Complex Regional Pain Syndrome Type I

Complex regional pain syndrome (CRPS) type I (formerly reflex sympathetic dystrophy) is a chronic pain condition of a limb that develops after an injury or surgery without a definable major nerve lesion. Pain is out of proportion to the initial event, with sensory, autonomic, vasomotor, sudomotor, motor and trophic changes.

It most often follows distal radius fracture (1 to 5 % of fractures), ankle fracture, surgery (carpal tunnel release, foot surgery), sprain or immobilisation in a cast, and can follow stroke or myocardial infarction.

The incidence is about 5 to 26 for every 100 000 person years. It is three to four times more common in women, with a peak at age 50 to 70 years, and the upper limb is more often affected than the lower limb. Risk factors are female sex, postmenopausal state, fracture (especially distal radius), cast immobilisation, high initial pain, smoking, previous CRPS, asthma, migraine and psychological distress (anxiety, depression, catastrophising).

The Budapest criteria define the diagnosis:

• continuing pain disproportionate to the inciting event
• at least one symptom in 3 of the 4 categories (sensory: hyperaesthesia or allodynia; vasomotor: temperature or skin colour asymmetry; sudomotor or oedema: oedema, sweating changes; motor or trophic: reduced range, weakness, tremor, dystonia, hair, nail or skin changes)
• at least one sign in 2 or more categories at examination
• no other diagnosis that better explains the findings

Warm (inflammatory) and cold (sympathetic) subtypes exist, and the course may progress from the acute to the chronic phase.

Complications are chronic pain, contracture, osteoporosis, disuse, depression, sleep disturbance, disability and loss of work. About 70 to 80% improve within a year, but 15 to 20% have long term disability.

Pathophysiology.

The mechanism is multifactorial. Contributors are:

• peripheral and central sensitisation
• neurogenic inflammation (release of substance P and calcitonin gene related peptide)
• small fibre neuropathy
• autoimmune factors (autoantibodies to autonomic receptors)
• sympathetic afferent coupling
• cortical reorganisation (shrinkage of the cortical representation of the limb)
• oxidative stress and genetic factors

Free radical injury is the rationale for vitamin C prophylaxis.

Burning, aching or deep pain out of proportion, allodynia (pain on light touch) and hyperalgesia, in a distal distribution (not following a single nerve), that begins within 4 to 6 weeks of the injury. Swelling, skin temperature and colour changes (warm and red early, cool and blue later), sweating changes, stiffness with loss of range of motion, weakness, tremor and dystonia, and trophic changes (shiny skin, nail and hair changes). Patients protect the limb and avoid use.

Examine both limbs for temperature, colour, swelling (volume), sweating, range of motion, strength, skin and nail changes, and allodynia to touch, pressure and cold. Check for other causes of pain, and ask about mood, sleep and function.

• The diagnosis is clinical, by the Budapest criteria; there is no confirmatory test.
• Radiographs: patchy (spotty) osteopenia in the affected limb after 4 to 8 weeks. Three phase bone scan shows increased uptake in the delayed phase (sensitivity about 80%, better in adults and early disease). MRI shows oedema and skin changes. These tests rule out other causes.
• Skin temperature measurement (difference over 1 degree Celsius), limb volumetry, and quantitative sensory testing support the diagnosis.
• Exclude other causes: infection, deep vein thrombosis, arterial insufficiency, fracture, arthritis, nerve entrapment, small fibre neuropathy, lymphoedema and malignancy.
• Blood tests as needed: full blood count, C-reactive protein, erythrocyte sedimentation rate, thyroid function, and glucose.

Differential diagnosis.

• Cellulitis, osteomyelitis and deep vein thrombosis.
• Peripheral nerve injury (CRPS type II), neuropathy and nerve entrapment.
• Peripheral vascular disease and Raynaud phenomenon.
• Arthritis, disuse pain and factitious disorder.

Early recognition and multidisciplinary treatment improve outcomes. The aims are to relieve pain, restore function, and manage psychological effects.

Prevention after distal radius fracture. Vitamin C (ascorbic acid) 500 mg orally once daily for 50 days from the day of injury (maximum 500 mg daily; the evidence is moderate). Avoid with a history of oxalate kidney stones, and limit with eGFR under 30 mL/min/1.73 m2. No routine monitoring. Early mobilisation and good analgesia reduce the risk.

