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|Complex Regional Pain Syndrome (CRPS)|
|Classification and external resources|
Reflex sympathetic dystrophy
|ICD-9||337.21, 337.22, 354.4, 355.71|
|Complex Regional Pain Syndrome (CRPS)|
|Classification and external resources|
Reflex sympathetic dystrophy
|ICD-9||337.21, 337.22, 354.4, 355.71|
Complex regional pain syndrome (CRPS) formerly reflex sympathetic dystrophy (RSD), "causalgia", or reflex neurovascular dystrophy (RND) is an amplified musculoskeletal pain syndrome (AMPS). It is a chronic systemic disease characterized by severe pain, swelling, and changes in the skin. CRPS is expected to worsen over time. 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.
Complex Regional Pain Syndrome is a multifactorial disorder with clinical features of neurogenic inflammation (swelling in the central nervous system), nociceptive sensitisation (which causes extreme sensitivity or allodynia), vasomotor dysfunction (blood flow problems which cause swelling and discolouration) and maladaptive neuroplasticity (where the brain changes and adapts with constant pain signals); CRPS is the result of an "aberrant [inappropriate] response to tissue injury". Treatment is complicated, involving drugs, physical therapy, psychologic treatments, and neuromodulation and is usually unsatisfactory, especially if begun late.
CRPS is associated with dysregulation of the central nervous system 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.
CRPS has the unfortunate honour of being described as the most painful long term condition (of those that have been tested), scoring 42 out of a possible 50 on the McGill pain scale, above such events as amputation and childbirth. Lack of social awareness has inspired patients to campaign for more widespread knowledge of CRPS, and lack of clinical awareness has led to the creation of support groups seeking to self-educate with the latest research.
Evidence suggests that CRPS has both physical and psychological factors. Although "research does not reveal support for specific personality or psychopathology predictors of the condition" there are psychosocial factors to CRPS, impaired social and occupational function, for example. And whilst CRPS is not caused by psychological factors, the constant pain and reduced quality of life has been known to cause psychological problems (which include increased depression and anxiety). Unsurprisingly, there is overwhelming evidence of limbic system involvement. Sadly the 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. The cause of CRPS is currently unknown. Precipitating factors include injury and surgery, although there are documented cases that have seemingly no injury to the original site.
Research (including data from functional MRI) is demonstrating Complex Regional Pain Syndrome is a systemic disease. Demonstrable changes in peripheral nerve fibers indicate central nervous system involvement as those changes are evident in not only the effected, but also the oppositional limb. Potentially any organ could be affected. 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. Recently work has shown how CRPS can spread to the stomach, with resulting symptoms of daily vomiting and extreme pain, though the pain experienced feels different from that in the extremity.
With the growing body of evidence persuasively indicating the progressive and systemic implications of chronic CRPS, there is concern that these patients may be erroneously also diagnosed with fibromyalgia. Fibromyalgia has a MPQ score of 35.7/50, 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. The similarities between multiple sclerosis and CRPS (which include symptoms of muscle twitching and tremors, wobbliness, falling, and visionary disturbances) have inspired research. 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).
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." However, this term was actually coined by Mitchell's friend Robley Dunglison from the Greek words for heat and for pain. 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. 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. In 1959, Noordenbos observed in caulsalgia patients that "the damage of the nerve is always partial." 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.
Evidence from functional MRI data indicates that CRPS is a systemic disease with a unified diagnosis (rather than a collection of symptoms). 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. 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). Wind-up (the increased sensation of pain with time) and central nervous system (CNS) sensitization are key neurologic processes that appear to be involved in the induction and maintenance of CRPS.
There is compelling evidence that the N-methyl-D-aspartate (NMDA) receptor has significant involvement in the CNS sensitization process. It is also hypothesized that elevated CNS glutamate levels promote wind-up and CNS sensitization. In addition, there is experimental evidence that demonstrates NMDA receptors in peripheral nerves. 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. Furthermore, trauma related cytokine release, exaggerated neurogenic inflammation, sympathetic afferent coupling, adrenoreceptor pathology, glial cell activation, cortical reorganisation, and oxidative damage (e.g., by free radicals) are all concepts that have been implicated in the pathophysiology of CRPS.
CRPS can strike at any age, but the mean age at diagnosis is 42. CRPS has been diagnosed in children as young as 2 years old. It affects both men and women; however, CRPS is three times more frequent in females than males. The number of reported CRPS cases among adolescents and young adults is increasing.
Investigators estimate that 2-5% of those with peripheral nerve injury, and 13-70 percent of those with hemiplegia (paralysis of one side of the body), 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.
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. 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.
Clinical features of CRPS have been found to be neurogenic inflammation, nociceptive sensitisation, vasomotor dysfunction, and maladaptive neuroplasticity. 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. 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.
