Complex regional pain syndrome
Complex regional pain syndrome


Complex Regional Pain Syndrome (CRPS) consists of persistent pain that is disproportionately severe relative to the event that has triggered it, in association with autonomic disturbance. CRPS was previously known as reflex sympathetic dystrophy, causalgia, Sudeck's atrophy, algoneurodystrophy.

Top: Pain circuit in a healthy individual; Bottom: Pathway of CRPS with onset at local sensory nerves sending stimuli to the brain, in turn aggravating nerve stimulation and neurogenic pain


Complex regional pain syndrome begins as ongoing pain following an injury, bone fracture or surgery and continues despite the recovery of the initial injury. CRPS affects the extremities, particularly the upper limbs, with higher incidence in women. The condition is usually resolved within 12 months with exceptions where pain develops into a debilitating, chronic disorder impairing daily living activities and quality of life.

The pain is initially localised to the area of trauma but may subsequently spread to the entire limb and even to the opposite limb. In CRPS the sensation of pain is intensified by minor, non-noxious stimuli:

clothing touching the skin (allodynia)

noxious stimulus like pinprick (hyperalgesia)

The aetiology of CRPS is unknown and it is believed to be a multifactorial process. Both, the nervous system as well as the immune system contribute. Normally, a pain stimulus travels from the periphery to the dorsal horn of the spinal cord and then to the thalamus in the brain, where it is transferred to the cortex. In the thalamus, the pain sensation is transformed into perception followed by the release of hormones to suppress pain. The somatosensory cortex helps localise pain and process pain into consciousness.

However, an ongoing noxious stimulus leads to increased excitability of nociceptive neurons in the spinal cord, thus enhancing the response to pain in the brain and reducing the thresholds to non-noxious stimuli (sensitisation).

The stimulation of sensory nerves and the leads to release of (excitatory neurotransmitters, substance P, serotonin) and other chemicals (potassium, bradykinin, histamine, prostaglandins, leukotrienes) resulting in vasodilation, local inflammation (neurogenic inflammation) and swelling. These processes exacerbate nerve stimulation and neurogenic pain, creating a vicious cycle.

Neuroimaging studies of patients with CRPS have demonstrated brain changes, with a reduction of the somatosensory cortex area of the affected limb, indicating the pathology has a structural impact on the brain altering the perception of pain, a fact debunking the theory of CRPS being a psychological disease.

Persistent and exaggerated activation of the immune system, after tissue injury or ischaemic-reperfusion injury and consequent vascular damage, seem to play a significant role. Detection of autoantibodies against neuronal antigens substantiate the development of autoimmunity, a hypothesised contributing factor to CRPS.

The concept of CRPS progression divided into three stages (acute, dystrophic, atrophic) has now been essentially abandoned due to the wide variability of the symptom patterns among the patient population.

Stage I: Evident oedema of the hand compared to the healthy hand due to CRPS


There are two types of CRPS:

Type I occurs after trauma and causes sensory, motor, autonomic and skin / bone changes in 95% of cases.

Type II also occurs after trauma but in the presence of a major nerve injury. Possible complications that may arise in long-standing CRPS include:

Swelling, atrophy, osteoporosis, pseudo-arthrosis, joint stiffness and tendon adhesions, which may lead to permanent functional disability. Secondary psychological complications include opiate drug dependence, depression and rarely suicide.

Stage I: Evident oedema of the hand compared to the healthy hand due to CRPS
Stage I: Evident oedema of the hand compared to the healthy hand due to CRPS
Surgical treatment of a distal radius fracture triggered the development of CRPS


The exact causes of CRPS remain unknown. Trauma has to be present to make the diagnosis of CRPS, most commonly after surgery or major interventions, fractures, prolonged limb immobilisation or even following minor surgery. Psychological factors per se do not seem to trigger CRPS. However, there may be an association of CRPS with depression and anxiety when patients suffer from chronic pain. Major causes include:

Injuries: sprains, surgery, arthroscopy, wounds, fractures, crush trauma, burns

Prolonged limb immobilisation

Prolonged use of a cast can lead to CRPS

Risk factors

The most commonly recognised risk factors for developing CRPS are:

History of CRPS


Blunt trauma


Prolonged limb immobilisation with a cast, splint or sling

Genetics (genes of major histocompatibility complex)

Psychological factors (high anxiety, still questioned but possible)

Brittle nails is a symptom of CRPS


Symptomatic manifestations of CRPS apart from pain which is often very severe include elevated or reduced skin temperature, sweating, and oedema due to vascular abnormalities. Additional symptoms are abnormal posture of the limb, tremor and weakness. The common symptoms of CRPS are:

