Complex regional pain syndrome

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Complex Regional Pain Syndrome (CRPS)

Classification and external resources

Reflex sympathetic dystrophy

ICD-10 M89.0, G56.4

ICD-9 337.21, 337.22, 354.4,355.71

DiseasesDB 12635 16345

MedlinePlus 007184

eMedicine pmr/123

MeSH D020918
Complex regional pain syndrome (CRPS), formerly reflex sympathetic dystrophy (RSD) or
"causalgia", reflex neurovascular dystrophy(RND), or amplified musculoskeletal pain syndrome (AMPS),
is a chronic systemic disease characterized by severe pain, swelling, and changes in the skin. CRPS is
expected to worsen over time.[1] It often initially affects an arm or a leg and often spreads throughout the body;
92% of patients state that they have experienced a spread, and 35% of patients report symptoms in their whole
body.[2] Recent evidence has led to the conclusion that Complex Regional Pain Syndrome is a multifactorial
disorder with clinical features of neurogenic inflammation, nociceptive sensitisation (which causes extreme
sensitivity or allodynia), vasomotor dysfunction, and maladaptive neuroplasticity, generated by an aberrant
response to tissue injury.[3] Treatment is complicated, involving drugs, physical therapy, psychologic treatments,
and neuromodulation and usually unsatisfactory, especially if begun late.[4]

CRPS is associated with dysregulation of the central nervous system[5] and autonomic nervous
system resulting in multiple functional loss, impairment, and disability. The International Association for the
Study of Pain has proposed dividing CRPS into two types based on the presence of nerve lesion following the
injury.

Type I, formerly known as reflex sympathetic dystrophy (RSD), Sudeck's atrophy, reflex
neurovascular dystrophy (RND), or algoneurodystrophy, does not have demonstrable nerve lesions. With
the vast majority of patients diagnosed with CRPS being of this type, most of the literature thus refers to
type I.

Type II, formerly known as causalgia, has evidence of obvious nerve damage. Type II CRPS tends
towards the more painful and difficult to control aspects of CRPS; type II scores 42 out of 50 on the McGill
pain scale [6] (however there is seemingly little or no data pertaining to type I specifically here). In Type II
the "cause" of the syndrome is the known or obvious nerve injury, although the cause of the mechanisms
of CRPS Type II are as unknown as the mechanisms of Type I.

CRPS has the unfortunate honour of being described as being one of the most painful long term conditions,
scoring 42 out of a possible 50 on the McGill pain scale, above such events as amputation and childbirth.
[7]
Lack of social awareness has inspired patients to campaign for more widespread knowledge of CRPS, [8] and
lack of clinical awareness has led to the creation of support groups seeking to self-educate with the latest
research.[9]

Evidence suggests that CRPS has both physical and psychological factors. CRPS is said to cause
physiological problems (rather than physiological problems causing CRPS); whilst "research does not reveal
support for specific personality or psychopathology predictors of the condition" there are psychosocial factors to
CRPS (such as reduced quality of life and impaired occupational function) and psychological problems (which
include increased depression and anxiety). [10] Unsurprisingly, there is overwhelming evidence of limbic
system involvement.[11] Sadly this very poor quality of life for some has led to high rates of depression and
suicide among sufferers, which has motivated appeals for greater understanding. The AFPS leaflet on CRPS
and prevention of suicide is available online here: CRPS and Suicide Prevention.

Daily vitamin C has been shown to reduce the risk of CRPS after an injury, leading to calls for greater
awareness, especially in the emergency room setting. In two placebo-controlled randomized clinical trials
Zollinger et al. showed that patients who took 500 mg of vitamin C daily after a wrist fracture were less likely to
incur the problem.[12] The cause of CRPS is currently unknown. Precipitating factors include injury and surgery,
although there are documented cases that have no demonstrable injury to the original site.

New research is demonstrating how Complex Regional Pain Syndrome is a systemic disease. Potentially any
organ could be affected.[13] There are many internal complications that are frequently not acknowledged. CRPS
affects the systems of cognition; constitutional, cardiac, and respiratory complications; systemic autonomic
dysregulation; neurogenic edema; musculoskeletal, endocrine, and dermatological manifestations; and
urological and gastrointestinal function.[14] Recently work has shown how CRPS can spread to the stomach,
with resulting symptoms of daily vomiting and extreme pain,[15] though the pain experienced feels different than
that in the extremity.