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. 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. 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".
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:
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.
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:
According to the IASP, CRPS II (causalgia) is diagnosed as follows:
The IASP criteria for CRPS I diagnosis has shown a sensitivity ranging from 98–100% and a specificity ranging from 36–55%. 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, Bruehl’s, or Veldman’s clinical criteria for diagnosis. While the IASP criteria are nonspecific and possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely in literature, including treatment trials.
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. 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.
In order to minimise the confounding influence of external factors, patients undergoing infrared thermographic testing must conform to special restrictions regarding the use of certain vasoconstrictors (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 16–20 °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.
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.
|This section does not cite any references or sources. (November 2012)|
Scintigraphy, plain radiographs, and magnetic resonance imaging (MRI) may all be useful diagnostically. 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.
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.
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.
The general strategy in CRPS treatment is often multi-disciplinary, with the use of different types of medications combined with distinct physical therapies.
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. 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. 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, 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 psychosocial and 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 reduce sensitization (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 individual’s physical capabilities.
A recent multiple single-case design study by Van de Meent et al. (2011) 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.
In children and teenagers, CRPS is often treated with an intense physical and occupational therapy program for amplified musculoskeletal pain syndromes. These programs also employ counseling, art therapy, and music therapy. Such programs can be found at The Children's Hospital of Philadelphia (University of Pennsylvania), Boston Children's Hospital (Harvard University) and several other children's hospitals around the US. These evidence-based programs report long-term pain resolution success rates as high as 88%. In one study of 103 children with CRPS, 92% finished such a program pain-free and 88% were pain-free five years later at the time of follow-up. The efficacy of such a program has not been studied in adults.
Physicians use a variety of drugs to treat CRPS, including antidepressants, anti-inflammatories such as corticosteroids, COX-inhibitors such as piroxicam, bisphosphonates, vasodilators, GABA analogs 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 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);. However, Lorimer Moseley (University of South Australia) has cautioned that the beneficial effects of mirror therapy for CRPS are still unproven. Importantly, the precise neural mechanisms of action are unknown and need to be studied using a combination of behavioural and neuroimaging approaches.
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) has now been tested in three  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.
Another approach to CRPS is based on a treatment called sensory discrimination training, which was used for phantom limb pain. A randomised controlled trial  demonstrated a significant drop in pain after ten days 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.
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.
Intramuscular botulinum injections have been shown recently to benefit patients with CRPS symptoms localized to one extremity. 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.
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). 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.
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. 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).
Ketamine, a dissociative anesthetic, is being used in the treatment of Complex Regional Pain Syndrome with anecdotal success. 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 of Drexel University College of Medicine in Philadelphia and researchers at the University of Tübingen in Germany but was first introduced in the United States by Doctor Ronald Harbut of Little Rock, Arkansas. 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 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 40–80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation". 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. 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 León, Mexico.
Bisphosphonates were described in 2009 as "among the only class of medications that has survived placebo-controlled studies showing statistically significant improvement (in CRPS) with therapy." Researchers in the 2000s used steadily increased dosages and experimented with other bisphosphonates to improve results, increase response, and put higher percentages of patients treated into long-term remission.
In Varenna et al.'s 2000 study, patients who had CRPS for up to a year were dosed 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. For Varenna et al.'s 2013 study, 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.
In their 2004 paper "Efficacy of Pamidronate in Complex Regional Pain Syndrome Type I", Robinson et al. report that with single 60 mg infusions, "several patients with established disease of several years duration responded to pamidronate, perhaps reflecting the heterogeneity of this condition".
The 2009 European Journal of Pain article "Bisphosphonates for the therapy of complex regional pain syndrome I - Systematic Review" by Florian Brunner et al. concluded 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". Varenna et al. report in their 2013 double blind placebo-controlled study of 80 patients that all 78 patients who participated in a lengthy follow-up were dramatically improved and continued to improve. The authors conclude that "These results provide conclusive evidence that the use of bisphosphonates, at appropriate doses, is the treatment of choice for CRPS-I" 
At the University of Verona, which participated in the 2013 Varenna et al. study, 7500 I.U. of Vitamin D per week are often given after treatment to help the bones heal. Varenna et al. states that the results are "conjectural, mainly because the exact pathophysiology of the disease is still unknown."
CRPS can also be treated with DMSO 50% cream. 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. 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.
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. Since this is the ultimate treatment of a painful extremity, it should be left as a last resort.
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.
Among the more notable people living with CRPS are:
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.
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; and Steinbrocker 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.
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 called microneurography, 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.
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.
The Netherlands currently has the most comprehensive program of research into CRPS, as part of a multi-million Euro initiative called TREND. German and Australian research teams are also pursuing better understanding and treatments for CRPS.
CRPS has also been described in animals.