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Complex Regional Pain Syndromes

Author: Anthony H Wheeler, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA more...

Updated: Apr 3, 2012

Background
In 1994, a consensus group of pain medicine experts gathered by the International Association for the
Study of Pain (IASP) agreed on diagnostic criteria for reflex sympathetic dystrophy (RSD) and
causalgia, and renamed them complex regional pain syndrome (CRPS) types I and II, respectively.
These designations were determined by the type of inciting event, rather than by any differences in
clinical presentation or pathophysiology. Many experts felt that the IASP diagnostic criteria were
ambiguous; however, these criteria were developed as just a starting point, and the IASP fully intended
[1, 2]
to validate them through clinical research studies.

CRPS type I requirements feature causation by an initiating noxious event, such as a crush or soft
tissue injury; or by immobilization, such as a tight cast or frozen shoulder. CRPS type II is characterized
by the presence of a defined nerve injury. Both types demonstrate continuing pain, allodynia, or
hyperalgesia that is usually disproportionate to the inciting event. At some point during the syndrome's
development, both show evidence of edema, changes in skin blood flow revealed by color changes and
skin temperature changes greater than 1.1°C from the homologous body part, or abnormal sudomotor
activity in the painful region. Both types require the exclusion of any other condition that might account
[1, 3]
for the degree of pain and dysfunction seen.

The 1994 IASP criteria have proven to be extremely sensitive (ie, they rarely miss a true case of
CRPS). However, since their inception, the 1994 taxonomy has been criticized by experts on clinical
criteria validation and specialists in pain medicine on the grounds that the criteria are insufficiently
specific (ie, use of the criteria results in overdiagnosis of CRPS). A small single center validation study
demonstrated empirically that the 1994 CRPS criteria did indeed cause overdiagnosis of the
[3]
syndrome.

In response to such concerns, investigators used factor analysis to categorize 123 patients with CRPS
[4]
into 4 statistically distinct subgroups. This resulted in modified diagnostic criteria felt to be valuable for
[4, 5]
further validation studies.

In 2003, a closed workshop was held in Budapest, Hungary to study and resolve this matter. Experts in
[6]
CRPS published the results of this workshop in a 2007 review article showing that the modified
criteria, mentioned above, produced better discrimination between CRPS and non-CRPS neuropathic
[6]
pain, yielding better diagnostic accuracy than the original unmodified criteria.

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The study results indicated that when 2 of 4 sign categories were present and 3 of 4 symptom
categories were present, the resultant sensitivity was 0.85 and the specificity was 0.69 for a clinical
diagnosis of CRPS. This appeared to be a good compromise between identifying as many patients as
possible in the clinical context and substantially reducing the high level of false-positive diagnoses
associated with the 1994 IASP criteria. However, a higher specificity is required to meet research
criteria, so the committee recommended that 2 of the 4 sign categories and all 4 symptom categories
must be positive for the diagnosis to be made in a research setting, resulting in a sensitivity of 0.70 and
specificity of 0.94.

Due to the combination of increased specificity and reduced sensitivity, about 15% of patients
previously diagnosed with CRPS were considered "without a diagnosis." Therefore, a third diagnostic
subtype, complex regional pain syndrome not otherwise specified (CRPS-NOS), was recommended to
[7]
categorize those patients. These new IASP diagnostic criteria have been submitted to the medical
committee for Classification of Chronic Pain of the IASP for future revision of formal taxonomy and
diagnostic criteria.

The criteria are given here in hopes that higher specificity for the identification of CRPS will enhance
research into the pathoetiology of this disorder without creating a reduced, or even harmful, rate of
clinical diagnosis that could deny affected patients access to treatment. In addition, these criteria may
[6, 8, 7]
result in more cost-effective approaches for the management of this disorder. At present, despite
these and numerous other studies, no universally accepted set of new consensus criteria has yet
emerged.

IASP-proposed revised CRPS clinical diagnostic criteria

A clinical diagnosis of CRPS can be made when the following criteria are met:

Continuing pain that is disproportionate to any inciting event

At least 1 symptom reported in at least 3 of the following categories:
Sensory: Hyperesthesia or allodynia
Vasomotor: Temperature asymmetry, skin color changes, skin color asymmetry
Sudomotor/edema: Edema, sweating changes, or sweating asymmetry
Motor/trophic: Decreased range of motion, motor dysfunction (eg, weakness, tremor,
dystonia), or trophic changes (eg, hair, nail, skin)
At least 1 sign at time of evaluation in at least 2 of the following categories:
Sensory: Evidence of hyperalgesia (to pinprick), allodynia (to light touch, temperature
sensation, deep somatic pressure, or joint movement)
Vasomotor: Evidence of temperature asymmetry (>1°C), skin color changes or asymmetry
Sudomotor/edema: Evidence of edema, sweating changes, or sweating asymmetry
Motor/trophic: Evidence of decreased range of motion, motor dysfunction (eg, weakness,
tremor, dystonia), or trophic changes (eg, hair, nail, skin)
No other diagnosis better explaining the signs and symptoms

