1. Complex regional pain syndrome
Utkan Aydin, MD
CMKI Morning Lecture, 11/9/2015

3. The painful patient
Beware of patients being erroneously labeled by physicians
Patients can be looking for a disease label to justify their symptoms.
They may think it enhances their claim and/or may be seeking the role of sick or injured. They can be manipulating a psychosocial situation.
Morton l . Kasdan, ASSH January 2011 Correspondence News

4. The painful patient
Humpty Dumpty sat on a wall, Humpty Dumpty had a great fall. All the king's horses and all the king's men Couldn't put Humpty together again
Morton l . Kasdan, ASSH January 2011 Correspondence News

5. The painful patient
Know your patient and evaluate any secondary agenda.
Ask ourselves are we really doing this patient help or harm by labeling with RSD (CRPS) without objective bilateral imaging.
Evaluate whether we doing the “right thing” - giving the patient a label that is not confirmed with objective findings?
Always confirm a diagnosis with clear objective findings.
Understand there is nothing wrong with telling a patient you have pain that I cannot explain (Code 729.5).
Morton l . Kasdan, ASSH January 2011 Correspondence News

6. Terminology Reflex Sympathetic Dystrophy Causalgia Neurodistrophy
Shoulder-hand syndrome
Sudeck’s atrophy
Sympathalgia
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

7. Terminology International Association for the Study of Pain (1994)
CRPS
Type I Pain syndrome without identifiable nerve lesion
Type II Syndrome with identifiable nerve injury or compression
Type III Other syndromes (e.g. fibromyalgia)
Multiple term have been used, current terminology is from 1994
CRPS is subdivided into CRPS-I (reflex sympathetic dystrophy) and CRPS-II (causalgia), reflecting, respectively, the absence or presence of documented nerve injury
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

8. Terminology Type II is a clinical diagnosis Supported by NCS
Type I and Type II can be divided into:
Sympathetically mediated pain
Sympathetically independent pain
Sympathetically independent pain is more refractory to pain, bears resemblance to compartment syndrome in case of Type II
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

9. Terminology
Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.
Pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life.
Many people report pain in the absence of tissue damage or any likely pathophysiological cause; usually this happens for psychological reasons.
There is usually no way to distinguish their experience from that due to tissue damage if we take the subjective report.
If they regard their experience as pain, and if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain.
This definition avoids tying pain to the stimulus. 

10. Terminology Allodynia
Pain due to a stimulus that does not normally provoke pain.
The stimulus leads to an unexpectedly painful response.
This is a clinical term that does not imply a mechanism.
the conditions seen in patients with lesions of the nervous system where touch, light pressure, or moderate cold or warmth evoke pain when applied to apparently normal skin.

11. Terminology Causalgia
A syndrome of sustained burning pain, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes.

12. Terminology Hyperalgesia
Increased pain from a stimulus that normally provokes pain.
Hyperalgesia reflects increased pain on suprathreshold stimulation.
This is a clinical term that does not imply a mechanism.
For pain evoked by stimuli that usually are not painful, the term allodynia is preferred, while hyperalgesia is more appropriately used for cases with an increased response at a normal threshold, or at an increased threshold, e.g., in patients with neuropathy.
It should also be recognized that with allodynia the stimulus and the response are in different modes,
whereas with hyperalgesia they are in the same mode.
Current evidence suggests that hyperalgesia is a consequence of perturbation of the nociceptive system with peripheral or central sensitization, or both, but it is important to distinguish between the clinical phenomena, which this definition emphasizes, and the interpretation, which may well change as knowledge advances.
Hyperalgesia may be seen after different types of somatosensory stimulation applied to different tissues.

13. Terminology Hyperesthesia
Increased sensitivity to stimulation, excluding the special senses.
Hyperesthesia may refer to various modes of cutaneous sensibility including touch and thermal sensation without pain, as well as to pain. The word is used to indicate both diminished threshold to any stimulus and an increased response to stimuli that are normally recognized.
Allodynia is suggested for pain after stimulation which is not normally painful. Hyperesthesia includes both allodynia and hyperalgesia, but the more specific terms should be used wherever they are applicable.

