Complex Regional Pain Syndrome (CRPS) 

Overview

CRPS is a disproportionate, regional pain syndrome of a limb that typically follows injury or surgery and features sensory, vasomotor, sudomotor/oedema, and motor/trophic changes. The prevalence after limb fracture/surgery varies widely (≈1–7% overall, higher in some distal radius cohorts) and early recognition with rehabilitation improves outcome. Important risk factors include fracture (especially wrist/ankle), immobilisation, high pain intensity, female sex and psychological distress; major complications are chronic disability, dystonia/contracture, osteoporosis, and reduced return-to-work [2,14,10,6].

Anatomy & Physiology 

• Pain pathways: peripheral nociceptors → dorsal horn → spinothalamic/limbic circuits (insula/ACC); descending modulation via PAG–RVM (5-HT/NA, endogenous opioids).
• Autonomic control: sympathetic vasomotor and sudomotor fibres regulate skin temperature, colour and sweating.
• Neuro-immune interface: neuropeptides (substance P, CGRP) and cytokines modulate vasodilation/oedema; glial activation sustains central sensitisation.

Aetiology and Risk Factors

Aetiology

• Multimechanistic: neurogenic inflammation (neuropeptides/cytokines), small-fibre dysfunction, autoantibody phenomena (subset), central sensitisation, and maladaptive cortical re-organisation [2,0].
• Precipitating events: fracture, surgery, sprain, crush injury, rarely without major trauma; higher with distal radius/ankle injuries and prolonged immobilisation [2,10].

 Risk factors

• Female sex, middle age
• High early pain/cast tightness
• Immobilisation
• Anxiety/depression
• Smoking
• Prior CRPS
• Nerve injury (CRPS II)

Pathophysiology 

• Inciting injury/surgery → intense nociceptive input + local neurogenic inflammation → vasomotor/sudomotor changes and oedema.
• Peripheral/central sensitisation → allodynia/hyperalgesia; cortical sensorimotor changes maintain pain and neglect-like phenomena.
• Autonomic dysregulation → “warm” (vasodilated) early phenotype; with time some progress to “cold” (vasoconstricted) phenotype with trophic change and dystonia [15].
• Disuse from pain/fear → stiffness, weakness, contractures; bone demineralisation.

Clinical Manifestations

• Pain: regional, continuous, disproportionate to injury; burning/deep ache; mechanical/thermal allodynia and hyperalgesia.
• Vasomotor: temperature or colour asymmetry (warm/red or cold/blue).
• Sudomotor/oedema: swelling, sweating asymmetry.
• Motor/trophic: weakness, tremor/dystonia, decreased ROM, nail/hair/skin changes; neglect-like symptoms or motor imagery difficulty.

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Diagnosis

Budapest clinical criteria

1. Ongoing pain that is disproportionate to any inciting event.
2. Presence of at least one symptom in three of the following four categories:
   • Sensory: hyperesthesia or allodynia
   • Vasomotor: temperature asymmetry or skin colour changes/asymmetry
   • Sudomotor/oedema: oedema, sweating changes or sweating asymmetry
   • Motor/trophic: decreased range of motion, motor dysfunction (e.g., weakness, tremor) or trophic changes (e.g., altered hair, nail, or skin)
3. At least one clinical sign in two or more of the same categories at the time of assessment:
   • Sensory: evidence of hyperalgesia or allodynia
   • Vasomotor: temperature or skin colour asymmetry
   • Sudomotor/oedema: oedema or sweating differences
   • Motor/trophic: observable motor dysfunction or trophic changes
4. No other diagnosis better explains the signs and symptoms.

Other Investigations (support/exclude)

• Plain x-ray for patchy osteopenia (late)
• MRI for marrow oedema/soft-tissue swelling
• 3-phase bone scan not required and inconsistent
• Thermography

Differential Diagnosis

• Cellulitis (fever/leukocytosis, warmth without allodynia)
• DVT (risk factors, duplex positive)
• Compartment syndrome (pain out of proportion + tense compartments)
• Neuropathic pain from specific nerve lesion (topographic distribution)
• Inflammatory arthritis (synovitis, raised CRP/ESR)
• Erythromelalgia (heat/redness without trophic/motor changes).

Classification

Complex regional pain syndrome is classified under chronic primary pain according to the International Classification of Diseases, 11th Revision (ICD-11). Chronic Primary Pain is pain that persists for ≥3 months and is not better explained by another condition. It is considered a disease in its own right, often associated with emotional distress or functional disability. Examples of chronic primary pain:

• Chronic widespread pain (CWP)
• Fibromyalgia
• Complex regional pain syndrome (CRPS)
• Chronic primary headache
• Chronic primary visceral pain (e.g., irritable bowel syndrome)
• Chronic primary musculoskeletal pain (e.g., non-specific low back pain)

Complex Regional pain syndrome classification

• By nerve injury: CRPS I (no identifiable nerve lesion) vs CRPS II (definable nerve injury)
• By temperature phenotype: Warm CRPS (vasodilated, often early) vs Cold CRPS (vasoconstricted, often chronic)
• By course: acute/early (<3–6 mo) vs persistent/chronic.
• Paediatric vs adult CRPS (management emphasis differs but Budapest criteria apply)
  

Treatment

• Foundations
  • Education (biopsychosocial model)
  • Early limb use and functional restoration
  • Desensitisation
  • Graded motor imagery (GMI)/mirror therapy
  • Structured physiotherapy/occupational therapy with pacing and flare plans
    
• Analgesic/neuropathic agents (individualised): short course oral corticosteroids early may help pain/oedema; bisphosphonates (e.g., neridronate IV or IM) reduce pain in CRPS-I (moderate evidence); consider gabapentinoids, TCAs/SNRIs; topical agents for focal allodynia; avoid long-term strong opioids [4,12,20,17].
  
