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AANA Journal Course
5
Update for Nurse Anesthetists
6 CE Credits*
Complex Regional Pain Syndrome: A Review of
Diagnostics, Pathophysiologic Mechanisms, and
Treatment Implications for Certified Registered
Nurse Anesthetists
Daniel Watts, RN, BS
Michael J. Kremer, CRNA, PhD, FAAN
The pathophysiologic mechanisms for complex
regional pain syndrome (CRPS) are complex and elusive. The proposed etiologic mechanisms for CRPS
include inflammatory responses, peripheral or central
sensitization, and sympathetic dysfunction. Anesthesia care of patients with CRPS is challenging.
Treatments including physiotherapy, peripheral vaso-
Objectives
At the completion of this course, the reader should be
able to:
1.Discuss the symptoms of complex regional pain syndrome.
2.
Delineate the diagnostic criteria for complex regional pain syndrome.
3.Review the major pathophysiologic mechanisms of
complex regional pain syndrome.
4.
Describe the role of sympathetic dysfunction in
complex regional pain syndrome.
5.Discuss interventional and pharmacologic therapies
for chronic regional pain syndrome.
Introduction
The diagnosis of complex regional pain syndrome
(CRPS) is based on the history of the patient, symptoms,
and findings at the time of diagnosis. A diagnosis of
CRPS requires the existence of regional pain and sensory
changes after a noxious event. The pain is associated
dilators, sympathetic blockade, analgesics, and other
systemic medications can help optimize mobility, perfusion, and pain relief for affected patients.
Keywords: Chronic regional pain syndrome, history,
taxonomy, treatment.
with symptoms that may include abnormal skin color,
temperature change, abnormal sudomotor activity (sweat
gland stimulation), and/or edema. The severity of these
findings in combination results in continuing pain that
is disproportionate to any inciting event. There are 2
recognized types of CRPS: type 1 occurs without detectable nerve trauma. Minor injuries or a limb fracture may
precede the onset of symptoms. Type 2 CRPS develops
following injury of a major peripheral nerve.1 Often,
research and scientific literature do not differentiate
between CRPS 1 and CRPS 2. The terms CRPS 1 and
CRPS 2 will be used when referencing material that discriminates between these 2 types of CRPS. Incorporation
of biological, psychological, and social concepts, resulting in a comprehensive biopsychosocial model, has also
been suggested to explain the genesis and maintenance
of chronic pain.2
Diagnosis and Clinical Manifestations
A diagnosis of CRPS is based on clinical criteria, and, to
*AANA Journal Course No. 31 (Part 5): AANA Journal course will consist of 6 successive articles, each with objectives for the
reader and sources for additional reading. At the conclusion of the 6-part series, a final examination will be published on the AANA
website and in the AANA Journal. Successful completion will provide the participant 6 CE credits (6 contact hours). This course has
been prior - approved by the American Association of Nurse Anesthetists for 6 CE credits; AANA code number: 1025705, expiration
date: July 31, 2012. The American Association of Nurse Anesthetists is accredited as a provider of continuing nursing education
by the American Nurses Credentialing Center’s Commission on Accreditation. This educational activity is being presented with the
understanding that any conflict of interest on behalf of the planners and presenters has been reported by the author(s). Also, there
is no mention of off-label use for drugs or products.
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date, there is no “gold standard” for its diagnosis or any
objective diagnostic tool.3-9 The official CRPS taxonomy
was proposed during a 1994 consensus workshop attended by clinicians and scientists with backgrounds in
pain medicine and neurology. These workshop participants developed a standardized set of criteria that were
broad, inclusive, and appropriate for clinical and research
purposes. The International Association for the Study
of Pain (IASP) later adopted the criteria and taxonomy,
which include the following10,11:
•The presence of an initiating noxious event or a
cause of immobilization
•Continuing pain, allodynia, or hyperalgesia in which
the pain is disproportionate to any known inciting event
•Evidence at some time of edema, changes in blood
flow in the skin, or abnormal sudomotor activity in the
region of pain
•No condition present that would otherwise account
for the degree of pain and dysfunction
•CRPS 1 and 2 entail the described signs and symptoms of CRPS. CRPS 1 does not involve major nerve
damage, while CRPS 2 includes nerve damage.
