1. Complex Regional Pain Syndrome
Gabriel Mattei, MD
Interventional Pain Fellow
Hudson Spine & Pain Medicine
5/4/2017

2. In 1993, the IASP introduced the term Complex regional pain syndrome to describe all pain states that previously would have been diagnosed as RSD or causalgia-like syndromes

3. Defining CRPS: IASP Consensus Workshop Orlando, Florida, 1993
The term RSD was:
Too over-used & non-specific to be of value
Inaccurate
CRPS type 1: (RSD)
CRPS type 2: (Causalgia)

4. Defining CRPS: IASP Consensus Workshop Orlando, Florida, 1993
CRPS type 1 is a syndrome that usually develops after an initiating noxious event
Not limited to the distribution of a single peripheral nerve
Disproportionate to the inciting event

5. Defining CRPS: IASP Consensus Workshop Orlando, Florida, 1993
Defining CRPS type 1: IASP, 1993
May be associated with evidence of:
Edema
Changes in skin blood flow
Abnormal sudomotor activity
Allodynia or hyperalgesia
The site is usually distal aspect of an affected extremity or with a distal to proximal gradient

6. IASP Did Not Include: The term sympathetic
Response to sympathetic blocks
Predisposing factors
Psychological factors
Stages
Osteoporosis
Impairment of motor function

7. Complex Regional Pain Syndrome:
a variety of painful conditions following injury which appears regionally having a distal predominance of abnormal findings, exceeding in both magnitude and duration the expected clinical course of the inciting event, often resulting in significant impairment of motor function, and showing variable progression over time.

8. Epidemiology CRPS I: 21 per 100,000 CRPS II: 4 per 100,000
Female-to-Male ratio: 3:1
Any age, but middle age predominates
Median 42 years
Onset 9 – 85 years of age
CRPS occurs in about 1-2% of patients who have had fractures and in approximately 2-5% of patients after peripheral nerve injuries

9. Differential diagnosis:
Unrecognized local pathology (fracture, sprain)
Traumatic vasospasm
Cellulitis
Lymphedema
Raynaud’s disease
Thromboangiitis obliterans
Erythromelalgia
DVT
Also, nerve entrapment syndromes, occupational overuse syndromes, and diabetic neuropathy

10. A modified diagnostic criteria was proposed by the IASP in 2007 to increase specificity (the ‘Budapest criteria’):
Continuing pain that is disproportionate to any inciting event
Must report at least one symptom in three of the four following categories:
Sensory: hyperalgesia, allodynia
Vasomotor: temp. asymmetry, skin color changes or asymmetry
Sudomotor/Edema: edema, sweating changes or asymmetry
Motor/Trophic: decreased range of motion, weakness, tremor, dystonia, trophic changes
Must display at least one sign at the time of evaluation in two or more of the following categories:
No other diagnosis better explains the signs and symptoms

11. CRPS Types 1 and 2: Features in common
Pain
Spontaneous or evoked
Allodynia and/or hyperalgesia
Disproportionate pain to the inciting event
Regional: not limited to a single peripheral nerve distribution
Evidence of edema or abnormal sudomotor activity
Diagnosis is excluded if other conditions could be account

12. Differentiating CRPS Types 1(RSD) and 2 (Causalgia)
Type 1 occurs after an initial noxious event other than nerve injury
Type 2 occurs after a nerve injury

13. Insults followed by CRPS 1
Trauma
Stroke or other CNS disorders
Shingles MI
Shoulder disorders
Malignancy
Other precipitants
Spontaneous

14. Pathophysiology Three main hypotheses
Facilitated neurogenic inflammation
Autonomic dysfunction
Neuroplastic changes within the CNS

15. Neurogenic inflammation
Classic inflammatory signs are present in CRPS: pain, swelling, erythema, hyperthermia and impaired function
However, when clinical chemistry parameters for inflammation are evaluated, there are no differences between CRPS patients and controls
With neurogenic inflammation, distinct classes of C-fibers called mechano-heat-insensitive C-fibers have both an afferent function in the mediation of pain and itch as well as an efferent neurosecretory function, releasing neuropeptides via ‘axon reflex’
Action potentials in these fibers can be conducted retrogradely to terminal branches via axon collaterals where neuropeptides such as substance P and calcitonin-gene-related peptide (CGRP) are released
Substance P provokes plasma protein extravasation (edema) and appears to have a role in osteoclastic activity
CGRP induces vasodilation (hyperthermia and erythema), increases sweating, and appears to be involved in hair growth

