backonja M, Gayles R, Rudin N, Bhugra MK,
Stanton-Hicks M. External validation of IASP
diagnostic criteria for complex regional pain
syndrome and proposed research diagnostic
criteria. Pain 1999; 81: 147–54.
84. Harden RN, Bruehl S, Stanton-Hicks M, Wilson
PR. Proposed new diagnostic criteria for complex
regional pain syndrome. Pain Med 2007; 8:
326–31.
694 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
85. Harden RN, Bruehl S, Perez RS, Birklein F,
Marinus J, Maihofner C, Lubenow T,
Buvanendran A, Mackey S, Graciosa J, Mogilevki
M, Ramsden C, Chont M, Vatine JJ. Validation of
proposed diagnostic criteria (the “Budapest
criteria”) for complex regional pain syndrome.
Pain 2010; 150: 268–74.
86. Harden RN, Oaklander AL, Burton AW, Perez RS,
Richardson K, Swan M, Barthel J, Costa B,
Graciosa JR, Bruehl S. Complex regional pain
syndrome: practical diagnostic and treatment
guidelines, 4th edition. Pain Med 2013; 14:
180–229.
87. Harden RN, Bruehl S, Galer BS, Saltz S, Bertram M,
Backonja M, Gayles R, Rudin N, Bhugra MK,
Stanton-Hicks M. Complex regional pain
syndrome: are the IASP diagnostic criteria valid and
sufficiently comprehensive? Pain 1999; 83: 211–9.
88. Sch€urmann M, Zaspel J, L€ ohr P, Wizgall I, Tutic
M, Manthey N, Steinborn M, Gradl G. Imaging in
early posttraumatic complex regional pain
syndrome: a comparison of diagnostic methods.
Clin J Pain 2007; 23: 449–57.
89. Arner S. Intravenous phentolamine test: diagnostic
and prognostic use in reflex sympathetic
dystrophy. Pain 1991; 46: 17–22.
90. Raja SN, Treede RD, Davis KD, Campbell JN.
Systemic alpha-adrenergic blockade with
Phentolamine: a diagnostic test for sympathetically
maintained pain. Anesthesiology 1991; 74: 691–8.
91. Verdugo RJ, Ochoa JL. Sympathetically
maintained pain: phentolamine block questions
the concept. Neurology 1994; 44: 1003–10.
92. Wasner G, Schattschneider J, Binder A, Baron R.
Complex regional pain syndrome – diagnostic,
mechanisms. CNS involvement and therapy.
Spinal Cord 2003; 41: 61–75.
93. Mackey S, Feinberg S. Pharmacologic therapies for
complex regional pain syndrome. Curr Pain
Headache Rep 2007; 11: 38–43.
94. Kingery S. A critical review of controlled clinical
trials for peripheral neuropathic pain and
complex regional pain syndromes. Pain 1997; 73:
123–39.
95. Perez RS, Kwakkel G, Zuurmond WW, de Lange
JJ. Treatment of reflex sympathetic dystrophy
(CRPS type I): a research synthesis of 21
randomized clinical trials. J Pain Symptom
Manage 2001; 21: 511–26.
96. Cossins L, Okell RW, Cameron H, Simpson B,
Poole HM, Goebel A. Treatment of complex
regional pain syndrome in adults: a systematic
review of randomized controlled trials published
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697

from June 2000 to February 2012. Eur J Pain 2013;
17: 158–73.
97. Fink K, Dooley DJ, Meder WP, Suman-Chauhan
N, Duffy S, Clusmann H, Gothert M. Inhibition of
neuronal Ca2+ influx by gabapentin and
pregabalin in the human neocortex.
Neuropharmacology 2002; 42: 229–36.
98. van de Vusse AC, Stomp-van den Berg SG,
Kessels AH, Weber WE. Randomised controlled
trial of gabapentin in Complex Regional Pain
Syndrome Type I. BMC Neurology 2004; 4: 13.
99. Serpell MG. Gabapentin in neuropathic pain
syndrome: a randomised, double-blind, placebo-
controlled trial. Pain 2002; 99: 557–66.