Rehabilitation (cornerstone).

• Graded physiotherapy and occupational therapy: desensitisation, graded motor imagery (laterality training, imagined movements, mirror therapy), graded exposure, pain limited active movement, stress loading and functional use.
• Compression, oedema control, contrast baths and elevation; avoid immobilisation and prolonged splinting.
• Pain psychology: cognitive behavioural therapy, pain education, sleep hygiene and treatment of anxiety and depression.

Drug treatment.

• Prednisolone 30 to 40 mg orally once daily in the morning for 2 to 4 weeks, then tapered over 2 to 4 weeks, for acute warm CRPS (within 3 to 6 months of onset; evidence is moderate and treatment is off label).
• Prednisolone monitoring: glucose, blood pressure and mood. Give gastric protection when risk factors are present; avoid with infection or uncontrolled diabetes.
• Bisphosphonate: alendronate 40 mg orally once daily for 8 weeks (off label; studied dose), or neridronate 100 mg intravenously on 4 occasions over 10 days where available. Evidence is best in the early stage with bone changes.
• Alendronate precautions: take fasting with a full glass of water and keep upright for 30 minutes; check calcium, 25-hydroxyvitamin D and creatinine; avoid with eGFR under 35 mL/min/1.73 m2, uncorrected hypocalcaemia or oesophageal stricture.
• Neuropathic pain agents: gabapentin 300 mg orally at night, increased by 300 mg every 1 to 3 days to 300 to 600 mg three times daily (maximum 1800 mg daily; reduce at creatinine clearance under 60 mL/min); monitor sedation and dizziness.
• Amitriptyline 10 mg orally at night, increased by 10 mg weekly to 50 to 75 mg (maximum 75 mg daily). Avoid with cardiac conduction disease, glaucoma, urinary retention or recent myocardial infarction; monitor sedation and anticholinergic effects.
• Pregabalin 75 mg orally twice daily (maximum 600 mg daily; reduce at creatinine clearance under 60 mL/min) is an alternative.
• Topical lidocaine 5% plaster (up to 3 plasters for 12 hours in 24) or capsaicin 8% patch for localised allodynia.
• Opioids are of limited value and are avoided for long term use.
• Ketamine infusions, intrathecal baclofen, and sympathetic blockade are specialist treatments for refractory disease.

Interventional treatment (specialist).

• Sympathetic blocks (stellate ganglion for the upper limb: bupivacaine 0.25% 5 to 10 mL, maximum 2 mg/kg and not exceeding 150 mg; lumbar sympathetic block for the lower limb) to facilitate rehabilitation when sympathetically maintained pain is present.
• Spinal cord stimulation or dorsal root ganglion stimulation for refractory chronic CRPS (after failure of conservative treatment for 6 months), with psychological screening and a test period.
• Amputation is rarely justified, and has a high risk of recurrence.

Analgesia.

• Paracetamol 1 g orally every 6 hours as needed for up to 5 to 7 days (maximum 4 g daily; 3 g daily when weight is under 50 kg, with chronic alcohol use or hepatic impairment).
• Ibuprofen 400 mg orally every 8 hours with food for up to 5 to 7 days (maximum 1200 mg daily); avoid with eGFR under 30 mL/min/1.73 m2, peptic ulcer, heart failure or anticoagulant use.

Monitoring. Pain score, function (Budapest criteria, range, grip and limb volume) and mood at every visit (every 2 to 4 weeks initially). Adverse effects of gabapentin, amitriptyline and steroids. Bone density if prolonged. Return to work and activity goals at 3 months.

Referral and escalation. Refer suspected CRPS early (within 4 weeks) to a pain service or a multidisciplinary clinic. Urgent referral for suspected infection, vascular compromise, rapidly progressive symptoms or suicidal thoughts.

Special groups.

• Children and adolescents: CRPS type I affects mostly girls aged 10 to 15 (lower limb); intensive physiotherapy and psychology give good results, and medication is limited.
• Postmenopausal women: higher risk; screen for osteoporosis.
• Surgery in a patient with previous CRPS: use regional anaesthesia, vitamin C prophylaxis and early mobilisation.
• Kidney impairment: avoid NSAIDs, and reduce gabapentin and pregabalin.