Pathophysiology
Hypothetical mechanisms

In most cases, experts believe that CRPS develops when persistent noxious stimuli from an injured
body region leads to peripheral and central sensitization, whereby primary afferent nociceptive
mechanisms demonstrate abnormally heightened sensation, including spontaneous pain and
hyperalgesia. Allodynia and hyperalgesia occur when central nervous system (CNS) somatosensory
processing misinterprets normal nonpainful mechanical stimuli, such as light touching of the skin, as
painful. Therefore, skin in the injured area becomes more sensitive to all stimuli, even nonpainful
stimuli. In addition, the sensitization can extend beyond the originally injured area, thus enlarging the
region of aberrant pain perception.

A similar impairment of CNS processing leads to motor aberrancies, such as weakness or tremor in the
affected area. The peripheral and central sensitization associated with impaired CNS processing is

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linked to proposed disturbances within the sympathetic nervous system (SNS) that lead to sympathetic
hyperactivity adversely affecting the injured area. Studies suggest that an augmented inflammatory
response coupled with impaired healing further contribute to the refractory nature of malevolent
[9, 2, 10, 11, 12]
CRPS.

Peripheral and central sensitization

Mechanical, thermal, and chemical stimuli activate peripheral nociceptors that transmit pain messages
through lightly myelinated A-delta fibers and unmyelinated C fibers projecting to Rexed layers I, II, and
V in the spinal cord. This process leads to the release of excitatory amino acids, such as glutamine and
asparagine, which then act upon N -methyl-D -aspartic acid (NMDA) receptors, causing the release of
substance P (SP). SP then lowers the threshold for synaptic excitability in normally silent second-order
[9, 2, 10, 11, 12]
interspinal synapses.

Peripheral sensitization occurs when persistent or repetitive noxious stimulation of high-threshold,

polymodal C fibers results in enhanced sensitivity, lower stimulus thresholds, and the prolonged,
enhanced activation of dorsal horn cells, especially those with glutamate receptors. In addition to SP,
algogenic substances that are typically involved in tissue damage and capable of inducing transduction
centripetally include potassium, serotonin, bradykinin, histamine, prostaglandins, and leukotrienes.
Neuropeptides, such as SP and calcitonin gene-related peptide (CGRP), are also transported to the
endings of nociceptive afferents where they can instigate ortho- and retrograde actions including, but
not limited to, neurogenic inflammation, which can incite a host of additional hostile algogenic
mechanisms.

Chronic CNS sensitization is engendered through afferent processing by second-order nociceptor-

specific neurons and wide-dynamic-range (WDR) neurons in the spinal cord. WDR neurons contribute
more to sensitivity than nociceptor-specific neurons, because both nociceptive and non-nociceptive
afferents converge to synapse on a single WDR neuron, and WDR neurons respond with equal intensity
regardless of whether the neural signal is noxious (hyperalgesia) or not.

Hyperalgesia and allodynia initially develop at the injury site. However, after CNS sensitization occurs
through WDR neural activity, the area of pain expands beyond the initial region of tissue pathology. The
peripheral changes described eventually cause an injury environment, where primary afferents,
including nociceptors, demonstrate an increased sensitivity to circulating or experimentally injected
[13, 2, 10, 11, 12, 14, 15, 16, 17, 18, 19]
subcutaneous norepinephrine.

Sympathetically maintained pain (SMP)

For decades, CRPS was thought to be caused by SNS hyperactivity, and the pain experienced by those
who suffer from CRPS was believed to be SMP. SNS involvement in CRPS is supported clinically by the
presence of abnormal patterns in skin temperature, skin color, and sweating in the affected extremities.
Surgical and chemical sympathectomy can relieve pain in some cases. However, under normal
physiological circumstances, there is no interaction between the sympathetic and peripheral afferent
[13, 2, 20, 21, 22]
nociceptive neurons. Furthermore, multiple discrepancies undermine the possibility of
SNS involvement. These discrepancies include the following: (1) plasma catecholamine concentrations
[23, 24]
are lower in CRPS-affected limbs , (2) most CRPS patients do not obtain significant or lasting pain
[25, 26]
relief from sympathetic blocks , and (3) skin temperature does not correlate with the activity of
[27]
sympathetic vasoconstrictor neurons.

