CRPS/RSD - Mechanisms, Diagnosis, and Treatment Targets

CRPS/RSD

Mechanisms, Diagnosis and Treatment Targets Norman Harden

Disclosure  Grant/Research Support: Reflex Sympathetic Dystrophy Association

Pain and Autonomic Dysfunction

Mechanisms/Therapeutic Targets

Sensory Changes in CRPS Allodynia Hyperalgesia Hyperesthesia –Increased sensitivity to a sensory stimulation

Hyperpathia –Abnormally exaggerated subjective response to painful stimuli

Peripheral Sensitization/Inflammation

Marchand F. et al. Nat. Rev. Neurosci. 6, 2005

Intraepidermal Nerve Fiber Density

Periquet, et-al. Painful Sensory Neuropathy. Neurology 1999; 53: 1641-1647

Neuropathic Pain

Marchand F. et al. Nat. Rev. Neurosci. 6, 2005

The Tetrapartite Synapse in Nerve Injury

Glial Cells React to Trauma and Injury

Astrocytes are activated following nerve injury (chronic constriction injury model)

 Glia (microglia, astrocytes, oligodendrocytes, Schwann cells) >70% of brain and sp cord  Generate pro- and antiinflammatory cytokines  Encase all synapses  Extensive gap junctions  Role limited to pathologic pain states –good therapeutic target  Exaggerated pain states could be predicted in the absence of peripheral injury Watkins et al., 2001

Vasomotor Changes

Extreme Trophic Changes

NK1 Receptors Are Present On Osteoclast Cell Membrane

Areas Active In CPPS

Motor Disturbance

Motor Changes: Weakness Dystonia Tremor/myoclonus secondary~contracture

Bradykinesia

September 19, 2007

Swelling/Edema

Sympathetically Maintained Pain Pain that is caused, ‘mediated’ or maintained by activity of the sympathetic nervous system (or its peripheral receptors) Either: hyperactivity of the SNS efferents Or: receptor up regulation in periphery

Effects of Sympathetic and Peptidergic Nerve Fibers on Skin and Immune Cells POSTSYNAPTIC SYMPATHETIC NERVE TERMINAL

NE

b2

NE NE

NE

a2

b2

mono Il-10 Il-6

PEPTIDERGIC / SENSORY NERVE FIBER

Th 1

b2

SP

SP

NK1

keratinocyte

NK1

macrophage IFNg

Th 2 Il-4, Il-10, Il-13

TNFa Il-12 Il-1

TNFa, Il-1 Il-6, Il-3 Il-8, TGFb

Blisters Blister formation to measure  mediators of inflammation

Measurement Of IL-6 And Tnf-α In Blisters 10000

10000

IL-6

TNF-α

1000

1000

100

100

10

10

1

1 non-involved

CRPS1

non-involved

CRPS1

Hypothesis: CRPS Maintained And Reinforced By Nested Positive Feed Forward (Afferent Nociceptors) And Feed Back (Efferent Sympathetic Nerves) Loops

Pain inflammation (NE, others)

Ganglia Dorsal horn

Lateral horn

Brain stem Hypothalamus Limbic system, cortex

Efferent

Afferent

Ephapses

Hypothesis: CRPS Maintained And Reinforced By Nested Positive Feed Forward (Afferent Nociceptors) And Feed Back (Efferent Sympathetic Nerves) Loops

Pain inflammation (NE, others)

Ganglia Dorsal horn

Lateral horn

Brain stem Hypothalamus Limbic system, cortex

Efferent

Afferent

Ephapses

Chronic Pain is a Bio-Psycho-Social Disease

Psychological Aspects

Psychopathology Fear  Anxiety  Anger  Suffering  Depression  Failure to Cope Raja SN et al. Anesthesiology. 2002;96:1254-1260.

Psychological Factors associated with CRPS  75% of the articles reviewed mentioned depression, anxiety, or life stress as associated with the disorder in adults and children  Correlations between Depression (BSI) and MPQ-Affective pain intensity were significantly stronger in both CRPS groups compared to the LBP group (.60/.66 vs .42)  Similar effect was noted for correlations between Anxiety (BSI) and MPQ-Affective.

Bruehl et al. (1996)

Strength Of White Matter Connections Between The Right VMPFC To The Right Nac Are Related To Anxiety In CRPS

Sociologic Factors

Operant Issues Work Comp 3rd Party Lawsuit Litigation Total IME’S

54% 17% 71% 23%

Return to Work

Diagnosis

Current Criteria: Problems

Solution Use statistically derived schemes (by internal and external validation that improve specificity, while attempting to conserve as much sensitivity as possible

To Determine The Validity Of The IASP Criteria:  Standardized symptom sign and test checklists were derived from123 CRPS patients at 6 sites  For external validation same signs and symptoms from 43 ‘neuropathic’ pain patients, primarily DM)

External Validation

Internal Validation

Statistically Derived Factors

Can Set Sensitivity, Specificity

Diagnostic Criterion One (Budapest) Continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion Description: –regional: no nerve territory, no dermatome disproportionate in site

