About CRPS

CRPS is a misunderstood disorder that leaves many patients under-treated

Complex regional pain syndrome

What is complex regional pain syndrome?

Complex regional pain syndrome, or CRPS, was formerly called Sudeck’s atrophy or reflex sympathetic dystrophy (RSD). CRPS is a neuropathic pain disorder of a body region, usually of the distal limbs, which is characterized by pain, swelling, limited range of motion often in the form of dystonia, vasomotor instability, skin changes, and patchy bone demineralization. CRPS is a result of trauma to a nerve that can be a result of soft tissue injury, limb fracture, or even surgery or injections. There are rare cases of spontaneous CRPS.

The consensus definition of CRPS by the International Association for the Study of Pain [IASP] is as follows: “CRPS describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time.”

The severity of symptoms is disproportionate to the causative event. The latest scientific findings show this disorder is a very complex syndrome that occurs on different integration levels of the nervous system.

There are two subtypes: type I, formerly known as reflex sympathetic dystrophy, and type II, formerly known as causalgia. Type I occurs in the absence of nerve trauma, while type II occurs in the setting of known nerve trauma. Clinically they are indistinguishable and follow a regional rather than a dermatomal or peripheral nerve distribution and favor the distal extremities, though spread outside of the initially affected area commonly occurs to the proximal or contralateral limb. CRPS is further subdivided into “warm” versus “cold,” and sympathetically-maintained (SMP) versus sympathetically-independent (SIP), which may affect prognosis and treatment options


Although the diagnostic criteria for CRPS were put forward in 1994, limited data from epidemiological studies are available before 2000. Sandroni et al. conducted the first population-based study of CRPS in 2003, where they reviewed and validated potential cases of CRPS of the local population of Olmsted County over a 10-year period using the IASP and Harden criteria (1). The incidence rate of CRPS type I was 5.46 per 100000 person-years, and the incidence rate of CRPS type II was 0.82 per 100000 person-years, giving rise to a combined incidence rate for both CRPS types I and II of 6.28 per 100000 person-years (2). However, a subsequent population-based study by de Mos et al. estimated the combined incidence rate of CRPS to be approximately four times greater at 26.2 per 100000 person-years. This has been attributed to differences in ethnic and socioeconomic background of the cohort as well as the application of the diagnostic criteria.

In contrast to Sandroni et al., the study by de Mos et al. did not require all cases to fulfill the diagnostic criteria but instead retained cases based on confirmation of the diagnosis by the general practitioner or specialist. Furthermore, the retrospective application of the IASP criteria to information on electronic charts as performed by Sandroni et al. may have been overly strict. CRPS occurs most frequently in individuals aged between 61 and 70 years and demonstrates a female predilection, affecting three times more females than males. There appears to be an increased preponderance for the upper limbs with a ratio of 3:2 compared to the lower limbs. Risk factors for this condition include menopause, individuals with a history of migraine, osteoporosis, asthma and angiotensin-converting enzyme (ACE) inhibitor therapy and individuals with an elevated intracast pressure due to a tight case or extreme positions. Furthermore, the prognosis of CRPS is poorer in smokers compared to non-smokers.

Causes of CRPS


The clinical presentation of the acute phase of CRPS supports the hypothesis that the development of this condition is due to an exaggerated inflammatory response to trauma. Clinical findings of the CRPS-affected limb reveal pain, oedema, erythema, increased temperature and impaired function—the five cardinal signs of inflammation (3). Tissue trauma triggers the release of pro-inflammatory cytokines such as interleukin(IL)-1β, IL-2, IL-6 and tumour necrosis factor-α (TNF-α) along with neuropeptides including calcitonin gene-related peptide, bradykinin and substance P. These substances increase plasma extravasation and vasodilation, producing the characteristic features of acute CRPS (4).

Altered cutaneous innervation

Initial neuronal injury, however imperceptible has been implicated as an important trigger in the development of both CRPS types I and II. This has been supported by studies demonstrating a reduction in C-type and Aδ-type cutaneous afferent neuron fiber density in the CRPS-affected limb compared to the unaffected limb, with these changes primarily affecting nociceptive fibers (5). The decrease in C-type and Aδ-type fibers was associated with an increase in aberrant fibers of unknown origin, and it has been postulated that the exaggerated pain sensation may be due to altered function of these fibers. One animal study on rats has shown a causal relationship between this neuronal trigger and a reduction in neuron fiber density, highlighting the possibility that altered cutaneous innervation of the CRPS-affected limbs may be a result of an initial neuronal injury (6). Human studies, however, have been unable to replicate this causative effect, thus, bringing into question whether the reduction in neuron fiber density is an epiphenomenon rather than being directly related to the condition.

Central and peripheral sensitisation

Following tissue damage and/or neuronal injury, alterations in the central and peripheral nervous systems lead to increased inflammation, and an enhanced responsiveness to pain. These adaptations act as protective mechanisms to promote avoidance of activities that cause further injury. Within the central nervous system (CNS), persistent and intense noxious stimulation of peripheral nociceptive neurons results in central sensitisation. Accordingly, there is alteration in nociceptive processing in the CNS and increased excitability of secondary central nociceptive neurons in the spinal cord. This is mediated by the release of neuropeptides such as substance P, bradykinin and glutamate by peripheral nerves, which sensitise and increase the activity of local peripheral and secondary central nociceptive neurons resulting in increased pain from noxious stimuli (hyperalgesia) and pain in response to non-noxious stimuli (allodynia) (4). Research has shown that CRPS patients have a significantly greater windup to repeated stimulation of the affected limb compared to the contralateral limb or other limbs (7).