Systematic validation research findings found that
these criteria had high sensitivity, but reports of specificity range from 0.36 to 0.60, leading to the potential for
overdiagnosis of CRPS.3-7 A consensus group endorsed
criteria for research (sensitivity, 0.70; specificity, 0.95)
and clinical use (sensitivity, 0.70; specificity, 0.69) that
improved the specificity from the IASP criteria.5,10 The
following proposed diagnostic criteria for CRPS await
endorsement by the IASP5,10:
•Continuing pain disproportionate to any inciting
event
•At least 3 of the 4 symptom categories:
1. Sensory: hyperesthesia
2. Vasomotor: temperature asymmetry and/or skin
color changes and/or skin color asymmetry
3.Sudomotor/edema: edema and/or sweating
changes and/or sweating asymmetry
4. Motor/trophic: decreased range of motion and/or
motor dysfunction (weakness, tremor, dystonia) and/or
trophic changes (hair, nail, skin)
•At least 2 positive sign categories:
1. Sensory: hyperalgesia (to pinprick) and/or allodynia (to light touch)
2. Vasomotor: temperature asymmetry and/or skin
color changes and/or asymmetry
3.Sudomotor/edema: edema and/or sweating
changes and/or sweating asymmetry
4.Motor/trophic: decreased range of motion
and/or motor dysfunction (weakness, tremor, dystonia, neglect) and/or trophic changes of the hair, nails,
or skin. Trophic changes can include wasting away of
the skin, tissue or muscle; thinning of the bones; and
changes in the growth or hair or nails, including thick-
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ening or thinning of hair or brittle nails.
Diagnostic tests used to rule out CRPS have ranged
from plain radiographs to electromyography, nerve velocity conduction studies, 3-phase bone scintigraphy,
and magnetic resonance imaging scans and Doppler flow
measurement. These tests all have low specificity for
CRPS. More recently, neurophysiologic techniques such
as transcranial magnetic stimulation, magnetoencephalography, and functional magnetic resonance imaging
studies have been used to elucidate pathologic central
signal processing changes that may be consistent with
CRPS. Other psychophysical analytic techniques have
been used to assess and quantify behavioral disturbances,
vascular dysfunction, and neurobehavioral changes.11,12
Genetic factors, including mutations in voltage-gated
sodium channels, may be involved in CRPS, based on
the occurrence of familial cases and several genetic association studies.13,14 Genetic assays can determine CRPS
prevalence and susceptibility, as demonstrated in a study
of the human leukocyte antigen (HLA) system in which
2 HLA alleles were found to be significantly associated
with CRPS.14
Although diagnostic criteria for CRPS exist, the clinical manifestations of this syndrome are variable. Most
often, CRPS occurs after physical trauma or surgery and
predominantly affects women. At least 50,000 new cases
of CRPS 1 occur annually in the United States within the
general population.15 A study in the Netherlands documented that 44% of patients with CRPS had a precipitating fracture and found the upper extremities to be more
commonly affected.16 There is a paucity of epidemiologic data on CRPS.17 Its incidence has been estimated to
include 1% to 2% of all fractures, 2% to 4% of all fractures
with peripheral nerve injuries, and as many as 35% of
Colles fractures.18 A retrospective review of 140 patients
with CRPS at the Mayo Clinic, Rochester, Minnesota,
found that 16% of cases occurred after surgery, with
the majority being orthopedic.19 Complex regional pain
syndrome is poorly understood, and there is scant information on the typical course of the disease. Although
changes in the diagnostic criteria have clarified identification of this syndrome, generalizable epidemiologic data
regarding CRPS are not available.17
Complex regional pain syndrome evolves through
different stages. The duration of each stage may be variable.20-23 Clinicians and researchers have described cases
categorized into 3 major sequential stages. The first stage
describes the acute changes related to pain and sensory
disturbances, vasomotor dysfunction, and edema and/or
sudomotor changes. The second stage occurs approximately 3 to 6 months after the first stage and includes
dystrophic changes with continuation of the signs and
symptoms associated with stage 1. The last stage is
described as atrophic with reduced pain and sensory
dysfunction, continued vasomotor dysfunction, and in-
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creased motor and/or trophic changes. A cluster analysis
study showed that CRPS signs and symptoms do not
exist sequentially, and that 3 specific CRPS subgroups
may exist24:
•A predominance of vasomotor dysfunction and
motor/tropic changes
•A predominance of sensory abnormalities and neuropathic pain signs and symptoms
•Higher frequencies of signs and symptoms from subgroup 1 and most signs and symptoms of subgroup 2
Further research is warranted to identify separate
physiologic mechanisms, diagnostic tools, and therapies
specific to each CRPS subgroup.24
Pathophysiologic Mechanisms
The pathophysiologic mechanisms for CRPS are complex
and remain elusive. One single causative mechanism is
unlikely. Many different mechanisms have been proposed for the major signs and symptoms associated with
CRPS. Proinflammatory neuropeptides and cytokines
such as tumor necrosis factor α and interleukins 1β, -2,
and -6 are implicated in the genesis of this syndrome.