100. Harcke H, Gretenkort P, Ladleif HU, Rahman S,
Harke O. The response of neuropathic pain and
pain in complex regional pain syndrome I to
carbamazepina and sustained-release morphine in
patients pretreated with spinal cord stimulation: a
double blinded randomized study. Anesth Analg
2001; 92: 488–95.
101. Rowbotham MC. Pharmacologic management of
complex regional pain syndrome. Clin J Pain
2006; 55: 425–9.
102. Cruccu G. Treatment of painful neuropathy. Curr
Opin Neurol 2007; 20: 531–5.
103. Sindrup SH, Bach FW, Madsen C, Gram LF,
Jensen TS. Venlafaxine versus imipramine in
painful polyneuropathy. A randomized, controlled
trial. Neurology 2003; 60: 1284–9.
104. Raskin J, Wang F, Pritchett YL, Goldstein DJ.
Duloxetine for patients with diabetic peripheral
neuropathic pain: a 6-month open label safety
study. Pain Med 2006; 7: 373–85.
105. Raskin J, Prichett YL, Wang F, D’Souza DN,
Waninger AL, Iyengar S, Wernicke JF. A double-
blind, randomized multicenter trial comparing
duloxetine with placebo in the management of
diabetic peripheral neuropathic pain. Pain Med
2005; 6: 346–56.
106. Gimbel JS, Richards P, Portenoy RK. Controlled-
release oxycodone for pain in diabetic neuropathy.
A randomized controlled trial. Neurology 2003;
60: 927–34.
107. Raja SN, Haythornthwaite JA, Pappagallo M,
Clark MR, Travison TG, Sabeen S, Royall RM,
Max MB. Opioids versus antidepressants in
postherpetic neuralgia: a randomized, placebo-
controlled trial. Neurology 2002; 59: 1015–21.
108. Watson CP, Moulin D, Watt-Watson J, Gordon A,
Eisenhoffer J. Controlled-release oxycodone relieves
neuropathic pain: a randomized controlled trial in
painful diabetic neuropathy. Pain 2003; 105: 71–8.
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
COMPLEX REGIONAL PAIN SYNDROME TYPE I
109. Rowbotham MC, Twilling L, Davies PS, Reisner
L, Taylor K, Mohr D. Oral opioid therapy for
chronic peripheral and central neuropathic pain. N
Engl J Med 2003; 348: 1223–32.
110. Gilron I, Bailey JM, Tu D, Holden RR, Weaver
DF, Houlden RL. Morphine, gabapentin, or their
combination for neuropathic pain. N Engl J Med
2005; 352: 1324–34.
111. Varenna M, Zucchi F, Ghiringhelli D, Binelli L,
Bevilacqua M, Bettica P, Sinigalla L. Intravenous
clodronate in the treatment of reflex sympathetic
dystrophy syndrome. A randomized, double blind,
placebo controlled study. J Rheumatol 2000; 27:
1477–83.
112. Manicourt DH, Brausseur JP, Boutsen Y,
Depreseux G, Devogelaer JP. Role of alendronate
in the therapy for posttraumatic complex regional
pain syndrome type I of the lower extremity.
Arthritis Rheum 2004; 50: 3690–7.
113. Adami S, Fossaluzza V, Gatti D, Fracassi E, Braga
V. Bisphosphonate therapy of reflex sympathetic
dystrophy syndrome. Ann Rheum Dis 1997; 56:
201–4.
114. Varenna M, Adami S, Rossini M, Gatti D, Idolazzi
L, Zucchi F, Malavolta N, Sinigaglia L. Treatment
of complex regional pain syndrome type I with
neridronate: a randomized, double-blind, placebo-
controlled study. Rheumatology 2013; 52: 534–42.
115. Zuurmond WW, LangendijK PN, Bezemer PD, Brink
HE, deLange JJ, van Loenen AC. Treatment of acute
reflex sympathetic with DMSO 50% in a fatty
cream. Acta Anaesthesiolog Scand 1996; 40: 364–7.
116. Gaspar M, Bovaira M, Carrera-Hueso FJ, Querol
M, Jimenez A, Moreno L. Efficacy of a topical
treatment protocol with dimethyl sulfoxide 50%
in type 1 complex regional pain syndrome. Farm
Hosp 2012; 36: 385–91.
