Complex regional pain syndrome

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Complex regional pain syndrome
SynonymsReflex sympathetic dystrophy (RSD), causalgia, reflex neurovascular dystrophy (RND)
Complex regional pain syndrome.jpg
Complex regional pain syndrome

Complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD), (and also sometimes referred to as the "suicide disease", due to the intensity of the discomfort experienced, and the lack of a cure or effective treatments[1][2]) is a disorder of a portion of the body, usually starting in a limb, which manifests as extreme pain, swelling, limited range of motion, and changes to the skin and bones. One version of the McGill pain index, a scale for rating pain, ranks CRPS highest, above childbirth, amputation and cancer.[3] It may initially affect one limb and then spread throughout the body; 35% of affected people report symptoms throughout their whole bodies.[4] There are multiple names for this disease, as well as two subtypes. Type I (originally called reflex sympathetic dystrophy (RSD)) occurs after an illness or injury with no direct evidence of nerve damage in the affected limb. This is approximately 90% of CRPS patients. Type II (causalgia) has distinct evidence of a nerve injury.[5]

Complex regional pain syndrome is uncommon, and its cause isn't clearly understood. Treatment is most effective when started early. In such cases, improvement and even remission are possible. CRPS typically develops after an injury, surgery, heart attack, or stroke. The pain is out of proportion to the initial event.[6][7]

It is proposed that inflammation and alteration of pain perception in the central nervous system play important roles. It has been suggested that persistent pain and the perception of non-painful stimuli as painful may be caused by inflammatory molecules (IL-1, IL2, TNF-alpha) and neuropeptides (substance P) released from peripheral nerves. This release may be caused by inappropriate crosstalk between sensory and motor fibers at the affected site.[8] CRPS is not a psychological illness, yet pain can cause psychological problems, such as anxiety and depression. There is often impaired social and occupational function.[9]

Treatment involves a multidisciplinary approach involving medications, physical and occupational therapy, psychological treatments, and neuromodulation. Despite this, the results are often unsatisfactory, especially if treatment is delayed.[10] Treatment is most effective when started early in the course of the illness.[6]

Signs and symptoms[edit]

Severe CRPS of right arm
CRPS visible on hands and wrists

Clinical features of CRPS have been found to be inflammation resulting from the release of certain pro-inflammatory chemical signals from the nerves, sensitized nerve receptors that send pain signals to the brain, dysfunction of the local blood vessels' ability to constrict and dilate appropriately, and maladaptive neuroplasticity.[11] The signs and symptoms of CRPS will usually manifest near the injury site. The most common symptoms are extreme pain including burning, stabbing, grinding, and throbbing. The pain is out of proportion to the severity of the initial injury.[6] Moving or touching the limb is often intolerable. With diagnosis of either CRPS I or II, patients may develop burning pain and allodynia (pain to non-noxious stimuli).  Both syndromes are also characterized by autonomic dysfunction, which presents with localized temperature changes, cyanosis, and/or edema.  The patient may also experience localized swelling; extreme sensitivity to non-painful things such as wind, water, noise and vibrations; extreme sensitivity to touch (by themselves, other people, and even their clothing or bedding/blankets); abnormally increased sweating (or absent sweating); changes in skin temperature (alternating between sweaty and cold); changes in skin colouring (from white and mottled to bright red or reddish violet); changes in skin texture (waxy, shiny, thin, tight skin); softening and thinning of bones; joint tenderness or stiffness; changes in nails and hair (delayed or increased growth, brittle nails/hair that easily break); muscle spasms; muscle loss (atrophy); tremors; dystonia; allodynia; hyperalgesia; decreased/restricted ability and painful movement of affected body part.[6] Drop attacks (falls), almost fainting, and fainting spells are infrequently reported, as are visual problems. The symptoms of CRPS vary in severity and duration. Since CRPS is a systemic problem, potentially any organ can be affected.

Symptoms may change over time, and they can vary from person to person. Symptoms can even change numerous times in a single day.

The pain of CRPS is continuous although varies in severity. It is widely recognized that it can be heightened by emotional or physical stress.[12]

Previously it was considered that CRPS had three stages; it is now believed that people affected by 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 of previously damaged areas. Thus, rather than a progression of CRPS from bad to worse, it is now thought, instead, that such individuals 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.


Investigators estimate that 2–5% of those with peripheral nerve injury,[13] and 13-70 percent of those with hemiplegia (paralysis of one side of the body),[14] will develop CRPS. In addition, some studies have indicated that cigarette smoking was strikingly present in patients and is statistically linked to RSD. This may be involved in its pathology by enhancing sympathetic activity, vasoconstriction, or by some other unknown neurotransmitter-related mechanism. This hypothesis was based on a retrospective analysis of 53 patients with RSD, which showed that 68% of patients and only 37% of controls were smokers. The results are preliminary and are limited by their retrospective nature.[15] 7% of people who have CRPS in one limb later develop it in another limb.[16]


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".[11] 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.[17] 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).[18] Wind-up (the increased sensation of pain with time)[19] and central nervous system (CNS) sensitization are key neurologic processes that appear to be involved in the induction and maintenance of CRPS.[20]