Peripheral and central sensitization both contribute to
the exaggerated pain response and behavioral changes
seen in patients with CRPS.25
The proposed pathophysiologic mechanisms for CRPS
have been described in terms of their impact on the
central and peripheral nervous systems.26-30 Table 1
describes the proposed pathophysiologic mechanisms
of CRPS in the central nervous system, and Table 2 illustrates the proposed pathophysiologic mechanisms of
CRPS in the peripheral nervous system.
Sympathetic Dysfunction
The sympathetic nervous system has a multifactorial role
in CRPS. Researchers have associated the hyperalgesia
and vasomotor changes with sympathetic dysfunction.
Animal models provide direct evidence that adrenoreceptors can be expressed on afferent nociceptors in response
to persistent pain. Studies have shown cutaneous injections of norepinephrine induce pain via adrenoreceptors
in patients who respond favorably to sympathetic blocks,
whereas patients who do not respond to sympathetic
blocks are unresponsive to norepinephrine. These data
imply that CRPS involves pathologic adrenoreceptors
expressed on nociceptors that when stimulated by circulating catecholamines, eg, norepinephrine, cause hyperalgesia and, perhaps, allodynia.31,32
Additional research demonstrated associations
between specific vasomotor dysfunctions in patients with
acute versus chronic CRPS 1. In the early stages of CRPS
1, increased cutaneous temperature and perfusion values
were observed in the affected extremity that were believed
to be due to loss of sympathetic vasoconstrictor activity.
In chronic CRPS cases, decreased cutaneous temperature
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Proposed role of N-methyl-d-aspartate receptor–mediated
hyperexcitability in the spinal cord dorsal horn
Spinal cord neuron hyperexcitability can account for pain that
has a distally generalized distribution.
A persistent source of nociceptor drive may maintain hyperexcitability in central neurons.
Unilateral inhibition of central sympathetic vasoconstrictor activity is involved in vascular abnormalities.
Motor abnormalities are generated in the central nervous
system.
Table 1. Proposed Pathophysiologic Mechanisms of
Complex Regional Pain Syndrome in the Central
Nervous System26-30
Abnormal characteristics of primary afferents after lesion in
CRPS 2, eg, spontaneous discharge, sensitization, ectopic
mechanosensitivity, or acquired responsiveness to
norepinephrine
Proposed role in spontaneous discharge of sodium channel
accumulation in the terminal membrane
Proposed role of acquired norepinephrine responsiveness in
intact C nociceptor terminals whose axons travel in a damaged
nerve
Potential role of an inflammatory reaction and neurogenic
inflammation in the acute phase of CRPS
Table 2. Proposed Pathophysiologic Mechanisms of
CRPS in the Peripheral Nervous System26-30
Abbreviation: CRPS, complex regional pain syndrome.
and perfusion values in the affected extremity were attributed to hypersensitive sympathetic activity related to
circulating catecholamines. To account for the increased
sympathetic activity, eg, vasoconstriction, investigators
suggested that up-regulation of α-adrenoreceptors in the
cutaneous microvasculature was the mechanism of hypersensitivity. These mechanisms are consistent with the
observation that patients with acute CRPS have warm,
red extremities, whereas patients with chronic CRPS 1
have cool, bluish extremities.33 Another research team
reviewed primary data that suggested peripheral nerve
injury, typical of CRPS type 2, and found that this type
of nerve trauma also produced up-regulation of catecholamine receptors.2
It has been speculated that psychophysical mechanisms are related to sympathetic dysfunction, behavioral
disturbances, and persistent pain in patients with CRPS.