With the growing body of evidence persuasively indicating the progressive and systemic implications of chronic
CRPS,[16] there is concern that these patients may be erroneously also diagnosed with fibromyalgia.
Fibromyalgia has a MPQ score of 35.7/50,[17] whereas CRPS averages a 42/50 MPQ. Chronic CRPS patients
would react to the pressure points of the brachial plexus, the intercostobrachial (ICB) nerve and concomitant
L5-S1, injury.[18] The similarities between multiple sclerosis and CRPS (which include symptoms of muscle
twitching and tremors, wobbliness, falling, and visionary disturbances) have inspired research; when MS
patients were tested for CRPS, incidents of the disease was more than 50 times higher than in the average
population.[19] As glial activation and central sensitization in the central nervous system are evident in both
CRPS and MS, favourable results were evident when CRPS was treated with low-dose naltrexone (a glial
attenuator used in the treatment of MS).[20]

History and nomenclature[edit]

The condition currently known as CRPS was originally described during the American Civil War by Silas Weir
Mitchell, who is sometimes also credited with inventing the name "causalgia." [21]However, this term was actually
coined by Mitchell's friend Robley Dunglison from the Greek words for heat and for pain. [22] Contrary to what is
commonly accepted, it emerges that these causalgias were certainly major by the importance of the vasomotor
and sudomotor symptoms but stemmed from minor neurological lesions. Mitchell even thought that the CRPS
etiology came from the cohabitation of the altered and unaltered cutaneous fibres on the same nerve
distribution territory.[23] In the 1940s, the term reflex sympathetic dystrophy came into use to describe this
condition, based on the theory that sympathetic hyperactivity was involved in the pathophysiology.[24] In 1959,
Noordenbos observed in caulsalgia patients that "the damage of the nerve is always partial." [25] Misuse of the
terms, as well as doubts about the underlying pathophysiology, led to calls for better nomenclature. In 1993, a
special consensus workshop held in Orlando, Florida, provided the umbrella term "complex regional pain
syndrome", with causalgia and RSD as subtypes.[26]

severe CRPS of right arm

CRPS visible on hands and wrists

Pathophysiology[edit]
Evidence from functional MRI data indicates that CRPS could be a systemic disease with a unified diagnosis
(rather than a collection of symptoms).[27]The "underlying neuronal matrix" of CRPS is seen to involve cognitive
and motor as well as nociceptive processing; pinprick stimulation of a CRPS affected limb was painful
(mechanical hyperalgesia) and showed a "significantly increased activation" of not just the S1 cortex
(contralateral), S2 (bilateral) areas, and insula (bilateral) but also the associative-somatosensory cortices
(contralateral), frontal cortices, and parts of the anterior cingulate cortex. [28] In contrast to previous thoughts
reflected in the name RSD, it appears that there is reduced Sympathetic Nervous System outflow, at least in
the affected region (although there may be sympatho-afferent coupling). [29] Wind-up (the increased sensation of
pain with time)[30] and central nervous system (CNS) sensitization are key neurologic processes that appear to
be involved in the induction and maintenance of CRPS. [31]

There is compelling evidence that the N-methyl-D-aspartate (NMDA) receptor has significant involvement in the
CNS sensitization process.[32] It is also hypothesized that elevated CNS glutamate levels promote wind-up and
CNS sensitization.[31] In addition, there is experimental evidence that demonstrates NMDA receptors in
peripheral nerves.[33] Because immunological functions can modulate CNS physiology, it has also been
hypothesized that a variety of immune processes may contribute to the initial development and maintenance of
peripheral and central sensitization.[34][35]Furthermore, trauma related cytokine release, exaggerated neurogenic
inflammation, sympathetic afferent coupling, adrenoreceptor pathology, glial cell activation, cortical
reorganisation,[36] and oxidative damage (e.g., by free radicals) are all concepts that have been implicated in
the pathophysiology of CRPS.[37]

The pathophysiology of Complex Regional Pain Syndrome has not yet been defined; there is conjecture that
CRPS, with its variable manifestations, could be the result of multiple pathophysiologies. [29]

It has been further suggested that CRPS is in fact an auto-immune disease where the body's own antibodies
are directed at ones own nerves.[38]

Susceptibility[edit]
CRPS can strike at any age, but the mean age at diagnosis is 42. [39] CRPS has been diagnosed in children as
young as 2 years old.[40] It affects both men and women; however, CRPS is three times more frequent in
females than males.[39] The number of reported CRPS cases among adolescents and young adults is
increasing.[41]

Investigators estimate that 2-5% of those with peripheral nerve injury,[39] and 13-70 percent of those
with hemiplegia (paralysis of one side of the body),[42] will suffer from CRPS. In addition, some studies have
indicated that cigarette smoking was strikingly present in patients and is statistically linked to RSD. In one
study, 68% of patients versus 37% of hospitalized controls were found. This may be involved in its pathology by
enhancing sympathetic activity, vasoconstriction, or by some other unknown neurotransmitter-related
mechanism.[43]

It is also theorized that certain people might be genetically predisposed to develop symptoms of RSD/CRPS
after a significant or seemingly insignificant injury has been sustained. [44] These tests are being performed by
The Reflex Sympathetic Dystrophy Syndrome Association (RSDSA), American RSD Hope, and Richard G.
Boles, M.D. Research began in October 2008, but the outcome has yet to be released to the medical
community.[45]

Symptoms[edit]

Clinical features of CRPS have been found to be neurogenic inflammation, nociceptive

sensitisation, vasomotor dysfunction, and maladaptive neuroplasticity.[3] The symptoms of CRPS usually initially
manifest near the site of an injury, which is usually minor. The most common symptoms overall are pain
sensations, including burning, stabbing, grinding, and throbbing. Moving or touching the limb is often
intolerable. The patient may also experience muscle spasms, local swelling, sensitivity to things such as water,
touch, and vibrations, abnormally increased sweating, changes in skin temperature (usually hot but sometimes
cold) and color (bright red or a reddish violet), softening and thinning of bones, joint tenderness or stiffness,
and/or restricted or painful movement. Falls, pre syncope, and syncope are infrequently reported, as are visual
problems. Regional Osteoporosis is possible. The symptoms of CRPS vary in severity and duration. Since
CRPS is a systemic problem, potentially any organ can be affected.