14. Terminology Noxious stimulus
A stimulus that is damaging or threatens damage to normal tissues.

15. IASP Diagnosis for CRPS
Initiating noxious event (Surgery, fracture etc.)
Continued pain disproportionate to event and beyond a single nerve distribution
Edema, skin blood flow abnormality, or abnormal sudomotor activity (e.g. sweating)
No other diagnosis
Last 3 criteria must be present
Sudomotor changes: sweating, edema, hot, cold.
Is a diagnosis of exclusion.
The last 3 has to be present, identifiable event may not to be there
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

16. Signs and Symptoms of CRPS
Pain starts in one limb but can present in the trunk (spine, abdomen, pelvis)
Constant pain, even at rest with intermittent exacerbations. Unexplained and diffuse
Severe pain
Temperature, color change.
Edema
Area of pain larger than the primary injury
Limited range of motion

17. Signs and Symptoms of CRPS
Allodynia ‐ pain on light touch
Nail growth changes (faster, distorted), hair growth changes (coarser, darker, rapid growth, hair falling), skin changes (atrophy of skin), skin lesions

18. Muscle symptoms in CRPS
Muscle spasms
Dystonia
Tremors
Myoclonus

23. Best Diagnostic tool A good history and physical examination
A repeat examination may be done to come to a diagnosis because of the fleeting nature of some of the symptoms (color change, temperature asymmetry)

24. Pain physiology Ascending nociceptive signals
Transmitted by Aδ and C afferent fibers
Dorsal horn of spinal cord (modulated)
Spinothalamic tract (cortical modulation)
Descending modulation
Periaqueductal gray matter
Nucleus raphe magnus (pons)
Small fibers of nervous system
Modulation all along the way, affecting how you feel things
Descending path decreases pain appreciation
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

25. Production of CRPS Cutaneous Epidermal neurite density
Altered symphathetic function
Afferent fiber desity
Increased nerve adrenergic receptors
Sensitization of peripheral nerves secondary to excitatory mediators
Sympatho-afferent coupling
Central sensitization
Upregulation of catecholamine receptors (vasoconstriction)
Spinal neurons
Genetic
Somatotopic maps
There are changes in all levels of pathways
Skin level –increase in amount of nerves
Changes in the brain related to the mapping of the pain
Changes in the sympathetic system and genetic factors
Complex interaction produces this problem
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

26. CRPS and Depression
CRPS causes suffering and affects mood but is NOT a psychogenic condition
22-78% chronic pain patients are depressed
Mersky, 1983
Mood improves with pain resolution
Mellick et al. Arch Phys Med Reh 1997
Is CRPS a psychogenic condition? Official answer is no. However, people w/ chronic pain are often depressed.
Test: not psycho, but there are psych factors;
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

27. Central Sensitization
Increase in the excitability of neurons within the central nervous system (CNS) so that normal inputs produce abnormal responses

28. CRPS Associations Anxiety prior to TKA predictive of CRPS at 1 month
Harden et al, Pain 2003
Allergy/Hypersensitivity associated with CRPS in orthopaedic patients
68% vs 34% in 115 CRPS vs 15 controls
Li et al, Orthopedics 2014
Longer duration of anesthesia during limb surgery
Sumitani et al, Rheumatology 2013
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

29. Epidemiology CRPS Type I incidence: 5.5 per 100,000 person-years
prevalence: 21 per 100K
fractures:
prospective studies: %
retrospective studies: 1-2 % ??
CRPS Type II
incidence: 0.8 per 100,000 person-years
prevalence: 4 per 100K
peripheral nerve injury: 1-5%