In addition to the up-regulation of vasoconstrictor
adrenoreceptors producing cool and pale skin, sympathetic receptor expression on afferent nociceptive
fibers causes spontaneous pain. This pain results in
increased circulating catecholamines that potentially
may exacerbate the sympathetically mediated symptoms.
Furthermore, avoidance behaviors because of the pain
may result in a decreased range of motion in the affected
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extremity and psychological dysfunction, which may
affect central signaling processes related to decreased
tactile and proprioceptive inputs and alter catecholamine
levels related to dysphoria.3
Certified Registered Nurse Anesthetists (CRNAs) have
a role in preventing CRPS and providing symptom
management. When individualizing the anesthetic care
plan, CRNAs must recognize patients with a history of
CRPS and patients who are at risk for the development
of CRPS.34 Precautions such as avoidance of vascular
access procedures and blood pressure measurement on
affected extremities should be taken. Analgesic requirements for patients with CRPS, as for other patients with
chronic pain, may be significantly increased. Preliminary
evidence shows a predictive value between the intensity
of preoperative knee pain and the development of CRPS
after total knee arthroplasty.35 Another documented risk
factor for CRPS is a family history of CRPS in patients
younger than 50 years.36 Several case reports have been
published that identify potential risk factors such as antecedent infections that raise the level of autoantibodies;
chronic inflammatory disorders, such as rheumatoid diseases; bone metabolic disorders; and amyotrophic lateral
sclerosis.37 One study found an association between
antecedent reports of headaches and the development
of CRPS.38
If a person has a history of CRPS or has known risk
factors, measures to reduce reoccurrence or exacerbation
should be instituted. It is recommended to delay surgery
on an affected extremity until the signs and symptoms
of CRPS are reduced at rest and perfusion is optimized.
Interventions such as physiotherapy, peripheral vasodilators, sympathetic blockade, and analgesia can help to
achieve optimized mobility, perfusion, and pain relief
before surgery. These interventions have been associated
with reduced postoperative incidence of CRPS.19
Regional anesthesia may be more appropriate because
of the blockade of sympathetic outflow seen with regional blocks. However, not all regional techniques are
completely sympatholytic. For example, carpal tunnel
surgery performed under local anesthesia does not result
in complete sympathetic blockade and has been associated with high reoccurrence rates of CRPS. In such cases, a
stellate ganglion block has reduced reoccurrence rates. A
prospective, double-blind, randomized study found that
intravenous regional blocks using lidocaine with clonidine were more effective than blocks with lidocaine alone
in reducing the reoccurrence rate of CRPS after hand
surgery.19 Similar findings have been reported related to
the use of epidural blocks and decreased reoccurrence of
CRPS after lower extremity surgery. In addition, pharmacologic therapies may be implemented preemptively
and/or postoperatively in patients with CRPS. Several
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Peripheral nerve blocksa
Spinal cord and peripheral nerve stimulators
Pump implantation
Treatment Approaches
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Interventional therapies
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Chemical and surgical sympathectomy
Deep brain stimulation
Pharmacologic therapies
Bisphosphonate compounds
Phentolamine
Systemic steroids
Antidepressants
Anticonvulsants
Opioids
Benzodiazepines
Table 3. Interventional and Pharmacologic Therapies
for Complex Regional Pain Syndrome (CRPS)39-41
a Believed to be the “gold standard” for treatment of sympatheti-
cally maintained pain in CRPS 1.
pharmacologic therapies have been used to reduce the
incidence of CRPS after high-risk surgery, eg, vitamin
C, calcitonin, dimethyl sulfoxide, N-acetylcysteine, mannitol, and carnitine.