The pain of CRPS is continuous, and it is widely recognised that it can be heightened by emotional or physical
stress.[46] Limbic system involvement suggests a propensity for trouble with sleeping, mood, appetite, and
sexual desire; in a study of 824 patients with CRPS, 92% reported insomnia; 78% irritability, agitation, and
anxiety; 73% depression, and 48% poor memory and lack of concentration. [47]

Patients are frequently classified into two groups based upon temperature, whether they are predominately
"warm" or "hot" CRPS or "cold" CRPS. The vast majority, approximately 70% of patients, have the "hot" type,
which is said to be an acute form of CRPS.[48] Cold CRPS is said to be indicative of a more chronic CRPS, with
poorer McGill Pain Questionnaire (MPQ) scores, increased central nervous system involvement, and a higher
prevalence of dystonia.[48] Prognosis is not favourable for cold CRPS patients; longitudinal studies suggest
these patients have "poorer clinical pain outcomes and show persistent signs of central sensitisation correlating
with disease progression".[49]

Previously it was considered that CRPS had three stages; it is now believed that patients with CRPS do not
progress through these stages sequentially. These stages may not be time-constrained and could possibly be
event-related such as ground-level falls or re-injuries in previous areas. Rather than a progression of CRPS
from bad to worse, it is now thought, instead, that patients are likely to have one of the three following types of
disease progression:

1. "Stage" one is characterized by severe, burning pain at the site of the injury, muscle spasms, joint
stiffness, restricted mobility, rapid hair and nail growth, and vasospasm. The vasospasm is that which
causes the changes in the color and temperature of the skin. Some may experience hyperhydrosis
(increased sweating). In mild cases this stage lasts a few weeks, in which it can subside
spontaneously or respond rapidly to treatment (physical therapy, pain specialist).

2. "Stage" two is characterized by more intense pain. Swelling spreads, hair growth diminishes, nails
become cracked, brittle, grooved, and spotty, osteoporosis becomes severe and diffuse, joints thicken,
and muscles atrophy.

3. "Stage" three is characterized by irreversible changes in the skin and bones, while the pain becomes
unyielding and may involve the entire limb. There is marked muscle atrophy, severely limited mobility
 of the affected area, and flexor tendon contractions (contractions of the muscles and tendons that flex
the joints). Occasionally the limb is displaced from its normal position, and marked bone softening and
thinning is more dispersed.
Diagnosis[edit]
CRPS types I and II share the common diagnostic criteria shown below. Spontaneous pain or allodynia (pain
resulting from a stimulus which would not normally provoke pain, such as a light touch of the skin) is not limited
to the territory of a single peripheral nerve and is disproportionate to the inciting event.

1. There is a history of edema, skin blood flow abnormality, or abnormal sweating in the region of the pain
since the inciting event.

2. No other conditions can account for the degree of pain and dysfunction.

The two types differ only in the nature of the inciting event. Type I CRPS develops following an initiating
noxious event that may or may not have been traumatic, while type II CRPS develops after a nerve injury.

No specific test is available for CRPS, which is diagnosed primarily through observation of the symptoms.
However, thermography, sweat testing, x-rays, electrodiagnostics, and sympathetic blocks can be used to build
up a picture of the disorder. Diagnosis is complicated by the fact that some patients improve without treatment.
A delay in diagnosis and/or treatment for this syndrome can result in severe physical and psychological
problems. Early recognition and prompt treatment provide the greatest opportunity for recovery.

The International Association for the Study of Pain (IASP) lists the diagnostic criteria for complex regional pain
syndrome I (CRPS I) (RSDS) as follows:

1. The presence of an initiating noxious event or a cause of immobilization

2. Continuing pain, allodynia (perception of pain from a nonpainful stimulus), or hyperalgesia (an
exaggerated sense of pain) disproportionate to the inciting event

3. Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the
area of pain

4. The diagnosis is excluded by the existence of any condition that would otherwise account for the
degree of pain and dysfunction.

According to the IASP, CRPS II (causalgia) is diagnosed as follows:

 1. The presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited
to the distribution of the injured nerve

2. Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the
region of pain

3. The diagnosis is excluded by the existence of any condition that would otherwise account for the
degree of pain and dysfunction.

