by Dr Jenner, Medicolegal Partners. A Consultant in Pain Medicine, Dr Christopher Jenner MB BS, FRCA FFPMRCA has expertise in treating more than 90 different pain conditions. www.medicolegal-partners.com
Complex Regional Pain Syndrome (CRPS) is an extremely painful chronic condition that usually occurs after injury or surgery, although there have been reports of spontaneously arising cases. The disease is characterised by pain, heat and swelling of the affected limb, along with skin changes, which are disproportionate to the initiating event and do not heal within the expected time frame for the original injury. In chronic cases, the affected limb can become pale and cold, and muscle spasm and tightening may occur (1). CRPS is subdivided into types I and II, depending on the absence or presence of a specific nerve injury. The condition affects three times more women than men, with the combined incidence of the two CRPS types varying between 6.28 and 26.2 per 100,000 person-years, the differences being due in part to variation in the application of the diagnostic criteria (1,2). However, these figures are probably conservative, as the condition is likely to be under-diagnosed due to a lack of knowledge about CRPS among health professionals (3). Diagnosis is based on the Budapest criteria, which includes the presence of at least two clinical signs, and three symptoms, in four categories(4), but there is no definitive test for the condition (1). Thus, diagnosis can be problematic.
Although CRPS was first described during the American Civil War (1), the cause of the condition is still unclear. It has been suggested that CRPS may be predominately psychological, or somatoform, in origin and that a diagnosis of CRPS validates a condition that often does not really exist (5). A somatoform disorder is one in which the symptoms presented mimic a physical disease or injury but for which there is no identifiable cause. Therefore, CRPS sufferers are often viewed as malingerers or vulnerable individuals who have been labelled as sick by the medical profession (6).
However, this view has been disputed by many CRPS experts (1,3,7–12). Individual studies have failed to find any correlation between psychological factors and the development of CRPS (3,7,11). In fact, scores for psychological symptoms are generally average or below average when compared to those of pain or psychiatric patients, and there is no evidence to support a diagnosis of CRPS I patients as being psychologically different (9). Combined evidence from 31 studies found no overall association, with the few prospective studies considered showing no relationship between CRPS I and depression, anxiety, neuroticism or anger. Results from retrospective and cross-sectional studies were contradictory, although a majority showed no association. Importantly, studies of higher methodological quality tended to report no relationship with psychological symptoms, but many of the studies were of poor quality (10). A more recent review also concluded that while CRPS is not surprisingly associated with negative psychological outcomes, there is no support for specific personality or psychopathology predictors of the condition(12). Furthermore, there is no evidence that psychological intervention alone is sufficient to cure the condition (6). It is also possible that the tendency of some practitioners to label CRPS as a psychological or psychiatric condition, when that is not the case, may actually be harmful to patients (7).
While the relationship between CRPS and psychological factors is unconvincing, there is better evidence of a pathophysiological cause for the condition and several mechanisms have been suggested. Much of the current research on CRPS centres around the possibility that it is a result of an exaggerated inflammatory response by the body to injury (2,8,13). Indeed, the clinical signs of CRPS, such as pain and swelling, are typical of inflammation (2). Following tissue damage or neuronal injury, alterations in the central and peripheral nervous systems may lead to increased inflammation and an enhanced responsiveness to pain (2). A review of 22 studies revealed that patients with CRPS had higher levels of inflammatory factors in their blood, blister fluid and cerebrospinal fluid, and that different profiles were found for acute and chronic cases (13). Risk factors for CRPS identified by epidemiological studies include asthma and ACE inhibitor intake, again suggesting that neurogenic inflammation is a likely contributor (7,14). For ACE inhibitors, the association with CRPS was stronger if the inhibitors were used for a longer time, or at higher dosages (14).
The presence of immunoglobulin G autoantibodies in the serum of patients with CRPS suggests that autoimmunity may also be important in the development of the condition. This is further supported by the results of a trial where CRPS patients treated with intravenous immunoglobulin showed a significant reduction in pain symptoms compared to those given a placebo (2).
There may also be a neurological aspect to CRPS. During the acute phase of CRPS, the affected limb shows a reduction in the levels of circulating plasma norepinephrine compared to the unaffected limb. This results in compensatory upregulation of peripheral adrenergic receptors causing supersensitivity to circulating catecholamines. Exposure to catecholamines causes excessive vasoconstriction and sweating, leading to the characteristic cold and blue limb extremity seen during the chronic phase of the condition (2).
Some patients undergoing standardised neurological examination, involving light touch, pinprick and vibration sense with eyes closed and then open, have reported referred sensations, which occurred in the body part immediately adjacent to the stimulated site. The sensations disappeared when stimulation ceased, or when a clinical improvement occurred. This suggests that the pain of CRPS is associated with central sensory changes (15). Furthermore, magnetic resonance imaging has demonstrated structural abnormalities of connectivity between brain structures in CRPS and these appear to be different from those seen in other chronic pain conditions (8). Postmortem examination of CRPS patients shows atrophy (wasting) of grey matter of the right insula, right ventromedial prefrontal cortex and right nucleus accumbens and a decrease in fractional anisotropy (measurement of the movement of water molecules) in the left cingulum-callosal bundle, along with re- organization of white matter connectivity, and these changes appear to be related to pain intensity and duration (16).
Finally, there is some evidence of a genetic basis and familial risk in CRPS but a clear pattern of inheritance has not yet been confirmed (1,2,8). Siblings of patients under 50 years old appear to be at three times higher risk of developing the condition. Additionally, genes coding the human leukocyte antigen, involved in immune response, have been found to strongly correlate with the development of CRPS (2).
In summary, there is no strong or convincing evidence that CRPS is psychological in origin. Rather, the evidence strongly leads to the opinion that the condition has a pathophysiological cause or causes, with the probable mechanisms involving inflammatory, neurological and autoimmune responses by the body.
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