Vitamin C was effective in a prospective, randomized,
double-blind placebo-controlled study of 217 patients
with wrist fractures. The patients received vitamin C or
a placebo, and statistically significant incidences of 7%
and 22%, respectively, for the development of CRPS were
found.39
Several interventional and pharmacologic therapies
exist for patients with CRPS. These therapies are described in Table 3.
The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine may have a role in alleviating severe pain
among inpatients with CRPS who are unresponsive to
traditional therapies. A retrospective study examined 33
patients with CRPS treated with subanesthetic ketamine
infusions and found that 76% of patients experienced
complete relief of their pain, while 18% had partial
relief and 6% had no relief. Furthermore, 100% of the
patients who underwent repeated courses of therapy had
complete relief of CRPS pain. The duration of effect was
longer than 3 months in 54% of patients, and with repeated courses, 33% of patients were pain-free for longer than
3 years.42 As previously described, spinal cord NMDA
receptors are implicated in central sensitization modifications in response to sustained noxious nociceptor stimulation. The authors concluded that prolonged ketamine
infusions may block the exaggerated effects of glutamate
on the NMDA receptor and potentially reverse the central
changes associated with windup mechanisms.42
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Conclusion
The etiologic factors for CRPS may include inflammatory
responses, peripheral and central sensitization, and sympathetic dysfunction. Proinflammatory neuropeptides
and cytokines such as tumor necrosis factor α and interleukins 1β, -2, and -6 are also implicated in the genesis
of this syndrome. Peripheral and central sensitization
both contribute to the exaggerated pain response and
behavioral changes seen in patients with CRPS. Central
expression of neuropeptides and cytokines induces sensitization and neuronal plasticity, with structural changes
resulting in dorsal horn neurons. Other brain abnormalities in patients with CRPS may include atrophic changes
in the insula, ventromedial prefrontal cortex, and nucleus
accumbens. The sympathetic nervous system has a multifactorial role in CRPS, including hyperalgesia and vasomotor changes associated with this syndrome.
Surgery involving limbs affected by CRPS should
be delayed until the signs and symptoms of CRPS are
reduced at rest and perfusion is optimized. Interventions
such as physiotherapy, peripheral vasodilation, sympathetic blockade, and analgesics can help achieve optimized mobility, perfusion, and pain relief before surgery.
Pharmacologic therapies that have been used to reduce
the incidence of CRPS after surgery include vitamin C,
calcitonin, dimethyl sulfoxide, N-acetylcysteine, mannitol, and carnitine.
Interventional and pharmacologic therapies for patients with CRPS include nerve blocks, spinal cord and
peripheral nerve stimulation, pump implantation, chemical and surgical sympathectomy, and deep brain stimulation. Peripheral nerve blocks and other sympatholytic
therapies are believed to be efficacious for the treatment
of sympathetically mediated pain in CRPS 1. Other
pharmacologic therapies may include bisphosphonate
compounds, adrenergic drugs such as phentolamine,
systemic steroids, various antidepressants, antiseizure
drugs, and various narcotics and benzodiazepines.
This complex syndrome continues to challenge people
afflicted with it and their treating clinicians. As the
pathophysiologic mechanisms of CRPS are further elucidated, additional treatment modalities may emerge that
provide long-lasting relief for patients with CRPS.
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AUTHORS
34. Nelson D, Stacey B. Interventional therapies in the management of
complex regional pain syndrome. Clin J Pain. 2006;22(5):438-442.
Daniel E. Watts, RN, BS, is a student in the Rush University College of
Nursing Nurse Anesthesia Program in Chicago, Illinois. Email: Daniel_
[email protected].
35. Harden RN, Bruehl S, Stanos S, et al. Prospective examination of
pain-related and psychological predictors of CRPS-like phenomena following total knee arthroplasty: a preliminary study. Pain.
2003;106(3):393-400.
Michael J. Kremer, CRNA, PhD, FAAN, is professor and director of the
Nurse Anesthesia Program in the Rush University College of Nursing, and
is a staff nurse anesthetist at Rush University Medical Center in Chicago,
Illinois. Email: [email protected].
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