• Interventional (refractory, specialist)
  • Dorsal root ganglion (DRG) stimulation offers higher treatment success than conventional spinal cord stimulation (SCS) at 3–12 months in lower-limb CRPS;
  • SCS remains an option
  • Consider sympathetic blocks for selected warm/vasomotor-dominant cases
  • Ketamine infusions and IV lidocaine only in specialised centres with careful selection [3,1,9].
    
• Prevention after fracture
  • Encourage early mobilisation
  • Vitamin C 500 mg daily for 6 weeks after wrist fracture may lower incidence though evidence is mixed
    
• Paediatric focus
  • Intensive physiotherapy + psychology (exposure, CBT
  •  school reintegration; medications are adjunctive [2].
    Remember: Functional restoration is the primary goal; medications and procedures are adjuncts, not substitutes [2,6].

Complications and Prognosis

Complications

• Contractures/dystonia
• Chronic functional limitation
• Disuse osteopenia/osteoporosis
• Depression/anxiety
• Medication harms
• Persistent oedema/skin changes 

 Prognosis

• Many improve within the first year with early rehab
• A subset progress to chronic cold CRPS with disability
• Poor prognostic factors include delayed diagnosis/treatment, cold phenotype, high early pain, psychological distress, and prolonged immobilisation [2,15]

References

1. Deer TR, Levy RM, Kramer J, et al. Therapy habituation at 12 months: dorsal root ganglion versus spinal cord stimulation in CRPS. J Pain. 2019;20(5):551–561. (Jpain)
   
2. Royal College of Physicians. Complex regional pain syndrome in adults (2nd ed.). London: RCP; 2018. (rcp.ac.uk)
   
3. Harden RN, Bruehl S, Perez RS, et al. Complex Regional Pain Syndrome: Practical Diagnostic and Treatment Guidelines, 5th ed. RSDSA; 2022. (issp-pain.org)
   
4. Varenna M, Adami S, Sinigaglia L, et al. Treatment of CRPS-I with neridronate: randomized placebo-controlled trial. Rheumatology (Oxford). 2013;52(3):534–542. (Oxford Academic)
   
5. Limakatso K, Madden V, Parker R. Graded motor imagery and mirror therapy for CRPS: systematic review. Biomedicines. 2023;11(9):2140. (MDPI)
   
6. Ferraro MC, Cashin AG, Wand BM, et al. Interventions for treating pain and disability in adults with CRPS: overview of systematic reviews. Cochrane Database Syst Rev. 2023;CD009416. (Cochrane)
   
7. IASP. Complex Regional Pain Syndrome Special Interest Group. 2024. (IASP)
   
8. Harden RN, Bruehl S, Perez RS, et al. Validation of the Budapest Criteria for CRPS. Pain. 2010;150(2):268–274. (ScienceDirect, baycrest.echoontario.ca)
   
9. Pain Relief Foundation. Clinical practice guideline review of reviews for CRPS management (2022). (painrelieffoundation.org.uk)
   
10. Kim HS, Jang CY, Kim JH, et al. Incidence and risk factors for CRPS after radius fractures: meta-analysis. Arch Orthop Trauma Surg. 2023;143(11):6639–6652. (SpringerLink)
    
11. Birklein F, Schlereth T. Complex regional pain syndrome—phenotypic characteristics and mechanisms. Nat Rev Neurol. 2018;14(9):607–617. (Nature)
    
12. Varenna M, Zucchi F, Ghiringhelli D, et al. Intramuscular neridronate in CRPS-I: randomized double-blind trial. Pain Med. 2021;22(10):2349–2359. (SAGE Journals, Europe PMC)
    
13. Faculty of Pain Medicine (UK). Criteria for diagnosis of CRPS (Budapest). 2021. (Faculty of Pain Medicine)
    
14. Macfarlane GJ et al. CRPS epidemiology (summary). BMJ. 2015;351:h2730. (BMJ)
    
15. Bruehl S, et al. Evidence for warm and cold CRPS subtypes. Pain. 2016;157(8):1674–1683. (Lippincott Journals)
    
16. Ferraro et al. Cochrane—physiotherapy for CRPS (background). Cochrane Database Syst Rev. 2015;CD010853. (Cochrane Library)
    
17. Cochrane overview and RSDSA guideline sections on steroids/ketamine (2022–2023). (Cochrane, issp-pain.org)
    
18. BSSH link to RCP guideline summary. 2018. (bssh.ac.uk)
    
19. Song K, et al. Vitamin C for preventing/treated CRPS: updated evaluation. Front Surg. 2024;11:1473311. (ScienceDirect)