Complex Regional Pain Syndrome

Complex Regional Pain Syndrome (CRPS) is a chronic neuropathic pain condition that typically affects a single extremity and is characterised by a constellation of sensory, autonomic, motor, and trophic disturbances that are disproportionate to the inciting event. The condition was historically divided into reflex sympathetic dystrophy (CRPS Type I) and causalgia (CRPS Type II).

In Australia, CRPS has an estimated incidence of 5.46–26.2 per 100,000 person-years, with the upper limbs affected more commonly than lower limbs (approximately 60:40 ratio). The condition is 3–4 times more common in females and peaks in incidence in the 5th–7th decades of life. Fractures remain the most common precipitant (approximately 40–46% of cases), followed by surgical procedures, sprains, and minor soft-tissue injuries.

The socioeconomic burden of CRPS in Australia is substantial: patients frequently experience loss of work capacity, prolonged opioid dependence, and reduced quality of life. The condition may lead to permanent limb dysfunction if not identified and managed within the critical early window. The Australian Commission on Safety and Quality in Health Care (ACSQHC) recognises chronic pain management as a priority area within the National Safety and Quality Health Service (NSQHS) Standards.

The Budapest Criteria (Harden et al., 2010) are the current international consensus diagnostic criteria for CRPS and should be used in all clinical assessments. They replaced the earlier IASP (1994) criteria, which had high sensitivity (0.98) but poor specificity (0.36).

Budapest Criteria — Required Elements

Diagnostic threshold: The patient must report at least one symptom in 3 of the 4 categories, and the clinician must identify at least one sign in 2 of the 4 categories. There must be no other diagnosis that better explains the signs and symptoms.

Specifiers (Modifier Descriptors)

Following a clinical diagnosis of CRPS, the following specifiers may be appended:

• "with predominant sympathetically maintained pain" — if sympatholytic therapy (e.g., sympathetic nerve block) produces significant pain relief.
• "without sympathetically maintained pain" — if sympathetic blockade does not produce relief (sympathetically independent pain).
• "without continuing identifiable peripheral nociceptive input" — when no ongoing peripheral driver can be identified.
• "with continuing identifiable peripheral nociceptive input" — when an ongoing peripheral driver is present (e.g., non-union fracture).

The distinction between CRPS Type I and Type II is based on the presence or absence of a definable nerve injury. Both types share the same diagnostic criteria and clinical features; the distinction primarily guides investigation and prognosis.

The pathophysiology of CRPS is complex and incompletely understood, involving peripheral and central nervous system mechanisms, neuroinflammation, and cortical reorganisation. Current evidence supports a multifactorial model.

Peripheral Mechanisms

• Peripheral sensitisation: Local release of pro-inflammatory neuropeptides (substance P, CGRP) from nociceptive C-fibres results in neurogenic inflammation — manifesting as oedema, erythema, and warmth.
• Sympathetic–afferent coupling: In sympathetically maintained pain (SMP), noradrenaline released by sympathetic efferents activates α-adrenoreceptors that have been aberrantly expressed on nociceptive afferents.
• Peripheral ischaemia: Vasomotor dysfunction leads to microvascular changes, contributing to trophic changes, skin atrophy, and osteopaenia.

Central Mechanisms

• Central sensitisation: Sustained nociceptive input produces wind-up in the dorsal horn, expansion of receptive fields, and reduced descending inhibitory modulation — leading to allodynia and hyperalgesia beyond the site of injury.
• Cortical reorganisation: Functional MRI studies demonstrate shrinkage of the somatotopic representation of the affected limb in S1 cortex, correlating with pain intensity and reversed by successful treatment (mirror therapy, graded motor imagery).
• Disrupted body schema: Patients frequently exhibit impaired proprioception, reduced left–right discrimination, and motor neglect of the affected limb — a key rationale for graded motor imagery programmes.

Genetic and Autoimmune Considerations

Emerging evidence suggests HLA associations (HLA-DQ8, HLA-B62) and autoantibodies against β2-adrenergic and muscarinic M2 receptors in a subset of CRPS patients, supporting a possible autoimmune phenotype — particularly in chronic, spreading CRPS. This remains an active area of research and does not currently alter standard management.

Sympathetic nervous system dysfunction is a hallmark of CRPS but is not uniformly present. Understanding the sympathetically maintained (SMP) vs sympathetically independent (SIP) distinction is important for guiding interventional pain management.

Clinical Manifestations of Sympathetic Dysfunction

• Vasomotor: Temperature asymmetry (affected limb cooler in SMP; may be warmer in early neurogenic inflammation), skin colour changes (mottled cyanosis, erythema, or pallor).
• Sudomotor: Ipsilateral hyperhidrosis or, less commonly, hypohydrosis.
• Trophic changes: Brittle nails, altered hair growth (initially increased, later absent), shiny atrophic skin, and subcutaneous fat atrophy.
• Bone changes: Periarticular osteopaenia visible on plain radiograph; regional osteoporosis on DEXA in chronic cases.

Diagnosing SMP vs SIP

The gold standard is the sympathetic ganglion block (stellate ganglion block for upper limb; lumbar sympathetic block for lower limb). A ≥50% reduction in pain intensity post-block indicates sympathetically maintained pain. Thermography may demonstrate temperature asymmetry (affected limb ≤1°C cooler) but is not diagnostic alone.