16. Autonomic dysfunction
Pathological sympatho-afferent coupling: Peripheral nociceptors develop adrenergic sensitivity (mainly alpha-2 receptors) such that tonic sympathetic efferent activity leads to their activation
Painful impulses via these nociceptors maintain the central nervous system in a sensitized state
Painful and non-painful stimuli to the affected limb result in hyperalgesia and allodynia, respectively
Catecholamine levels, however, are actually lower in the affected extremity, thus, it is not a problem of excessive sympathetic nerve output

17. Neuroplastic changes within the CNS
Studies using functional brain imaging in patients with CRPS have found a significant degree of cortical reorganization in the central sensory and motor cortices
The amount of reorganization positively correlates with the extent of pain intensity
The areas of reorganization were found to be reversible in adequately treated patients

18. Clinical Presentation
PAIN, PAIN, PAIN
Spontaneous, constant, burning, aching, throbbing
Disproportionate to the injury and persists beyond normal or expected recovery period
Asymmetrical and not in the distribution of a peripheral nerve. Worst distally.
Severe mechanical and thermal allodynia, hyperalgesia, and hyperpathia

19. Clinical Presentation
Autonomic (Sympathetic) Abnormalities
Vascular
Hot, swollen, erythemetous
Cold, blanched
Mottled
Sudomotor
Hyperhydrosis
Hypohydorosis

20. Clinical Presentation
Motor
Diffuse weakness of the extremity, but normal EMG/NCS until late in the course of the disease.
Tremor
Dystonia occasionally

21. Clinical Presentation
Trophic Changes
Nail growth
Loss of function: muscle, joint and tendon atrophy, contractures and fibrosis
Hair changes (coarse hair, loss of hair)
Skin--thin and glossy, loss of elasticity, ulceration.
Osteoporosis

22. Clinical Presentation Time Course
Three stages:
Stage 1 (acute)
Stage 2 (dystrophic)
Stage 3 (atrophic)

23. Stage One: Initial Phase MOST LIKELY TO BE REVERSED AND CURED
Duration: weeks to months
Limb pain
Skin is variable: cold/cyanotic/sweaty or warm/red/dry
Hair and nail growth may be increased
Swelling with associated decreased range of motion or stiffness

24. Stage 1 (Acute)

25. Stage Two: Dystrophic Phase
Duration: 3-6 months
Limb pain spreads diffusely, but may decrease overtime
Brawny edema: swelling evolves into thickened dermis and fascia
Nails show ridges, splits, and decreased growth
Early signs of muscular atrophy and osteoporosis

26. Stage 2 (Dystrophic)

27. Stage 2 (Dystrophic)

28. Stage Three: Atrophic Stage
Pain persists, but may be less intense
Muscle atrophy and osteoporosis may worsen
Irreversible trophic skin changes: smooth glassy skin, tapered digits, contractures.
Skin is pale, cyanotic, & cool

29. Atrophic Stage 3
Severe Mottling

30. Atrophic Stage 3
Contractures
Skin Ulceration
Migratory/progressive

31. Diagnosing CRPS CRPS is a clinical diagnosis
There is no gold standard for diagnosing CRPS

32. Diagnostic Tests Plain Radiographs Bone scans
Skin temperature and thermography
Sweat tests
EMG/NCS
Response to sympathetic blockade

33. Plain Radiographs
Sudeck’s atrophy- patchy osteopenia, ground glass appearance
Osteopenia is more than expected from disuse alone
Nonspecific
Osteopenia occurs in a small % of cases

34. Plain Radiographs Atrophic stage
Late findings only showing bone loss and patchy osteoporosis

35. Triple-Phase Bone Scan
First two phases are nonspecific
Third phase bone scan-abnormal, with enhanced uptake in the periarticular structures.
Hyperperfusion
Suggestive and supportive of the diagnosis of CRPS, but not diagnostic

36. Skin temperature
Two degrees side to side difference in limb skin temperature
Temperature may be variable and inconsistant, limiting it’s usefulness

37. Diagnostic Tests Skin Temperature
Thermography may show asymmetry. Affected limb is warmer than normal in acute stage and later becomes cooler. Subject to many variables.