The IASP criteria for CRPS I diagnosis has shown a sensitivity ranging from 98100% and a specificity ranging
from 3655%. Per the IASP guidelines, interobserver reliability for CRPS I diagnosis is poor. Two other criteria
used for CRPS I diagnosis are Bruehl's criteria and Veldman's criteria, which have moderate to good
interobserver reliability. In the absence of clear evidence supporting one set of criteria over the other, clinicians
may use IASP, Bruehls, or Veldmans clinical criteria for diagnosis. While the IASP criteria are nonspecific and
possibly not as reproducible as Bruehls or Veldmans criteria, they are cited more widely in literature, including
treatment trials.[50]

Thermography[edit]
Presently, established empirical evidence suggests against thermography's efficacy as a reliable tool for
diagnosing CRPS. Although CRPS may, in some cases, lead to measurably altered blood flow throughout an
affected region, many other factors can also contribute to an altered thermographic reading, including the
patient's smoking habits, use of certain skin lotions, recent physical activity, and prior history of trauma to the
region. Also, not all patients diagnosed with CRPS demonstrate such "vasomotor instability" less often, still,
those in the later stages of the disease.[51] Thus, thermography alone cannot be used as conclusive evidence
for - or against - a diagnosis of CRPS and must be interpreted in light of the patient's larger medical history and
prior diagnostic studies.[52]

In order to minimise the confounding influence of external factors, patients undergoing infrared thermographic
testing must conform to special restrictions regarding the use of
certainvasoconstrictors (namely, nicotine and caffeine), skin lotions, physical therapy, and other diagnostic
procedures in the days prior to testing. Patients may also be required to discontinue certain pain medications
and sympathetic blockers. After a patient arrives at a thermographic laboratory, he or she is allowed to reach
thermal equilibrium in a 1620 C, draft-free, steady-state room wearing a loose fitting cotton hospital gown for
approximately twenty minutes. A technician then takes infrared images of both the patient's affected and
unaffected limbs, as well as reference images of other parts of the patient's body, including his or her face,
upper back, and lower back. After capturing a set of baseline images, some labs further require the patient to
undergo cold-water autonomic-functional-stress-testing to evaluate the function of his or her autonomic nervous
system's peripheral vasoconstrictor reflex. This is performed by placing a patient's unaffected limb in a cold
water bath (approximately 20 C) for five minutes while collecting images. In a normal, intact, functioning
autonomic nervous system, a patient's affected extremity will become colder. Conversely, warming of an
affected extremity may indicate a disruption of the body's normal thermoregulatory vasoconstrictor function,
which may sometimes indicate underlying CRPS.[53]

Sweat testing[edit]
Abnormal sweating can be detected by several tests. A powder that changes color when exposed to sweat can
be applied to the limbs; however, this method does not allow for quantification of sweating. Two quantitative
tests that may be used are the resting sweat output test and the quantitative sudomotor axon reflex test. These
quantitative sweat tests have been shown to correlate with clinical signs of CRPS. [54]

Radiography[edit]
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Patchy osteoporosis (post-traumatic osteoporosis), which may be due to disuse of the affected extremity, can
be detected through X-ray imagery as early as two weeks after the onset of CRPS. A bone scan of the affected
limb may detect these changes even sooner. Bone densitometry can also be used to detect changes in bone
mineral density. It can also be used to monitor the results of treatment since bone densitometry parameters
improve with treatment.

Electrodiagnostic testing[edit]
Electromyography (EMG) and Nerve Conduction Studies (NCS) are important ancillary tests in CRPS because
they are among the most reliable methods of detecting nerve injury. They can be used as one of the primary
methods to distinguish between CRPS I & II, which differ based on whether there is evidence of actual nerve
damage. EMG & NCS are also among the best tests for ruling in or out alternative diagnoses. CRPS is a
"diagnosis of exclusion", which requires that there be no other diagnosis that can explain the patient's
symptoms. This is very important to emphasise because otherwise patients can be given a wrong diagnosis of
CRPS when they actually have a treatable condition that better accounts for their symptoms. An example is
severe Carpal Tunnel Syndrome, which can often present in a very similar way to CRPS. Unlike CRPS, Carpal
Tunnel Syndrome can often be corrected with surgery in order to alleviate the pain and avoid permanent nerve
damage and malformation.[55]

Both EMG and NCS involve some measure of discomfort. EMG involves the use of a tiny needle that is
inserted into specific muscles to test the associated muscle and nerve function. Both EMG & NCS involve very
mild shocks that in normal patients are comparable to a rubber band snapping on the skin. Although these tests
can be very useful in CRPS, thorough informed consent needs to be obtained prior to the procedure,
particularly in patients experiencing severe allodynia. In spite of the utility of the test, these patients may wish to
decline the procedure in order to avoid discomfort.

Treatment[edit]
The general strategy in CRPS treatment is often multi-disciplinary, with the use of different types of medications
combined with distinct physical therapies. The treatment principles in children and teenagers are similar.