117. Perez RS, Zuurmond WW, Bezemer PD, Kuik DJ,
van Loenen AC, de Lange JJ, Zuidhof AJ. The
treatment of complex regional pain syndrome type
I with free radical scavengers: a randomized
controlled study. Pain 2003; 102: 297–307.
118. Zollinger PE, Tuinebreijen WE. Effect of vitamin
C on frequency of reflex sympathetic dystrophy in
wrist fractures: a randomised trial. Lancet 1999;
354: 2025–8.
119. Kapural L. Spinal cord stimulation for intractable
chronic pain. Curr Pain Headache Rep 2014; 18: 406.
120. Cepeda MS, Lau J, Carr DB. Defining the
therapeutic role of local anesthetic sympathetic
blockade in complex regional pain syndrome: a
narrative and systematic review. Clin J Pain 2002;
18: 216–33.
695
 M. BUSSA ET AL.
121. Rho RH, Brewer RP, Lamer TJ, Wilson PR.
Complex regional pain syndrome. Mayo Clin Proc
2002; 77: 174–80.
122. Oerlemans HM, Oostendorp RA, de Boot T, Goris
RJ. Pain and reduced mobility in complex
regional pain syndrome I: outcome of a
prospective randomised controlled clinical trial of
adjuvant physical therapy versus occupational
therapy. Pain 1999; 83: 77–83.
123. Stanton-Hicks M. Complex regional pain
syndrome: manifestations and the role of
neurostimulation in its management. J Pain
Symptom Manage 2006; 31(4 Suppl.): S20–4.
124. Cruccu G, Aziz TZ, Garcia-Larrea L, Hansson P,
Jensen TS, Lefaucheur JP, Simpson BA, Taylor RS.
EFNS guidelines on neurostimulation therapy for
neuropathic pain. Eur J Neurol 2007; 14: 952–70.
125. Kemler MA, Barendse GA, Van Kleef M, Van Den
Wildenberg FA, Weber WE. Electrical spinal cord
stimulation in reflex sympathetic dystrophy:
retrospective analysis of 23 patients. J Neurosurg
1999; 90: 79–83.
126. Linderoth B, Foreman R. Physiology of spinal
cord stimulation: review and update.
Neuromodulation 1999; 2: 150–64.
127. Oakley JC, Prager JP. Spinal cord stimulation.
Spine 2002; 27: 2574–83.
128. Cui JG, O’Connor WT, Ungerstedt U, Linderoth B,
Meyerson BA. Spinal cord stimulation attenuates
augmented dorsal horn release of excitatory
amino-acids in mononeuropathy via a Gabaergic
mechanism. Pain 1997; 73: 87–95.
129. Robaina FJ, Dominguez R, Diaz M, Rodriguez JL,
de Vera JA. Spinal cord stimulation for relief of
chronic pain in vasospastic disorders of the upper
limbs. Neurosurgery 1989; 24: 63–7.
130. Barolat G, Schwartzman R, Woo R. Epidural
spinal stimulation in the management of reflex
sympathetic dystrophy. Steretact Funct Neurosurg
1989; 53: 29–39.
131. Kumar K, Nath RK, Toth C. Spinal cord
stimulation is effective in the management of
reflex sympathetic dystrophy. Neurosurgery 1997;
40: 503–9.
132. Kemler MA, Barendse GA, van Kleef M, de Vet
HC, Rijks CP, Furnee CA, van den Wildenberg
FA. Spinal cord stimulation in patients with
chronic reflex sympathetic dystrophy. N Engl J
Med 2000; 343: 618–24.
133. Kemler MA, de Vet HC, Barendse GA, van den
Wildenberg FA, van Kleef M. The effect of spinal
cord stimulation for chronic complex regional pain
syndrome type I: five-year final follow-up of
696 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
patients in a randomized controlled trial. J
Neurosurg 2008; 108: 292–8.