To explain these incongruities, the pathophysiology of SMP was hypothesized to involve an abnormal
[28]
coupling between sympathetic efferent and nociceptive afferent neurons. Two possible conditions
may lead to pathological coupling: interactions between sympathetic efferents and intact or regenerating
peripheral nociceptive C-fiber neurons, or between sympathetic vasoconstrictor neurons and afferent
[29]
somata within the dorsal root ganglion (DRG).

This coupling is mediated by norepinephrine, which is released from newly expressed sympathetic
terminals and adrenoreceptors onto afferent nociceptive neurons. Indeed, increased mRNA for alpha-

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[30]
2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury. Therefore, an
increased number of targeted and functionally upregulated adrenoreceptors on lesioned nociceptive
afferents, which has been demonstrated, would explain how reduced SNS activity in CRPS is capable
[21, 2]
of maintaining pain.

Evidence suggests that early autonomic symptoms and signs of CRPS are indicative of CNS
[31]
dysfunction. Wasner et al suggest that warmth of the affected extremity in the early stages of CRPS I
is caused by the functional inhibition of central cutaneous vasoconstrictor activity, leading to cutaneous
[22]
vasodilation. However, over time, this inhibition may lead to adrenergic hypersensitivity from
peripheral denervation and/or sympathetic denervation.

Thus, in CRPS I, the early inhibition of central cutaneous vasoconstrictor activity leads to vasodilation in
the denervated area causing it to feel warm. The later increased sensitivity to circulating
catecholamines due to upregulation of cutaneous adrenoreceptors causes vasoconstriction and
coolness. Interestingly, studies of direct nerve injuries (CRPS II) show the same results. Initially,
vasodilation is present within the denervated area, causing the skin adjacent and on the same side to
become abnormally warm at first and then change to a chronically cold status. Other mechanisms
include an increased density of cutaneous α-adrenoreceptors and a pathological upregulation of
[13, 2, 26, 20, 28, 29, 30, 31, 22]
α-adrenergic receptors.

Based on recent clinical studies, patients with neuropathic pain presenting with similar clinical signs and
symptoms can be clearly divided into 2 groups by the positive and negative effects of selective
sympathetic blockade, selective activation of sympathetic activity, and antagonism of α-adrenergic
[32]
receptor mechanisms. Pain relieved by sympatholytic procedures is considered to be SMP. SMP is
now defined as a symptom or underlying mechanism in a subset of patients with neuropathic disorders.
CRPS is one such neuropathic disorder. However, SMP is not a clinical entity per se. Nor is it a sine
qua non for CRPS as was previously believed. Thus, the positive effect of sympathetic blockade is not
essential for the diagnosis of CRPS. On the other hand, the only way to differentiate between SMP and
sympathetically independent pain (SIP) is to test the efficacy of a correctly applied sympatholytic
[33]
intervention.

Sensory and motor dysfunction

In both types of CRPS, peripheral and central sensitization explain the pathophysiology of spontaneous
pain and hyperalgesia.
[34]
Clinical findings in patients consistently show sensory impairments that medic
spread beyond the injured territory, and spontaneous pain that often engulfs a quadrant or hemisensory olegal
region. These abnormal patterns are due to altered central afferent processing and have been
[35, 36, 37]
delineated with functional imaging studies.

Likewise, the evidence to date supports the presence of similar mechanisms involving abnormalities of
CNS motor processing (rather than pain, edema, disuse, trophic changes, or nerve injury) that are
responsible for causing impairments of muscle strength in the involved distal extremity. Kinematic
analysis studies suggest that motor deficits are probably due to impaired integration of visual and
[38]
sensory afferent input within the parietal cortex. Also, an increased amplitude of physiological tremor
[39]
due to CNS mechanisms is common, occurring in about 50% of patients under observation.

Aberrant healing and exaggerated inflammation

After tissue injury, the body's response is programmed to promote healing, with the goal of regaining full
use of the injured body part. Some experts have hypothesized that CRPS is caused by an aberrant
healing response that includes exaggerated and persistent inflammation and guarding.

At the site of injury, peripheral C-fiber nociceptors transmit pain messages that cause ortho- and
retrograde release of SP and CGRP into the damaged tissues, resulting in vasodilation, extravasation
of pronociceptive mediators, reactivation and further sensitization of C-fiber afferents, and increased
[13, 10]
tissue comorbidity in the injured area. These neuropeptides prompt the physical signs of
inflammation, including redness, warmth, and swelling, that are also commonly present in early CRPS.