Physical and occupational therapy[edit]

Physical and occupational therapy are important components of the management of CRPS primarily by
desensitising the affected body part, restoring motion, and improving function. Physical therapy interventions
for CRPS can include specific modalities such as transcutaneous electrical nerve stimulation, progressive
weight bearing, tactile desensitization, massage, and contrast bath therapy. These interventions tailored
specifically to each individual person can be used to improve pain and function to help people return to normal
activities of daily living.[56] Some people at certain stages of the disease are incapable of participating in
physical therapy due to touch intolerance. This may be where Graded Motor Imagery and Mirror Therapy (see
below) are particularly helpful. People with CRPS often develop guarding behaviors where they avoid using or
touching the affected limb. This inactivity exacerbates the disease and perpetuates the pain cycle. Therefore,
optimizing the multimodal treatment is paramount to allow for use of the involved body part. Physical therapy
works best for most patients, especially goal-directed therapy, where the patient begins from an initial point,
regardless of how minimal, and then endeavors to increase activity each week. Therapy is directed at
facilitating the patient to engage in physical therapy, movement, and stimulation of the affected areas. One
difficulty with the idea of physical therapy, however, is that it means different things to different people. There is
one systematic review of the use of physical and occupational therapy for the treatment of CRPS. [57] That
review concluded, "Narrative synthesis of the results, based on effect size, found there was good to very good
quality level II evidence that graded motor imagery is effective in reducing pain in adults with CRPS-1,
irrespective of the outcome measure used. No evidence was found to support treatments frequently
recommended in clinical guidelines, such as stress loading. CONCLUSIONS: Graded motor imagery should be
used to reduce pain in adult CRPS-1 patients."

Physical therapy has been used under light general anesthesia in an attempt to remobilize the extremity. Such
remobilization is used cautiously to avoid damage to atrophied tissue and bones that have
become osteodystrophic.

Although there is no denying the importance of a multidisciplinary approach in the management of CRPS,
[58]
recent research suggests that physical therapy intervention may be successful in decreasing symptoms of
CRPS without the use of medications. Pain exposure physical therapy (PEPT) is based on the premise that
pain may be exacerbated and maintained by psychosocialand behavioural factors, and therefore, these factors
must be addressed as a component of CRPS management. PEPT combines a progressive loading exercise
program with pain-avoidance behaviour management. Progressive loading (i.e., loading extremities beyond
limit of pain) includes passive and active exercises to mobilize joints and muscle stretching and is believed to
reducesensitization (both central and peripheral) and may also restore autonomic deregulation and cortical
representation in CRPS. As the name suggests, pain avoidance behaviour management attempts to reduce
behaviours that maintain disuse and pain avoidance (e.g., kinesiophobia, pain avoidance and learned non-use,
and pain catastrophizing), with the goal of increasing self-confidence in the individuals physical capabilities.[59]

A recent multiple single-case design study by Van de Meent et al. (2011) [59] found PEPT to be a safe and
effective method of treatment for individuals with CRPS. Results showed improvements on a variety of
outcomes measures, including pain intensity, kinesiophobia, muscle strength, arm/shoulder/hand disability,
walking speed, and perceived health. However, although these results are promising, this is a relatively new
topic of study and more research needs to be done in the area.

Drugs[edit]
Physicians use a variety of drugs to treat CRPS, including antidepressants, anti-inflammatories such
as corticosteroids, COX-inhibitors such as piroxicam, bisphosphonates, vasodilators, GABAanalogs such
as gabapentin and pregabalin, alpha- or beta-adrenergic-blocking compounds, and the entire pharmacy of
opioids. Occasional uses of Butorphanol also can be helpful during moments of heightened pain.

Mirror box therapy[edit]

Mirror box therapy uses a mirror box, or a stand alone mirror, to create a reflection of the normal limb such that
the patient thinks they are looking at the affected limb. Movement of this reflected normal limb is then
performed so that it looks to the patient as though they are performing movement with the affected limb
(although it will be pain free due to the fact it is a normal limb being reflected).

Mirror box therapy appears to be beneficial in early CRPS (McCabe et al., 2003b);.[60] However, Lorimer
Moseley (University of South Australia) has cautioned that the beneficial effects of mirror therapy for CRPS are
still unproven.[61] Importantly, the precise neural mechanisms of action are unknown and need to be studied
using a combination of behavioural and neuroimaging approaches. [62]

Graded motor imagery[edit]

Because studies have shown that problems in the primary motor cortex are found in patients who suffer from
CRPS, treatments have been developed that focus on normalizing motor representations in that part of the
brain. One treatment (graded motor imagery)[63] has now been tested in three [64][65][66] randomised controlled
trials and has shown to be effective at reducing pain and disability in people with chronic CRPS or phantom
limb pain after amputation or avulsion injury of the brachial plexus.
Graded motor imagery is a sequential process that consists of (a) laterality reconstruction, (b) motor imagery,
and (c) mirror therapy.[67][68]

Tactile discrimination training[edit]

Another approach to CRPS is based on a treatment called sensory discrimination training, which was used for
phantom limb pain. A randomised controlled trial [69] demonstrated a significant drop in pain after ten days
[61] [70]
training. For CRPS, a replicated case series and a randomised repeated measures experiment both
demonstrated an effect of tactile discrimination training on pain, disability, and sensory function in people with
CRPS of various durations. This treatment has not been tested in a randomised controlled trial.