There is compelling evidence that the N-methyl-D-aspartate (NMDA) receptor has significant involvement in the CNS sensitization process.[21] It is also hypothesized that elevated CNS glutamate levels promote wind-up and CNS sensitization.[20] In addition, there is experimental evidence that demonstrates NMDA receptors in peripheral nerves.[22] 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.[23][24] Furthermore, trauma related cytokine release, exaggerated neurogenic inflammation, sympathetic afferent coupling, adrenoreceptor pathology, glial cell activation, cortical reorganisation,[25] and oxidative damage (e.g., by free radicals) are all concepts that have been implicated in the pathophysiology of CRPS.[26]

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.[18]


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 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.[27]


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.[28] 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.[29]

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.[30]


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 and can almost confirm the disease. 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.[31]

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.


  • Type I, formerly known as reflex sympathetic dystrophy (RSD), Sudeck's atrophy, or algoneurodystrophy, does not exhibit demonstrable nerve lesions. As the vast majority of patients diagnosed with CRPS have this type, it is most commonly referred to in medical literature as Type I.
  • Type II, formerly known as causalgia, has evidence of obvious nerve damage. Despite there being evidence of nerve injury, the cause of the mechanisms of CRPS Type II are as unknown as the mechanisms of Type I.

Patients are frequently classified into two groups based upon temperature: "warm" or "hot" CRPS in one group and "cold" CRPS in the other group. The majority of patients (approximately 70%) have the "hot" type, which is said to be an acute form of CRPS.[32] Cold CRPS is said to be indicative of a more chronic CRPS and is associated with poorer McGill Pain Questionnaire (MPQ) scores, increased central nervous system involvement, and a higher prevalence of dystonia.[32] 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".[33]


Vitamin C may be useful in prevention of the syndrome following fracture of the forearm.[34]


Treatment of CRPS often involves a number of modalities.[35]


Physical and occupational therapy have low quality evidence to support their use.[36] Physical therapy interventions may include transcutaneous electrical nerve stimulation, progressive weight bearing, graded tactile desensitization, massage, and contrast bath therapy.

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.

Mirror box therapy appears to be beneficial in early CRPS.[36] However, Lorimer Moseley (University of South Australia) has cautioned that the beneficial effects of mirror therapy for CRPS are still unproven.[37]

Graded motor imagery[edit]

Graded motor imagery appears to be useful for people with CRPS-1.[38]

Graded motor imagery is a sequential process that consists of (a) laterality reconstruction, (b) motor imagery, and (c) mirror therapy.[35][39]


Tentative evidence supports the use of bisphosphonates, calcitonin, and ketamine.[36] Doing nerve blocks with guanethidine appears to be harmful.[36] Evidence for sympathetic nerve blocks generally is insufficient to support their use.[40] Intramuscular botulinum injections may benefit people with symptoms localized to one extremity.[41]


Ketamine, a dissociative anesthetic, appears promising as a treatment for complex regional pain syndrome.[42] It may be used in low doses if other treatments have not worked.[43][44] No benefit on either function or depression, however, has been seen.[44]

Bisphosphonate treatment[edit]

As of 2013 low quality evidence supports the use of bisphosphonates.[36] A 2009 review found "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".[45]


Opioids such as oxycodone, morphine, hydrocodone, and fentanyl are effective in reducing pain. These drugs must be prescribed and monitored under close supervision of a physician, as these drugs may be addictive.[46] Thus far, no long-term studies of oral opioid use in treating neuropathic pain, including CRPS, have been performed. Even without solid scientific support, though, most experts believe that opioids should be given as part of a comprehensive pain treatment program for CRPS. Opioids should be prescribed immediately if other medications do not provide sufficient analgesia. [47]


Spinal cord stimulators[edit]

Spinal cord stimulator appears to be an effective therapy in the management of patients with CRPS type I (Level A evidence) and type II (Level D evidence).[48] While they improve pain and quality of life, evidence is unclear regarding effects on mental health and general functioning.[49]


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.[50] 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.


There is no randomized 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 as 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.[51] 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 one is diagnosed with Complex Regional Pain Syndrome, the likelihood of it resurfacing after going into remission is significant. It is important to take precautions and seek immediate treatment upon any injury.[citation needed]


CRPS can occur at any age with the average age at diagnosis being 42.[13] It affects both men and women; however, CRPS is three times more frequent in females than males.[13]

CRPS affects both adults and children, and the number of reported CRPS cases among adolescents and young adults has been increasing,[52] with a recent observational study finding an incidence of 1.16/100,000 among children in Scotland.[53]


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."[54] However, this term was actually coined by Mitchell's friend Robley Dunglison from the Greek words for heat and for pain.[55] 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 cause of CRPS came from the cohabitation of the altered and unaltered cutaneous fibres on the same nerve distribution territory.[56] 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.[57] In 1959, Noordenbos observed in causalgia patients that "the damage of the nerve is always partial."[58] 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.[59]


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.[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.[60] German and Australian research teams are also pursuing better understanding and treatments for CRPS.

Other animals[edit]

CRPS has also been described in animals, such as cows.[61]

Notable cases[edit]


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