38. Sweat Test
May be variable and inconsistant, limiting it’s usefulness

39. EMG/NCS
Are essentially normal in CRPS-1

40. Response to Sympathetic Blockade
For diagnosing RSD, the IASP ignores the response to sympatholytic procedures

41. Quantitative Studies
Quantitative Sensory Testing: Rarely available and no specific profile for CRPS
QSART: Quantitative Sudomotor Axon Reflex Test of autonomic function. Rarely available

42. Treatment
Early recognition and treatment of CRPS has a much favorable prognosis if <6months
Dumitru 1991
Multimodal treatment is recommended

43. Treatment Goals = Relief of pain Return of function
Prevent or slow progression
EARLY
TREATMENT
IMPROVED
OUTCOME =

44. Treatment Physical Therapy Physical Agents Pharmacology
Sympathetic blockade
Surgical Sympathectomy
Psychological aids
Other

45. Physical Therapy
In the acute stage PT is the most important factor in reversing the syndrome.
Later, it can improve pain & function and help prevent progression and migration.
Aggressive PT may only be possible with treatment of pain: pain meds, sympathetic and/or somatic blockade.

46. Physical Therapy Prevents disuse atrophy Usually requires analgesia
Start with gently active exercise, progressing to active-assistive
Stress loading techniques

47. Physical Agents
TENS
Electro-acupuncture
Ultrasound
Heat or cold

48. Pharmacology
Drugs demonstrated to be effective for CRPS based on randomized controlled trials, and their proposed mechanism of action:
Prednisone (oral): anti-inflammatory, neuronal membrane stabilizer
Vitamin C (oral): antioxidant
Alendronate (IV): osteoclast inhibitor
Bretylium (IV): Autonomic ganglia blocker
Ketansarin (IV): serotonin and alpha receptor antagonist
Phentolamine (IV): alpha-1 receptor antagonist
Lidocaine (IV): sodium channel blocker
DMSO (topical): free radical scavenger
Calcitonin (intranasal): osteoclast inhibitor
Clonidine (epidural): alpha-2 receptor agonist
Baclofen (intrathecal): GABA-B receptor agonist

49. Pharmacology NSAIDs-Mild to moderate pain
Opioids-potential benefit for severe neuropathic pain. Beware of all issues related to chronic opioid use.
Steroids-Proven effective in acute (inflammatory) stage.
Gabapentin and Pregabalin-Effective

50. Pharmacology Tricyclics-Effective for a variety of neuropathies
Sodium channel blockers-IV lidocaine, Lidoderm, mexilitene, lamotrigine.
NMDA blockers-Ketamine, dextromethorphan
Topical Clonidine- 2-agonist: prevents release of catecholamines? Maybe helpful.

51. Sympathetic Blockade Lumbar sympathetic block Stellate ganglion block
Guanethidine test
If effective, sympathetic blockade often gives relief well past the duration of the block.
Repeated blocks can be reverse the course of the disease.
Very helpful in facilitating PT.

52. Sympathetic Block
Local anesthetic is injected at the stellate ganglion (UE) or the lumbar paravertebral ganglion (LE)
If relief, then suspect sympathetic etiology
Proper response to a stellate ganglion block: Ipsilateral Horner’s Syndrome-Anhidrosis, conjunctival injection, nasal congestion, vasodilation and increased skin temperature.

53. Surgical Sympathectomy
If block beneficial but transient
Only for profoundly disabled patients who have responded positively to sympathetic blockade and have no other treatment options.
Pain commonly recurs within 6-12 months after procedure.
Pittman DM, 1997

54. Other treatment/procedures
Implantable pumps
Spinal cord stimulators
Botox

55. Prognosis Remains guarded No single definitive treatment
Early intervention
Pain often continues

57. Summary
CRPS has an extremely complex pathophysiology involving sensory, motor and autonomic abnormalities
It is unknown as to how the autonomic abnormalities and inflammatory processes affect the pain and sensory/motor abnormalities
It is unknown if and how the syndrome can be prevented

58. References
Baron R, Raja SN. Role of adrenergic transmitters and receptors in nerve and tissue injury related pain.
Malmberg AB, Chaplan SR (eds.). Mechanisms and Mediators of Neuropathic Pain. 2002, Birkhauser Verlag Basil/Switzerland
Sommer C. Cytokines and Neuropathic Pain. Hansson PT, Fields HL, Hill RG, Marchettini P. (eds.) IASP Press,Seattle, 2001, 37-62
Baron R, Binder A, Schattschneider J, Wasner G. Pathophysiology and treatment of complex regional pain syndrome. Dostrovsky JO, Carr DB, Koltzenburg M. (eds.). IASP Press, Seattle, 2003,