Local anaesthetic blocks/injections[edit]

Injection of a local anesthetic, such as lidocaine, is often the first step in treatment. Injections are repeated as
needed. The results of local anesthetic injections are short lasting, and the procedure is risky. However, early
intervention with non-invasive management may be preferred to repeated nerve blockade. The use of topical
lidocaine patches has not been shown to be of use in the treatment of CRPS-1 and 2. [citation needed]

Intramuscular botox injections[edit]

Intramuscular botulinum injections have been shown recently to benefit patients with CRPS symptoms
localized to one extremity.[71] These injections may reduce the muscle spasm associated with CRPS and likely
also decrease the inflammation associated with CRPS. The main advantages of this treatment are that it is
relatively cheap, safe, and easy to administer. The major disadvantage is that it may need to be repeated after
a few months.[citation needed]

Spinal cord stimulators[edit]

Neurostimulation (spinal cord stimulator) may also be surgically implanted to reduce the pain by directly
stimulating the spinal cord. These devices are surgically placed by trained physicians. An electrode is placed in
the epidural space in the region of the spinal cord associated with the body part to be treated. Once placed,
programming by a knowledgeable clinician will personalize the device to each patient's pain complaints for the
optimal outcome. High frequencies are normally utilized for CRPS patients. A systematic review concluded that
spinal cord stimulation appears to be an effective therapy in the management of patients with CRPS type I
(Level A evidence) and type II (Level D evidence).[72] Moreover, there is evidence to demonstrate that SCS is a
cost-effective treatment for CRPS type I.

A randomised controlled trial performed by Kemler et al. (2000) on spinal cord stimulation (SCS) in patients
with refractory RSD demonstrated that the group receiving SCS + physical therapy (n=36) had a mean
reduction of 2.4 cm (using Visual analogue scale) in the intensity of pain at six months compared to a mean
increase of 0.2 cm in the group assigned to receive physical therapy alone (n=18). The intensity of pain was
found to be statistically significantly different between the two groups (P < 0.001). In addition, a greater
proportion of patients in the SCS + physical therapy reported a 6 (much improved outcome) based on a global
perceived effect scale compared to physical therapy alone (39% vs. 6%, P = 0.01). However, the study did not
find clinically significant improvement in functional status. [73]

Sympathectomy[edit]
Surgical, chemical, or radiofrequency sympathectomy interruption of the affected portion of the sympathetic
nervous system can be used as a last resort in patients with impending tissue loss, edema, recurrent
infection, or ischemic necrosis.[74] However, there is little evidence that these permanent interventions alter the
pain symptoms of the affected patients, and in addition to the normal risks of surgery, such as bleeding and
infection, sympathectomy has several specific risks, such as adverse changes in how nerves function.
However, there is some research suggesting good prognosis for patients who have responded favorably to a
series of sympathetic blocks (3-6).[citation needed]

Ketamine[edit]
Ketamine, a dissociative anesthetic, is being used in the treatment of Complex Regional Pain Syndrome with
anecdotal success.[31] During the infusion the patient is monitored constantly, and it should be administered only
by a qualified physician such as an anesthesiologist. The theory of ketamine use in CRPS/RSD is primarily
advanced by neurologist Dr. Robert J. Schwartzman ofDrexel University College of Medicine in Philadelphia
and researchers at the University of Tbingen in Germany but was first introduced in the United States by
Doctor Ronald Harbut of Little Rock, Arkansas. [citation needed] The hypothesis is that ketamine
blocks NMDA receptors that might reboot aberrant brain activity.

There are two treatment modalities; the first consists of a low-dose subanesethesia Ketamine infusion of 10
90 mg per hour over several treatment days. This can be delivered on an outpatient basis and is called the
awake or subanesethesia technique.

One study[75] demonstrated that 83% of the patients who participated had complete relief, and many others had
some relief of the symptoms. Another evaluation of a ten-day infusion of intravenous ketamine (awake
technique) in the CRPS patient concluded that "a four-hour ketamine infusion escalated from 4080 mg over a
10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased
autonomic dysregulation".[76] Unfortunately, these study designs are very prone to bias, which means high
quality randomised controlled trials of ketamine infusion for CRPS are still needed to learn about its effects and
side effects.