Altered sympathetic nervous system function

In the chronic (cold) phase of the clinical course of CRPS, the CRPS-affected limb is cyanosed and clammy as a result of vasoconstriction and sweating. This suggests that excessive sympathetic nervous system outflow is a driving factor in progression of the condition and maintenance of the pain (8). Animal studies have observed adrenergic receptor expression on nociceptive fibres following nerve trauma, which may provide a possible mechanism of the sympathetically induced pain. In addition, expression of adrenergic receptors on nociceptive fibres following injury may contribute to sympatho-afferent coupling increasing the pain intensity (6). This has been demonstrated in patients with sympathetically mediated CRPS pain where high sympathetic nervous system activity increased spontaneous pain by 22% and increased the spatial extent of dynamic and punctate hyperalgesia by 42 and 27% respectively (9).

Circulating catecholamines

Variation in the clinical features of CRPS as the condition progresses from the acute (warm) phase to the chronic phase may be attributed to alterations in catecholaminergic mechanisms (7). During the acute phase, the CRPS-affected limb demonstrates a reduction in the levels of circulating plasma norepinephrine compared to the unaffected limb (10). As a result, there is compensatory upregulation of peripheral adrenergic receptors causing supersensitivity to circulating catecholamines. Consequently, excessive vasoconstriction and sweating occurs following exposure to catecholamines, giving rise to the characteristic cold and blue extremity seen during the chronic phase.


The presence of immunoglobulin G (IgG) autoantibodies against surface antigens on autonomic neurons in the serum of patients with CRPS suggests that autoimmunity may play a role in the development of this condition (11). This is supported by the results of a small pilot trial where patients with CRPS who were given intravenous immunoglobulin treatment demonstrated a significant reduction in pain symptoms when compared with those given a placebo.

Brain plasticity

Neuroimaging studies of patients with CRPS have demonstrated a decrease in area representing the CRPS-affected limb in the somatosensory cortex compared to the unaffected limb (12). The sensory representation of the affected limb, as part of the Penfield homunculus is distorted, with shrinkage and shifting of the area (12). The extent of reorganisation bears significant correlation with the pain intensity and degree of hyperalgesia experienced by the patient, and these alterations return to normal following successful CRPS treatment (13).

Genetic factors

Although there is a lack of consensus regarding the influence of genetic factors in CRPS, family studies have suggested a genetic preponderance towards developing this condition. Siblings of CRPS patients under 50 years were at three times higher risk of developing the condition, with a mitochondrial inheritance pattern (14). Furthermore, the genes of the major histocompatibility complex encoding the human leukocyte antigen (HLA) molecules, HLA-B62 and HLA-DQ8 alleles were found to strongly correlate with the development of CRPS (15).

Psychological factors

Due to the prevalence of anxiety and depression in patients with CRPS and the unusual nature of symptoms, psychological factors have been hypothesised to play a role in the development or propagation of CRPS. Puchalski et al. observed a higher occurrence of CRPS following fractures of the distal radius in elderly patients with psychological and/or psychiatric illness, thereby implicating the role of psychological factors (16). However, evidence regarding this remains inconclusive as other studies have failed to confirm this association, and a definitive causation has yet to be identified

The personal impact of CRPS

CRPS causes debilitating mental and physical suffering. People who suffer from CRPS often feel alone and without hope as the majority of the population are not aware of this disorder. Patients visit numerous doctors and are given various medications and interventions that have strong side effects.

Furthermore, patients with CRPS do not fully understand all of their symptoms or what symptoms may occur in the future. These symptoms are extremely traumatizing and debilitating. This can lead to feelings of estrangement and guilt, not being able to take part in life’s enjoyable moments with friends and family.

1. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study.
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3. Clinical features and pathophysiology of complex regional pain syndrome. Marinus J, Moseley GL, Birklein F, Baron R, Maihöfner C, Kingery WS, van Hilten JJ. Lancet Neurol. 2011 Jul; 10(7):637-48.
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10. Norepinephrine and epinephrine levels in affected versus unaffected limbs in sympathetically maintained pain. Harden RN, Duc TA, Williams TR, Coley D, Cate JC, Gracely RH. Clin J Pain. 1994 Dec; 10(4):324-30.
11. Autoantibodies in complex regional pain syndrome bind to a differentiation-dependent neuronal surface autoantigen. Kohr D, Tschernatsch M, Schmitz K, Singh P, Kaps M, Schäfer KH, Diener M, Mathies J, Matz O, Kummer W, Maihöfner C, Fritz T, Birklein F, Blaes F. Pain. 2009 Jun; 143(3):246-51.
12. Patterns of cortical reorganization in complex regional pain syndrome. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F. Neurology. 2003 Dec 23; 61(12):1707-15.
13. Cortical reorganization during recovery from complex regional pain syndrome. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F. Neurology. 2004 Aug 24; 63(4):693-701.
14. Increased risk of complex regional pain syndrome in siblings of patients? de Rooij AM, de Mos M, van Hilten JJ, Sturkenboom MC, Gosso MF, van den Maagdenberg AM, Marinus J. J Pain. 2009 Dec; 10(12):1250-5.
15. HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia. de Rooij AM, Florencia Gosso M, Haasnoot GW, Marinus J, Verduijn W, Claas FH, van den Maagdenberg AM, van Hilten JJ. Pain. 2009 Sep; 145(1-2):82-5.
16. Complex regional pain syndrome type 1 after fractures of the distal radius: a prospective study of the role of psychological factors. Puchalski P, Zyluk A. J Hand Surg Br. 2005 Dec; 30(6):574-80.