30. Incidence and Demographics
Olmsted county, Minnesota (2003)
5.5/100,000 person/years incidence
20.7/ person/years prevalence
Median age of onset 46 years
Women 4:1
Upper extremity 2:1
4-39% incidence with distal radius fracture
Sandroni et al, Pain 2003
Zollinger et al, JBJS 2007
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

31. Epidemiology CRPS Type I: ~50% work-related 90% related to Trauma
80% of CRPS type I resolve within 18 months

32. Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

33. Why Distal Radius Fractures?
Increased pressures in the carpal tunnel
18 mmHg (neutral wrist), 27 mmHg (20° flexion), 47 mmHg (40° flexion)
2/23 patients ≥ 43 mmHg at neutral
Gelberman et al, J Trauma 1984
30/35 cases demonstrated as Type II
70% CTS, 47% cubital tunnel
Monsivais et al JHS (Br) 1993
CT pressure goes up with DRF. Even with a bad casting technique avoided. This will lead to type II CRPS. Majority of CRPS related to CRPS is type II. Most CT related, some CuTS related.
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

34. Disease Burden Mean duration of pain:3 years
30% of patients out of work for ≥ 1 year
Geertzen et al, Acta Orthop Scand Suppl 1998
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

35. Lankford and Evans - Stages of RSD
onset
exam
imaging
acute
0-3 mo
pain, swelling, warmth, redness, decr ROM, hyperhidrosis
XR normal
(+) 3-phase bone scan (incr)
subacute
3-12 mo
worse pain, cyanosis, dry skin, stiffness, skin atrophy
osteopenia on XR
chronic
>12 mo
diminished pain, fibrosis, glossy skin, joint contractures
extreme osteopenia on XR

36. Staging Acute Aching, burning, hyperemia Dystrophic Tissue thickening
Atrophic
Less pain, cool skin, contracture
No clear time-course
No consensus on staging.
Classic progression I,II, III
Not always present during acute stage, they don’t go through stage and no fixed time course
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

37. Staging
Hot vs Cold
Others argue that when pain is gone there is no more CRPS
Compartment syndrome and Volkmann’s
Hot pain and sweaty
Cold atrophic contracted stiff
Some argue that the CRPS is only hot phase and the cold phase is a consequence of it.
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

38. Recognizing CRPS Patients
Anxious, unable to sleep despite narcotics
Burning, aching, allodynia
Reluctant for physician to touch
Temperature changes, swelling, skin color changes
Joint contracture
Holding the arm with other hand, pulling it away.
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

39. Differential Diagnosis
Neuropathy
Plexopathy
diabetic, etc
Nerve entrapment
Post-traumatic neuralgia
Vasculitis / vascular
anatomically defined territory
Psychiatric
Toxic
CNS disorders
Infectious
stroke
tumor
viral MS
fungal
trauma
Lyme disease
Spinal cord
Iatrogenic
Radiculopathy

40. Work Up Rule out other diagnoses CBC
Inflammatory arthropathy / vasculitis:
ESR, CRP
ANA, RF, complement fixation panel
DM: glucose, HgbA1c
EMG / NCS
vascular studies
3-phase bone scan (early)
Plain XR (late)

41. Imaging and Diagnostic Testing
No single definitive test
Xray: peri-articular demineralization
Triple phase technetium 99m bone scan
Increased periarticular activity in 3rd phase
Sensitivity (50-90%), specificity (75-92%)
Thermography after sympathetic block, cold stress test with laser Doppler fluximetry, resting sweat test
There is no definitive test
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

42. Imaging and Diagnostic Testing
Periarticular demineralization following distal radius fracture
Hard to differentiate from disuse osteopenia.
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

43. Sympathetic Mediated?
Diagnostic stellate ganglion block or oral sympatholytic challenge
Blocks must produce Horner’s, increased extremity peripheral venous engorgement
Influence of sympathetic system in a patient may vary over time
Block has to create sympathetic symptoms such as Horner’s etc. to make sure that the pain is symphatheticly mediated.
This can change overtime.
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