The second treatment modality consists of putting the patient into a medically induced coma, then
administering an extremely high dosage of ketamine; typically between 600 and 900 mg.[77]This version,
currently not allowed in the United States, was also banned in Germany before 2010. The only trials are taking
place now only in Monterrey, Nuevo Len, Mexico.
Bisphosphonate treatment[edit]
As recently as 2009, bisphosphonates were described as "among the only class of medications that has
survived placebo-controlled studies showing statistically significant improvement (in CRPS) with therapy." [78]

Bisphosphonates are often used in diseases featuring bone problems and pain, including osteoporosis and
cancer. Studies for CRPS carried out in the 1990s with moderate bisphosphonate dosage levels (including the
use of alendronate) did not appear to achieve long-term remission or cures, but offered hope. Throughout the
early 2000s, researchers in Paris[79] and northern Italy [80]steadily increased dosages and experimented with
other bisphosphonates to improve results, increase response, and put higher percentages of patients treated
into long-term remission. Varenna et al's study with Clodronate ("Intravenous Clodronate in the Treatment of
Reflex Sympathetic Dystrophy Syndrome. A Randomized, Double Blind, Placebo Controlled Study", 2000) used
patients who had CRPS for up to a year and dosed them with 300 mg infusions of clodronate on ten
consecutive days (3000 mg total). The group receiving clodronate reported pain falling significantly in the first
40 days and average pain in the group was reported as being close to zero 180 days following treatment.

In Varenna et al's 2013 paper, "Treatment of complex regional pain syndrome type I with neridronate: a
randomized, double-blind, placebo-controlled study", [81] patients were given four infusions of 100 mg of
intravenous neridronate within 4 to 10 days (400 mg total). The group receiving the neridronate infusions
reported rapid reduction in pain levels.

Though Varenna et al's 2000 and 2013 studies exclude patients over one year chronic in one case and over
four months chronic in the other case, in Kubalek et al's 2001 paper in which patients were dosed with 60 mg
pamidronate on three consecutive days ("Treatment of Reflex Sympathetic Dystrophy with Pamidronate: 29
Cases"), four patients were treated who had had the disease for 100+ weeks. Of these, three were reported as
pain free by day 45 (including the patient who was over three years chronic).

In their 2004 paper "Efficacy of Pamidronate in Complex Regional Pain Syndrome Type I", [82] Robinson et al
report that even with single 60 mg infusions, "several patients with established disease of several years
duration responded to pamidronate, perhaps reflecting the heterogeneity of this condition".

In spite of such results, the 2009 European Journal of Pain article "Bisphosphonates for the therapy of complex
regional pain syndrome I - Systematic Review" by Florian Brunner et al presents the conclusion that the "very
limited data reviewed showed that bisphosphonates have the potential to reduce pain associated with bone
loss in patients with CRPS I, however, at present there is not sufficient evidence to recommend their use in
practice".[83] However, in 2013 Varenna et al argued that their recent 80 patient double blind, placebo controlled
study in which all 78 patients who participated in a lengthy follow-up were dramatically improved and continued
to improve (including a normalization of all available follow-up scintigraphy), provided "conclusive evidence that
the use of bisphosphonates, at appropriate doses, is the treatment of choice for CRPS." [81] Though neridronate
dosed 4 times at 100 mg within 4 to 10 days (400 mg total) is currently the bisphosphonate of choice among
the university clinics of northern Italy, Varenna et al recommend that in nations where neridronate is not
available, 90 mg of pamidronate, administered four times within 4 to 10 days (360 mg total) is the current
treatment of choice. It is possible that earlier, low dose exposure to bisphosphonates might desensitize
individuals to the effectiveness of the full dose treatments on the level of Kubalek et al and Varenna et al and
as such, if the goal of total remission of CRPS is sought, although there is some evidence that they may be of
some use, lower doses of bisphosphonates than those recommended in these studies should be avoided. In
fact, individuals previously exposed to bisphosphonates were excluded from the 2013 study by Varenna et al. [81]

At the University of Verona, which participated in the Varenna et al study, 7500 I.U. of Vitamin D per week are
often given after treatment to help the bones in their healing process. Finally, as Varenna et al states, "The
mechanism of action responsible for the brilliant results (of the 2013 study) observed with bisphosphonates for
the treatment of CRPS-I remains conjectural, mainly because the exact pathophysiology of the disease is still
unknown."[81]

Topical treatment[edit]
CRPS can also be treated with DMSO 50% cream.[84] A novel approach to treat CRPS is with the multimodal
stepped care approach. Step by step a topical analgesic will be tried to examine its effectiveness in reducing
pain. When a topical analgesic has some pain reducing effects, though not completely, another topical
analgesic from a different class can be added to enhance the pain reducing effects. [85] Usually one to four
topical agents can be used simultaneously to get an optimal pain reducing effect. Combination therapy
between ketamine cream and the anti-inflammatory palmitoylethanolamide seems worth mentioning.

Adjunctive treatment[edit]
EEG Biofeedback,[86] various forms of psychotherapy,[87] relaxation techniques, and hypnosis [88] are adjunctive
treatments that assist coping.

Amputation[edit]
There is no randomised study in medical literature that has studied the response with amputation of patients
who have failed the above-mentioned therapies and who continue to be miserable. Nonetheless, there are
reports that on average cite about half of the patients will have resolution of their pain, while half will develop
phantom limb pain and/or pain at the amputation site. It is likely that like in any other chronic pain syndrome,
the brain becomes chronically stimulated with pain, and late amputation may not work as well as it might be
expected. In a survey of fifteen patients with CRPS Type 1, eleven responded that their life was better after
amputation.[89] Since this is the ultimate treatment of a painful extremity, it should be left as a last resort.