134. Harke H, Gretenkort P, Ladleif HU, Rahman S.
Spinal cord stimulation in sympathetically
maintained complex regional pain syndrome type
1 with severe disability. A prospective clinical
study. Eur J Pain 2005; 9: 363–73.
135. Kumar K, Rizvi S, Bnurs SB. Spinal cord
stimulation is effective in management of complex
regional pain syndrome 1: fact or fiction.
Neurosurgery 2011; 69: 566–80.
136. Van Eijs F, Geurts JW, Van Zundert J, Faber CG,
Kessels AG, Joosten EA, van Kleef M. Spinal cord
stimulation in complex regional pain syndrome
type 1 of less than 12-month duration.
Neuromodulation 2012; 15: 144–50.
137. Kemler MA, Furn" ee CA. Economic evaluation of
spinal cord stimulation for chronic reflex sym-
pathetic dystrophy. Neurology 2002; 59: 1203–9.
138. Taylor RS, Van Buyten JP, Buchser E, North R,
Bayliss S. The cost effectiveness of spinal cord
stimulation in the treatment of pain: a systematic
review of the literature. J Pain Symptom Manage
2004; 4: 370–8.
139. Taylor RS, Van Buyten JP, Buchser E. Spinal cord
stimulation for complex regional pain syndrome: a
systematic review of the clinical and cost-
effectiveness literature and assessment of
prognostic factors. Eur J Pain 2006; 10: 91–101.
140. Bulanova E, Bulfone-Paus S. P2 receptor,
mediated signaling in mastcell biology. Purinergic
Signal 2010; 6: 3–17.
141. Abraham SN, St John AL. Mast cell-orchestrated
immunity to pathogens. Nat Rev Immunol 2010;
10: 440–52.
142. Hogan QH, Abram SE. Neural blockade for
diagnosis and prognosis: a review. Anesthesiology
1997; 86: 216–41.
143. Cepeda MS, Carr DB, Lau J. Local anaesthetic
sympathetic blockade for complex regional pain
syndrome. Cochrane Database Syst Rev 2005; 4:
CD004598.
144. Stanton TR, Wand BM, Carr DB, Birklein F,
Wasner GL, O’Connel NE. Local anaesthetic
sympathetic blockade for complex regional pain
syndrome. Cochrane Database Syst Rev 2013; 8:
CD004598.
145. De Mos M, Huygen FJ, Dieleman JP, Koopman
JS, Stricker BH, Sturkenboom MC. Medical
history and the onset of complex regional pain
syndrome (CRPS). Pain 2008; 139: 458–466.
146. Beerthuizen A, Stronks DL, Huygen FJ, Passchier
J, Klein J, Spijker AV. The association between
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697

psychological factors and the development of
complex regional pain syndrome type 1 (CRPS1)-
A prospective multicenter study. Eur J Pain 2011;
15: 971–5.
147. Sharma A, Williams K, Raja SN. Advances in
treatment of complex regional pain syndrome:
recent insights on a perplexing disease. Curr Opin
Anaesthesiol 2006; 19: 566–72.
148. Freedman M, Greis AC, Marino L, Sinha AN,
Henstenburg J. Complex regional pain syndrome.
Phy Med Rehabil Clin N Am 2014; 25: 291–303.
149. Perez RS, Zollinger PE, Dijkstra PU, Thomassen-
Hilgersonm IL, Zuurmond WW, Rosebrand KC,
Geertzen JH. CRPS I task force. Evidence based
guidelines for complex regional pain syndrome
type I. BMC Neurology 2010; 10: 20.
150. Goebel A, Barker CH, Turner-Stokes L, Cameron H,
Cossins L, Eedy DJ, Haynes L, Johnson M, Lewis J,
McCabe CS, Nurmikko TJ, Okell R, Poole H,
Serpell M, Shenker N, Simpson B, Smith BH.
Complex regional pain syndrome in adults: UK
guideline for diagnosis, referral and management
in primary and secondary care. London: RCP, 2012.
151. Salibi A, Searle AE, Lindau TR. Complex regional
pain syndrome: a systemic review of the literature,
the past, present and future management. J Pain
Relief 2014; 3: 1–11.