44. Treatment Prevention Avoid tight casts Protect causalgic nerves
Vitamin C and distal radius fractures
Radial sensory branch Radial nerve, superficial radial
Palmar cutaneous branch median nerve
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

45. Vitamin C
Antioxidant with capillary protective effect that decreases wall permeability
Zollinger, et al JBJS 2007
Randomized, double blind placebo controlled w/416 patients after wrist fracture
Vitamin C doses: 200, 500, 1500 mg
2.4% vs 10.1% CRPS in placebo
Recommend 500 mg for 50 days following distal radius fracture
Burn literature: decreases edema, by decreasing cell wall permeability in small blood vessels
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

46. Vitamin C Besse, et al F&A Surg, 2009
2 groups (total 420 patiens) w/ and w/o Vit C
1 gram post op daily for 45 days
1.7% incidence vs 9.6 incidence CRPS
Is Vitamin C totally safe?
Supported by evidence in foot and ankle literature
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

47. Vitamin C use: Jaiman A, Lokesh M, Neogi DS.,2011
A dose of 1000 mg for 45 days is nearly 10 times the recommended daily dosage of 90–100 mg
Levine et al. studied the relationship between vitamin C doses and steady-state concentrations in healthy young women
At doses of 200 mg daily and higher, there was little change in plasma concentrations, with saturation between 200 and 400 mg daily.
Circulating neutrophils, monocytes, and lymphocytes contained 0.5– 4.0 mM concentrations of vitamin C and also saturated between and 400 mg daily

48. Vitamin C use
In a study by Taylor and Curhan, participants consuming mg/day or more of vitamin C excreted 6.8 mg/day more urinary oxalate than participants consuming <90 mg/day (P trend < 0.001)
Multivariate relative risk of kidney stone formation for men consuming 1000 mg or greater of vitamin C per day was 41% higher than those consuming less than the recommended dietary allowance of 90 mg/day.

49. Vitamin C use: Besse JL. 2012
Our study used a 1000 mg Vitamin C protocol for Foot and Ankle surgery, it is logical for us to recommend this dose.
For six years, our orthopaedic and traumatologic department has used this protocol for all operations. We can estimate that more than 10,000 patients received this mg Vitamin C prevention and we never observed any adverse effects. We only checked history of (uric acid) kidney stone.
However I agree that in light of the last Zollinger publication [4], 500 mg of Vitamin C is probably enough.

50. Treatment As a hand surgeon the greatest impact is to:
Make the diagnosis
Distinguish type II disease and decompress involved nerves
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

51. Treatment Ideally incorporates a multidisciplinary team: Hand surgeon
Primary medical providers
Pain specialists
Therapists
Psychologists
Social workers
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

52. Treatment OT and PT Minimize pain and edema
Maximize comfortable mobility
Nerve stimulation (PNS/CNS)
Gate theory
Geurts et al, Neuromodulation 2013
Nerve blocks (esp. sympathetics)
Medication (None FDA approved)
Antidepressants, anticonvulsants, antiadrenergic, steroids, bisphosponates
Nerve stimulators to decrease pain signals going to the brain
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

53. Treatment Options Corticosteroids CCBs Calcium-reg drugs Beta blockers
Opioids
Oral sympatholytics
NSAIDs
Clonidine
TCAs / SSRIs
Sympathetic blocks
Sodium channel blockers
Ketamine
Spinal cord stimulator
GABA agonists
PT/OT
Gabapentin
Psych

54. Treatment Bisphophonates Class of drugs used to treat bone loss.
Calcium regulating drugs – in refractory cases
Clodronate (300mg) daily IV for 10 days – pain, swelling, movement range in acute CRPS
Alendronate (7.5mg) once IV ‐ pain, swelling, movement range in acute CRPS
Pamidronate 60mg IV
Forouzanfar T, Koke AJ, Kleef M van, Weber WE. Treatment of complex regional pain
syndrome type I. Eur J Pain 2002;6(2):105‐22.
Adami S, Fossaluzza V, Gatti D, Fracassi E, Braga V. Bisphosphonate therapy of reflex
sympathetic dystrophy syndrome. Ann Rheum Dis 1997;56(3):201‐4.

