Complex regional pain syndrome (CRPS) describes a variety of painful conditions that are characterised 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 International Association for the Study of Pain (IASP) has proposed dividing CRPS into two types, based on the presence or otherwise of a nerve lesion.

Type 1 

Reflex sympathetic dystrophy, Sudeck’s atrophy, reflex neurovascular dystrophy: no demonstrable nerve lesion (no clinical signs of peripheral nerve damage).

Type 2 

Causalgia: evidence of obvious nerve damage.

The Budapest criteria (2010) were devised to streamline diagnosis:

• Continuing pain, which is disproportionate to any inciting event
• Patients must report at least one symptom in three of the four following categories
  • Sensory – reports of hyperaesthesia and/or allodynia
  • Vasomotor – reports of temperature asymmetry and/or skin colour changes and/or skin color asymmetry
  • Sudomotor/oedema – reports of oedema and/or sweating changes and/or sweating asymmetry
  • Motor/trophic – reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
• Patients must display at least one sign at time of evaluation in two or more of the following categories:
  • Sensory – evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or temperature sensation and/or deep somatic pressure and/or joint movement)
  • Vasomotor – evidence of temperature asymmetry (> 1°C) and/or skin color changes and/or asymmetry
  • Sudomotor/oedema – evidence of oedema and/or sweating changes and/or sweating asymmetry
  • Motor/trophic – evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nail, skin)
• There is no other diagnosis that better explains the signs and symptoms. 

The female to male ratio is three to one with a mean age of onset of 40-50 years. Trauma accounts for 45-65% of cases. Post-surgery accounts for 10-20%, inflammatory processes 2%, cardiac 3%, and no precipitating cause is found in 10-20%.

Pathophysiology

The pathophysiology of CRPS is multifactorial and complex. Different features predominate in different patients, and an understanding is necessary to elucidate predominant features in individual patients in order to target therapy.

CRPS is a disease of both the CNS and PNS. It is hypothesised that some form of initial tissue damage initiates the following cascade of events.  

Both central sensitisation and peripheral sensitisation are recognised as playing a vital role. Peripheral sensitisation is elicited by tissue damage. This results in primary afferent neurons releasing pro-nociceptive neuropeptides (substance P, bradykinin) which cause an increased background firing rate of nociceptors, increased firing in response to nociceptive stimuli and a decreased firing threshold for thermal and mechanical stimuli, causing hyperalgesia and allodynia.

Central sensitisation is the increased excitability of spinal cord nociceptive neurons as a result of persistent or intense noxious input (resulting from the tissue/nerve damage). This is mediated by nociception-induced release of neuropeptides (substance P and bradykinin) and glutamate acting at spinal N-methyl-D-aspartate (NMDA) receptors, and results in hyperalgesia and allodynia. 

Altered sympathetic nervous system (SNS) function is responsible for many of the classic signs and symptoms of CRPS. After nerve trauma, adrenergic receptors are expressed on nociceptive fibres, which results in sympatho-afferent coupling (catecholamines directly triggering nociceptive firing). It has been shown that intradermal injection of adrenaline significantly increases CRPS pain intensity. Excessive SNS outflow is not necessarily responsible, however. Studies have demonstrated that decreased levels of SNS activity are observed in the affected and unaffected limbs of patients with CRPS. It is thought that decreased SNS activity causes relative vasodilatation, which is responsible for the warm red extremity associated with acute CRPS. This decreased activity in the acute phase leads to compensatory upregulation of peripheral adrenergic receptors. This results in supersensitivity to circulating catecholamines (released due to life stress or pain), causing exaggerated sweating and vasoconstriction, and the characteristic cool blue sweaty extremities typical of chronic CRPS. It is also thought that vasoconstriction facilitates regional accumulation of pro-nociceptive substances and induces hypoxia resulting in trophic changes (skin, nails, hair).

Inflammatory factors are also implicated in the pathophysiology of CRPS. Patients with CRPS display significantly increased levels of pro-inflammatory cytokines (IL–1ß, -2, -6, and TNF-a) compared to pain-free controls. These mediators are released directly from nociceptive fibres in response to triggers including nerve injury. They produce peripheral sensitisation.

Several neuroimaging studies show a reorganisation of the somatotrophic maps, particularly a reduction in size of the representation of the CRPS-affected limb in the somatosensory cortex. The degree of reorganisation correlates with pain intensity and degree of hyperalgesia, and CRPS patients exhibit impaired two-point discrimination and localisation of tactile stimuli. 

Finally, genetic and psychogenic factors have also been implicated in the pathophysiology. Familial cases have been identified and demonstrate more frequent spontaneous onset, and onset at a younger age. Psychogenic distress is associated with increased catecholamine levels, and increased depression levels are a predictor of greater subsequent CRPS pain intensity. 