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Also, algogenic substances are released, which increase nociception and initiate the process of
peripheral sensitization previously discussed. Skin sensitivity and tenderness spread into adjacent
regions, which are thought to be caused by secondary hyperalgesia from CNS alterations that are
consistent with the described sensitization process.

Protective disuse

Decreased use of an injured body part would appear to be a normal postinjury reaction. After injury, the
organism protects and guards the injured body part to optimize healing and prevent reinjury. A normally
healing organism gradually increases its use of the injured region, which aids in recovery and
reintegration of the body part into the organism’s normal sense of self. However, excessive protection
and guarding, such as casting or splinting, is commonly promoted by care providers, increasing the
patient’s disuse of the extremity and promoting fear-avoidance, which may progress into a neurological
neglect-like syndrome.
[39]
This phenomenon has been postulated as a cause in some patients with CRPS. Many of the
symptoms and signs of CRPS are consistent with those that would naturally develop from lack of use.
For example, an unused dependent limb eventually develops swelling (dependent edema), coolness
[13, 2, 40]
(decreased blood flow), and trophic changes (decreased blood flow).

Epidemiology
Frequency

United States

A population-based study by Sandroni et al showed an incidence of approximately 5.5 per 100,000

[41]
person-years at risk and a prevalence of about 21 per 100,000 for CRPS type I. The same study
[41,
showed an incidence of 0.8 per 100,000 and a prevalence of about 4 per 100,000 for CRPS type II.
13] [41, 13]
Therefore, the incidence of CRPS type I is higher than that of CRPS type II. The reported
[13]
incidence of CRPS type I is 1-2% after various fractures , while that of CRPS type II approximates
[13, 42] [43]
1-5% after peripheral nerve injury . The incidence of CRPS is 12% after a brain injury and 5%
[44]
after a myocardial infarction .

Mortality/Morbidity

Despite treatment, many patients are left with varying degrees of chronic pain, trophic changes, and
disability. Pain is the most important factor leading to disability. Some have suggested that the
aggressive treatment of pain in an acute setting could reduce the incidence of CRPS type I; however,
further studies are needed to support this contention. Remissions followed by relapses have also been
described. The frequency of the HLA-DQ1 antigen appears to be higher in patients with CRPS than in
[45,
controls, and HLA-DR13 is associated with progression towards multifocal or generalized dystonia.
46] [47]
Recently, a new HLA I locus was detected that may predict the spontaneous onset of CRPS.

Race

CRPS affects all races; no differences in incidence or prevalence have been observed.

Sex
[13, 48,
Females experience CRPS more commonly than males do by a ratio that varies from 2:1 to 4:1.
41, 49, 50, 5, 51]

Age

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[13, 48,
CRPS is distributed across age groups, but reaches its peak incidence between 37 and 50 years.
41, 49, 50, 5, 51]
CRPS has an increased incidence in adolescents, compared with children, with females
affected more frequently at a ratio of 4:1 and increased occurrence in the lower extremities rather than
the upper by a ratio of 5.3:1. The mean age of onset is 12.5 years in a cohort of 396 children. The
highest incidence of the disease appears to be in adults aged 40-49 years. CRPS appears frequently in
almost every age group except children. CRPS type I has been seen in children, but the incidence is
much lower than in adults.

Contributor Information and Disclosures

Author
Anthony H Wheeler, MD Pain and Orthopedic Neurology, Charlotte, North Carolina

Anthony H Wheeler, MD is a member of the following medical societies: American Academy of

Neurology, American Academy of Pain Medicine, North American Spine Society, and North Carolina
Medical Society

Disclosure: Allergan, Inc. Salary Speaking and teaching; Gralise None Consulting

Specialty Editor Board

Jorge E Mendizabal, MD Consulting Staff, Corpus Christi Neurology

Jorge E Mendizabal, MD is a member of the following medical societies: American Academy of

Neurology, American Headache Society, National Stroke Association, and Stroke Council of the
American Heart Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical
Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular

Diseases, Washington University School of Medicine; Director of Neurology Clinic, St Louis
ConnectCare; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology,
American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa

Disclosure: Baxter Grant/research funds Other; Amgen Grant/research funds None

Chief Editor
Stephen A Berman, MD, PhD, MBA Professor of Neurology, University of Central Florida College of
Medicine

Stephen A Berman, MD, PhD, MBA is a member of the following medical societies: Alpha Omega
Alpha, American Academy of Neurology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

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