55. Treatment
Ketamine
CRPS ‐ activation and proliferation of NMDA receptors
Strong NMDA Receptor blocker
One of the safest anesthetic drugs
Powerful analgesic even at low doses
Poor absorption when administered orally.
Effective as IV or submucosal (Troche)

56. Ketamine

57. Ketamine
Psychonautics (from the Greek ψυχή psychē ["soul", "spirit" or "mind"] and ναύτης naútēs ["sailor" or "navigator"] — "a sailor of the soul") refers both to a methodology for describing and explaining the subjective effects of altered states of consciousness, including those induced by meditation or mind-altering substances.

58. Low dose Ketamine in CRPS
Administered in sub‐anesthetic doses – blocks NMDA receptors without causing too many side effects
In CRPS it decreases Central Sensitization
Administration: IV, sublingual, nasal
Rough estimates – 85% show improvement in daily activities, reduction in their medications and improved lifestyles
It is not a cure. It is to be done along with other therapies

59. N‐ Acetyl Cysteine (NAC)
Useful for cold allodynia
N‐Acetylcysteine 600mg three times a day for three months
Perez RS, Zuurmond WW, Bezemer PD, Kuik DJ, Loenen AC van, Lange JJ de, et al. The treatment of complex regional pain syndrome type I with free radical scavengers: a randomized controlled study. Pain 2003;102(3):297‐307

60. Opioids
Repeated exposure to opioids leads to enhanced pro‐inflammatory cytokine release from glia
Taking long term opioids for CRPS is not a good idea.
Maybe okay to take it for a short term to get over a flare up

61. acute subacute chronic
opiods; NSAIDs
Pain Mgmt?
opiods; NSAIDs
Pain Mgmt referral
NSAIDs
amitriptyline 75mg QHS
neurontin 900  2400 mg/d
Medrol dosepak
< 6 months:
pulsed prednisone -
*** early PT/OT ***
intranasal calcitonin (or bisphosphonate?)
lidocaine patch?
clonidine gel? (PO if HTN)
trial: sympathethectomy (chemical  surgical?)
ketamine infusion
psychologic / cognitive therapy
DR: VitC 500mg/d x50d
spinal cord stimulator?

62. Outcomes
Good outcomes in 94% of 105 patients when treating within 4 months of symptoms
No permanent CNS changes
50% of those untreated for 12 months will have permanent impairment
Digit contracture at 3 months correlates with 10 year CRPS morbidity following distal radius fracture
Outcomes are better if the therapy is initiated earlier, if recognized late, more permanent disability.
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

63. Outcomes Nerve Decompression for Type II Placzek, et al JHS 2005
8 patients at 13 weeks after index procedure
Resolved hypersensitivity, swelling
Improved DASH (71 to 30), VAS (7.5 to 1.8)
Grundberg and Regan, JHS 1991
26/29 patients improved swelling, PIP motion (35 to 76°) and strength
Type II hypersensitivity, median nerve symptoms, treat at the time of diagnosis.
Second study: got better after treating the involved nerve.
People are scared to treat it, but this is the situation. You can make a difference
Doctor cut this off: High recurrence rate
Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

64. Surgery after CRPS
Perioperative stellate ganglion block may reduce recurrence
Recurrence 10% vs 72% in 100 patients
Reuben et al, 2000
What about the consequent sx on the same extremity or other extremities? Recurrence rate is high Peri op ganglion block may reduce the recurrence rate.

65. Summary
CRPS is likely the end result of a complex interaction of multiple inter-related nervous system changes
CRPS leads to marked and prolonged morbidity
Vitamin C is effective for prevention of CRPS associated with distal radius fracture

66. Summary Early treatment of CRPS optimizes outcomes
Type II CRPS should be treated with nerve decompression

67. Thank you !