Spontaneous burning or aching pain of the affected extremity

Skin sensitivity

Skin discoloration



Temperature changes (2/3 warmer, 1/3 colder)

Brittle nails

In chronic CRPS, the main symptoms can become more severe. In the long term, patients may develop non-dermatomal sensory deficits, disturbances of the body perception, and motor deficits leading to:

Pain spread to the entire limb and often to the opposite limb

Severe muscle dystrophy

Limb weakness

Reduced joint motion


Examiner testing sensory function of the finger tip


The diagnosis of CRPS is based on medical assessment using both subjective symptom reports and objective signs on clinical assessment. Early diagnosis of CRPS is critical to prevent the transition into a chronic condition. The International Association for the Study of Pain (IASP) has established the Budapest diagnostic criteria of CRPS following the 2004 meeting in Budapest to achieve a higher specificity compared to previous definitions. The main criteria are:

A continuing pain that is disproportionate to the initial pathological event.

The patient must report at least one CRPS symptom in three of the four categories:

Sensory symptoms: hyperalgesia (noxious stimulus) and allodynia (non-noxious stimulus)

Vasomotor symptoms: skin temperature asymmetry, skin colour changes, skin colour asymmetry to opposite side

Sudomotor symptoms/oedema: swelling/oedema, sweating changes, sweating asymmetry to opposite side

Motor & trophic symptoms: Reduced range of motion, motor dysfunction (weakness, tremor), trophic alterations of the skin, nail, hair.

At time of clinical evaluation, the patient must display at least one sign in two or more of the above categories.

Diagnosis of CRPS is confirmed if no other diseases fit the array of symptoms identified on clinical examination.

Additional diagnostic methods may support the findings of the clinical examination or be used for differential diagnosis:

Electromyography & nerve conduction studies (CRPS II)

Triple phase bone scintigraphy (increased bone metabolism)

MRI of extremity looking for bone oedema

Quantitative sudomotor axon reflex test

Trial of sympathetic ganglion block

X-rays and MRI to exclude nerve compression at the spine

Other tests to rule out alternative conditions such as deep vein thrombosis, arthritis, diabetes or infection.

A mirror is used to create a reflective illusion of an affected limb to trick the brain into thinking movement has occurred without pain

Nonoperative treatment

The treatment of CRPS remains a challenge. Because of the lack of consensus on a standardised treatment for CRPS, several strategies are currently recommended mostly based on a multidisciplinary management. Some of these are not proven to be efficacious:

Physical/occupational therapy (especially for CRPS Type I)

Oral corticosteroids (acute phase)


Opioid analgesics (morphine derivatives)

Anti-convulsant drugs (pregabalin, gabapentin, topiramate)

Local injection of anaesthetics early in the disease

Calcitonin (calcium modulation)


Calcium channel blockers

Anaesthetics (ketamine)

Intravenous immunoglobulins

Psychological therapy


Mirror box therapy (restore correct image of affected limb)

Hyperbaric oxygen therapy (emerging therapy)

Cross-section of the spinal cord showing the thick nerve ganglia in yellow that are ablated with radiofrequency

Surgical treatment

Surgical intervention is used in case conservative treatment fails but it may not resolve the symptoms. Surgical approaches include:

Spinal cord stimulation: small electrodes are implanted along the spine with the purpose of delivering mild electric impulses to the affected sensory nerves

Pain pump implantation: it consists of the implantation near the abdomen of a small device that releases analgesic medications directly to the spinal cord

Radiofrequency ablation: destruction of the sympathetic ganglion either via radiofrequency ablation or using chemicals

Rarely, amputation becomes the last resource for CRPS

High frequency and repetitive transcranial magnetic stimulation: may reduce pain when combined with medical treatment

Amputation: in rare cases, amputation of the affected limb may be the last option.

Physiotherapist assisting a patient with gentle wrist-hand exercise


Physical and occupational therapy can be very effective in treating pain and reduced function caused by CRPS. Psychological counseling may be recommended if these therapeutic strategies are not successful. Common rehabilitative strategies include:


Mirror therapy


Weight bearing

Stretching / fine motor exercises


Pilates / Yoga

Physical activity is efficaceous method to prevent CRPS


The main strategy for preventing CRPS is to treat pain at the onset of the first symptoms especially after injury or trauma. It is essential to maintain regular physical activity of the affected limb to avoid muscle wasting, joint stiffness and ultimately disability.

Vitamin C is the most efficacious preventative therapy after a fracture or surgery due to its antioxidant properties, which may reduce inflammation.

Minimising the duration of the tourniquet use to block blood flow during limb surgery to reduce ischaemic-reperfusion injury mediated by oxidative stress when blood flow is restored

Bisphosphonate administration may help to restore bone metabolism

Topical ketamine for analgesia