152. Treede RD, Jensen TS, Campbell JN, Cruccu G,
Dostrovsky JO, Griffin JW, Hansson P, Hughes R,
Nurmikko T, Serra J. Neuropathic pain:
redefinition and a grading system for clinical and
research purpose. Neurology 2008; 70: 1630–5.
153. Naleschinski D, Baron R. Complex regional pain
syndrome type I: neuropathic or not? Curr Pain
Headache Rep 2010; 14: 196–202.
154. Oaklander AL, Rissmiller JG, Gelman LB, Zheng
L. Chang Yuchiao, Gott R. Evidence of focal
small-fiber axonal degeneration in complex
regional pain syndrome-I (reflex sympathetic
dystrophy). Pain 2006; 120: 235–43.
155. Albrecht PJ, Hines S, Eisenberg E, Pud D, Finlay
DR, Connolly MK, Pare M, Davar G, Rice FL.
Pathologic alterations of cutaneous innervation
and vasculature in affected limbs from patients
with complex regional pain syndrome. Pain 2006;
120: 244–66.
156. Goebel A, Blaes F. Complex regional pain
syndrome, prototype of a novel kind of
autoimmune disease. . Autoimmun Rev 2013; 12:
682–6.
157. Kohr D, Tschernatsch M, Schmitz K, Singh P,
Kaps M, Sch€afer KH, Diener M, Mathies J, Matz
Acta Anaesthesiologica Scandinavica 59 (2015) 685–697
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
COMPLEX REGIONAL PAIN SYNDROME TYPE I
O, Kummer W, Maih€ ofner C, Fritz T, Birklein F,
Blaes F. Autoantibodies in complex regional pain
syndrome bind to a differentiation-dependent
neuronal surface autoantigen. Pain 2009; 143: 246–
51.
158. Goebel A, Leite MI, Yang L, Deacon R, Cendan
CM, Fox-Lewis A, Vincent A. The passive transfer
of immunoglobulin G serum antibodies from
patients with longstanding Complex Regional
Pain Syndrome. Eur J Pain 2011; 15: 504.
e1–e6.
159. Goebel A, Baranowski A, Maurer K, Ghiai A,
McCabe C, Ambler G. Intravenous immuno-
globulin treatment of the complex regional pain
syndrome: a randomized trial. Ann Intern Med
2010; 152: 152–8.
160. O’Connell NE, Wand BM, McAuley J, Marston L,
Moseley GL. Interventions for treating pain and
disability in adults with complex regional pain
syndrome. Cochrane Database Syst Rev 2013; 4:
CD009416. doi: 10.1002/
14651858.CD009416.pub2.
161. Schwartzman RJ, Alexander MG, Grothusen JR.
The use of ketamine in complex regional pain
syndrome: possible mechanisms. Expert Rev
Neurother 2011; 11: 719–34.
162. Zhou HY, Chen SR, Pan HL. Targeting N-metil-D-
aspartate receptors for treatment of neuropathic
pain. Expert Rev Clin Pharmacol 2011; 4: 379–88.
163. Kosharskyy B, Almonte W, Shaparin N,
Pappagallo M, Smith H. Intravenous infusion in
chronic pain management. Pain Physician 2013;
16: 231–49.
164. Blonk MI, Koder BG, van den Bemt PM, Huygen
FJ. Use of oral ketamine in chronic pain
management. Eur J Pain 2010; 14: 466–72.
165. Pickering AE, McCabe CS. Prolonged ketamine
infusion as a therapy for complex regional pain
syndrome: synergism with antagonism? Br J Clin
Pharmacol 2013; 77: 233–8.
166. Finnerup NB, Sindrup SH, Jensen TS. The
evidence for pharmacological treatment of
neuropathic pain. Pain 2010; 150: 573–81.
167. Cho S, McCracken LM, Heiby EM, Moon DE, Lee
JH. Pain acceptance-based coping in complex
regional pain syndrome Type I: daily relations
with pain intensity, activity, and mood. J Behav
Med 2013; 36: 531–8.
168. Ost LG. The efficacy of acceptance and
commitment therapy: an updated systematic
review and meta-analysis. Behav Res Ther 2014;
61: 105–21.
697