Diagnosis

Diagnosis is based primarily on history and clinical exam, requiring the clinician to elicit the signs and symptoms of the Budapest criteria. In many cases it is a diagnosis of exclusion. 

The most important role for testing is to rule out other conditions. Investigations include:

• Radiography – x-rays, bone scans and bone densitometry can be used to demonstrate patchy osteoporosis, often associated due to disuse of the affected extremity
• Thermography – CRPS can lead to measurable altered blood flow through an affected region. However, as many other factors can cause an altered thermographic reading, established empirical evidence suggests against thermography as a reliable tool for diagnosing CRPS
• Sweat testing – the resting sweat output test and the quantitative sudomotor axon reflex test are quantitative sweat tests that have been shown to correlate with clinical signs of CRPS
• Laboratory studies – the following tests are used to rule out infection and rheumatological disease – FBC, complement fixation, erythrocyte sedimentation rate (ESR), ANA, rheumatoid factor.

Early diagnosis is essential for effective management before the development of any permanent disability. The combination of self-reported symptoms, clinical observation, supportive testing and diagnostic imaging is needed to confirm a diagnosis. 

Management

Management relies on the multidisciplinary team approach to provide adequate analgesia and attain functional restoration as quickly as possible. 

Physiotherapy helps to restore range of motion and function with a gradually increasing exercise programme tailored to the patient. Psychotherapy is crucial in managing the psychiatric complications of CRPS (depression, anxiety, post-traumatic stress disorder).

Sympathetic nerve block (such as stellate ganglion or lumbar sympathetic block) can provide significant pain relief for some patients. Placement of a percutaneous infusion catheter can provide sufficient relief to take part in physical therapy and rehabilitation programmes. 

Many different classes of medication are used in the treatment of CRPS. Agents used to target neuropathic pain are usually commenced early on. These include anticonvulsants (pregabalin, gabapentin, valproate and carbamazepine) and antidepressants (amitriptyline and desipramine). Opioids are also useful in selective patients. Non-steroidal anti-inflammatory drugs (NSAIDs) are useful alone and for opioid-sparing effects. They may directly target the inflammatory basis of the pathophysiology, as would corticosteroids which have been used with some benefit. 

Calcitonin has shown limited benefit, while bisphosphonates have been useful in those with osteoporosis. Topical agents such as transdermal lidocaine and capsaicin may also provide temporary relief to affected regions.

Spinal cord stimulators have also been used with success. Continuous burning pain is replaced by a pleasant tingling sensation in the painful area. Intrathecal drug pumps allow smaller concentration of drugs to be used, thus limiting systemic affects. They have been shown to provide good pain relief with opioids and local anaesthetics directly targeting nociceptive neurons. 

Neuroablative techniques and surgical sympathectomy should be reserved for resistant cases where conservative therapy has failed to maintain control. There must have been a history of response to sympathetic blockade. 

Treatment in the first three to six months has been reasonably successful. After six months treatment becomes more difficult, and the success rate decreases the longer the condition goes untreated. The most important intervention appears to be appropriate, aggressive, active and passive physical therapy along with cognitive behavioural therapy.

Prognosis

Prognosis improves with early treatment. Long duration of symptoms and signs, trophic changes and primarily cold CRPS are associated with higher chances of poor outcome and disability. The prognosis varies from patient to patient. Spontaneous remission occurs in some people. Others have unremitting pain and crippling irreversible changes in spite of treatment.

Summary

• A spectrum of disability from the self-limiting to the irreversible and permanently debilitating
• Pathophysiology is multifactorial with tissue damage, SNS dysfunction and peripheral and central sensitisation at its core
• Symptoms include continuous severe burning out of proportion in intensity and time to injury, associated with sudomotor dysfunction and trophic changes
• Diagnosis is clinical
• Management primarily relies on early and aggressive rehabilitation in association with analgesia
• Prognosis varies greatly.  

References

1. Turner-Stokes L, Goebel A. Complex regional pain syndrome in adults: concise guidance. Clinical Med 2011; 11(6): 596-600
2. Hooshmand H, Phillips E. Spread of complex regional pain syndrome. Vero Beach, Florida: Neurological Associates Pain Management Center 
3. MD Guidelines, Medical DIsability Advisor. Complex regional pain syndrome: comorbid conditions (http://www.mdguidelines.com/complex-regional-pain-syndrome/comorbid-conditions – accessed March 28, 2012) 
4. Perez R, Zuurmond W, Bezemer P et al. The treatment of complex regional pain syndrome type I with free radical scavengers: a randomized controlled study. Pain 2003; 102(3): 297-307