CRPS typically presents within days to weeks of an inciting event (fracture, surgery, immobilisation, minor injury) but may develop insidiously. The clinical course is often divided into three phases, though not all patients follow this pattern:

Red Flags — Consider Alternative Diagnoses

CRPS remains a clinically diagnosed condition. Investigations are used to exclude alternative diagnoses, quantify bone involvement, and assess for nerve injury (Type II). No single investigation is diagnostic of CRPS.

Multidisciplinary rehabilitation is the cornerstone of CRPS management and should be initiated as early as possible — ideally within the first 3 months. The NHMRC-endorsed chronic pain framework emphasises a biopsychosocial approach combining physical therapy, psychological support, education, and pharmacotherapy.

Graded Motor Imagery Programme

This is the most evidence-based physiotherapy intervention for CRPS, with Level I evidence from randomised controlled trials (Moseley, 2004; Bowering et al., 2013).

Additional Physiotherapy Components

• Desensitisation: Graded exposure to textures — start with the least provocative (silk, cotton) and progress (wool, denim, velvet). Multiple sessions daily.
• Graded exercise therapy: Progressive loading of the affected limb — aerobic exercise, gentle resistance training, aquatic therapy. Avoid aggressive ROM in acute phase (may worsen pain).
• Stress loading: TENS (transcutaneous electrical nerve stimulation) and scrunch tasks — evidence from Oerlemans et al. (1999) supports combined exercise and stress loading.
• Oedema management: Elevation, compression garments (introduced gradually), manual lymphatic drainage.
• Functional restoration: Occupational therapy focus on ADLs, workplace modification, and graded return to function.

Psychological Support

Pain-related catastrophising, kinesiophobia (fear of movement), anxiety, and depression are common in CRPS and predict poorer outcomes. Evidence supports:

• Cognitive behavioural therapy (CBT): Addresses pain catastrophising, fear-avoidance, and coping strategies. Level I evidence.
• Acceptance and commitment therapy (ACT): Increasingly used in Australian chronic pain programmes.
• Eye movement desensitisation and reprocessing (EMDR): Emerging evidence for trauma-associated CRPS onset.
• Pain neuroscience education: Explaining central sensitisation mechanisms reduces catastrophising and improves engagement with rehabilitation.

Pharmacotherapy for CRPS should be initiated early and used as an adjunct to — not a substitute for — multidisciplinary rehabilitation. Current evidence supports a stepwise approach. International guidelines (IASP, European Pain Federation) and Australian practice are broadly aligned.

First-Line Agents: Gabapentinoids

Second-Line Agents

Ketamine Infusion Therapy

Opioid Analgesia

Other Agents

• Topical capsaicin 8% patch (Qutenza®): Specialist-applied under local anaesthesia. Repeated application may benefit localised CRPS. PBS Authority Required.
• Topical lidocaine 5% patch: May help localised allodynia. Not PBS-listed for this indication (available as authority for postherpetic neuralgia).
• Clonidine: Oral or transdermal — may benefit sympathetic-mediated symptoms. Not PBS-listed for CRPS.
• Corticosteroids: Short-course oral prednisolone (30–40 mg/day for 2–4 weeks with taper) — may benefit very early CRPS (within 3 months of onset) based on limited evidence. Avoid in chronic CRPS.

Regular structured monitoring is essential to track disease trajectory, medication adverse effects, functional improvement, and psychological wellbeing.

Outcome Measures

Medication Monitoring

• Gabapentinoids: FBC, LFTs, renal function at baseline and 3-monthly. Monitor for sedation, dizziness, peripheral oedema, weight gain.
• Amitriptyline: ECG at baseline if >60 years or cardiac risk factors (QTc monitoring). FBC, LFTs annually.
• Alendronate: Renal function (contraindicated eGFR <30). Dental review before initiation (osteonecrosis of jaw risk). DEXA at 12 months.
• Ketamine infusions: LFTs, renal function, FBC at baseline and during infusion. Continuous cardiorespiratory monitoring during inpatient infusion.
• Opioids (if used short-term): Opioid Risk Tool (ORT) screening. Naloxone co-prescribing discussion. Urine drug screening as per RACGP guidelines.

Prognosis in CRPS is heterogeneous and depends on disease duration at presentation, treatment initiation, type (I vs II), and psychosocial factors.

Prognostic Factors

Expected Outcomes

• CRPS Type I (early, <6 months): Approximately 70% of patients achieve significant improvement or complete remission within 12–18 months with appropriate multidisciplinary treatment.
• CRPS Type I (chronic, >2 years): Approximately 30–40% continue to experience significant pain and disability at 5 years.
• CRPS Type II: More protracted course; recovery of nerve function and pain resolution are less likely but still achievable with combined rehabilitation and interventional management.
• Spread: Occurs in approximately 7–24% of patients — most commonly to the contralateral limb. Spread is associated with longer disease duration and higher pain intensity.
• Recurrence: Re-injury or re-immobilisation of the previously affected limb may trigger recurrence. Patients should be counselled regarding prevention.

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