Prognosis[edit]
Good progress can be made in treating CRPS if treatment is begun early, ideally within three months of the first
symptoms. If treatment is delayed, however, the disorder can quickly spread to the entire limb, and changes in
bone, nerve, and muscle may become irreversible. The prognosis is not always good. Johns Hopkins Hospital
reports that 77% of sufferers have spreads from the original site or flares in other parts of the body. The limb, or
limbs, can experience muscle atrophy, loss of use, and functionally useless parameters that require
amputation. RSD/CRPS will not "burn itself out", but if treated early, it is likely to go into remission. Once you
are diagnosed with Complex Regional Pain Syndrome the likelihood of it resurfacing after going into remission
is significant. It is important that you take precautions and seek immediate treatment upon any injury. Notify the
treating physicians of your prior history of Complex Regional Pain Syndrome. [citation needed]

People living with CRPS[edit]

Among the more notable people living with CRPS are:

Rachel Morris, British paralympic cyclist.[90]

Danielle Brown, British paralympic archer.[91]

Radene Marie Cook, American broadcaster and artist.[92][93]

Jill Kinmont Boothe, US ski slalom champion.[94]

Tiiu Leek, Estonian-Canadian model and journalist, presenter of "That's My Line".[95]

Paula Abdul, American singer and TV personality

Shin Dong Wook, South Korean actor and model.[96]

Jane Egan, British paratriathlete.[97]

Gemma Collis, British paralympic fencer.[98]

Similar disorders[edit]

There are significant similarities between Multiple Sclerosis and CRPS since glial activation and central
sensitisation in the central nervous system are present in both. Alongside the symptoms of dystrophy, dystonia,
vasomotor, and temperature changes, CRPS patients experience symptoms traditionally associated with MS:
pain, strange sensations, numbness and tingling, spasms, allodynia, problems with mobility and balance, visual
issues, bladder and bowel problems, sleeping problems, and changes in libido. [citation needed]
CRPS has characteristics similar to those of other disorders, such as shoulder-hand syndrome, which
sometimes occurs after a heart attack and is marked by pain and stiffness in the arm and shoulder; Sudeck
syndrome, which is prevalent in older people and women and is characterized by bone changes and muscular
atrophy but is not always associated with trauma; andSteinbrocker syndrome, which includes symptoms such
as gradual stiffness, discomfort, and weakness in the shoulder and hand. Erythromelalgia also shares many
components of CRPS (burning pain, redness, temperature hypersensitivity, autonomic dysfunction,
vasospasm); they both involve small fiber sensory neurosympathetic components. Erythromelalgia involves a
lack of sweating, whereas CRPS often involves increased sweating. Subvariations of both exist. New
information lends credibility to previous positions that this is an autoimmune response disease that can be
caused by injury or non injury, and can progress from the injured location throughout the entire body to include
optic nerves, ear nerves, and other facial nerves. Regarding the facial nerves, the eyes seem to be most
vulnerable, with no specific pattern as to one or both. It also has the ability to affect sexual function in both the
male and female anatomy, though the ability to engage in sexual activity is limited by the disease itself. There is
further information that some cases may have a genetic predisposition for the disease, as with other
autoimmune diseases. Myasthenia Gravis is another disease that mirrors many of the symptoms of CRPS. [citation
needed]

Current research[edit]
The National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health
(NIH), supports and conducts research on the brain and central nervous system, including research relevant to
RSDS, through grants to major medical institutions across the country. NINDS-supported scientists are working
to develop effective treatments for neurological conditions and ultimately, to find ways of preventing them.
Investigators are studying new approaches to treat CRPS and intervene more aggressively after traumatic
injury to lower the patient's chances of developing the disorder. In addition, NINDS-supported scientists are
studying how signals of the sympathetic nervous system cause pain in CRPS patients. Using a technique
calledmicroneurography, these investigators are able to record and measure neural activity in single nerve
fibers of affected patients. By testing various hypotheses, these researchers hope to discover the unique
mechanism that causes the spontaneous pain of CRPS, and that discovery may lead to new ways of blocking
pain. Other studies to overcome chronic pain syndromes are discussed in the pamphlet "Chronic Pain: Hope
Through Research", published by the NINDS.[citation needed]

Research into treating the condition with Mirror Visual Feedback is being undertaken at the Royal National
Hospital for Rheumatic Disease in Bath. Patients are taught how to desensitize in the most effective way, then
progress to using mirrors to rewrite the faulty signals in the brain that appear responsible for this condition. [citation
needed]
The Netherlands currently has the most comprehensive program of research into CRPS, as part of a multi-
million Euro initiative called TREND.[99] German and Australian research teams are also pursuing better
understanding and treatments for CRPS.

In animals[edit]
CRPS has also been described in animals.[100]