Diagnostic Criteria (Budapest): Research  Symptoms – – – –

 Signs – – – –

Factor 1 Factor 2 Factor 3 Factor 4

Positive sensory symptoms Vascular symptoms Edema, sweating abnormalities Motor, trophic changes

Factor 1 Factor 2 Factor 3 Factor 4

Positive sensory signs Vascular signs Edema, sweating abnormalities Motor, trophic changes

= 4 symptoms ≥ 2 signs

Sens. 0.70

Spec. 0.94

Diagnostic Criteria (Budapest): Clinical  Symptoms – – – –

Factor 1 Factor 2 Factor 3 Factor 4

Positive sensory symptoms Vascular symptoms Edema, sweating abnormalities Motor, trophic changes

– – – –

Factor 1 Factor 2 Factor 3 Factor 4

Positive sensory signs Vascular signs Edema, sweating abnormalities Motor, trophic changes

 Signs

≥ 3 symptoms ≥ signs

Sens. 0.85

Spec. 0.69

 Positive sensory sx: allodynia, hyperalgesia,deep somatic allodynia  Signs at time of diagnosis

Treatment

Very Few RCTS!

Barriers:  Randomization Ethics  Control (?)  Blinding Difficult  Economic  Referral Bias  What outcome?  Very high placebo rates

CRPS “Evidence-Based Guidelines” Conclusions  Level 1 evidence: (one systematic review or at least 2 independent high quality RCTs) for calcitonin (conflicting results), bisphosphonates, and i.v. ketanserin (Level 1 evidence IVSB and percutaneous SB didn’t work)  Level 2 evidence: (at least 2 independent moderate quality RCTs) for topical DMSO, and PT on “coping” outcomes  Level 3 evidence: (“insufficient evidence”; one high or moderate quality RCT, or one non-controlled trial) for NSAIDS, opioids, local anesthetics, sub-anesthetic ketamine, NAC, bot A, IT baclofen, steroids, Ca+ blockers, sympathectomy (conflicting), SCI, amputation, PT, OT  Level 4 ‘evidence’: (“no evidence"; opinions, anecdotes) for dozens and dozens of other therapies, many mentioned in earlier consensus based Rx guidelines Perez et al, BMC Neurology, 2010

Interdisciplinary Team Approach OT Psych

PT

Voc RT

PATIENT MD

SW RN

Report Of The Malibu Consensus Conference

“Malibu” Algorithm

AJPMR

PT: Reactivation, Aerobic Conditioning

Physical Therapy De-emphasizing high tech, passive modalities Emphasizing low tech, self management and active modalities Reactivation “Reanimation” Stretch/strengthen Desensitization Mirror Therapy

Occupational Therapy Scrub Loading Work/fun station analysis, correction Postural training Orthotics (?) Casting (!) Work hardening

Vocational Rehabilitation Job description Site analysis Testing Return to work assessment Placement

Identify Crucial Psychosocial Targets

Psychotherapy  Cognitive behavioral therapy  Stress management  Coping skills  Relaxation techniques  Imagery  Self hypnosis

Biofeedback Autogenic training EMG biofeedback Progressive muscle relaxation Meditation Sleep hygiene

Mirror therapy for CRPS  Daily exercise of cardinal movements of the affected limb while viewing an image of their unaffected limb in a mirror for 30 minutes daily has been shown to improve pain, motor function, and edema1 http://www.congressinfo.ch/abstracts/eurohand2008/upload/1_c7392282_482.jpg

 Sensory discrimination training while looking toward the affected body part but seeing the opposite part of the body in the mirror also decreased pain and increased tactile acuity2

1: Cacchio C et al.; New England Journal of Medicine 2009; 361;6; 634-636.

2: Moseley GL et al.; Pain, 2009; 144; 314-19

Pharmacotherapy

Pharmacotherapy (cont’d) Reason For Inability To Begin Or Progress

Action

Mild to moderate pain

Simple analgesics and/or blocks (see section 5)

Excruciating, intractable painâ€

Opioids and/or blocks or later, more experimental interventions (see section 5)

Inflammation/swelling and edema

Steroids, systemic or targeted (acutely) or NSAIDs (chronically); immunomodulators

Depression, anxiety, insomnia

Sedative, analgesic antidepressant/anxiolytics and/or psychotherapy (see section 4)

Significant allodynia/hyperalgesia

Anticonvulsants and/or other sodium channel blockers and/or NMDAreceptor antagonists

Significant osteopenia, immobility and trophic changes

Calcitonin or bisphosphonates

Profound vasomotor disturbance

Calcium channel blockers, sympatholytics and/or blocks (section 5)

Just A Little Controversy

Unfortunately, Opioids are clearly not the Panacea we had hoped; they are merely another set of tools, with substantial risk, mortality and morbidity.

Marketing poster, omnipresent at the 2000 APS meeting

Do Opioids cause hyperalgesia, allodynia?

If you are a rat, yes. But in man?

See J. Mao multiple refs

Prevention Vitamin C  In doses of 0.5-1gm Vitamin C daily it has been shown do decrease the incidence of CRPS after foot and ankle surgery1 as well as following wrist fracture2  Vitamin C appears to be a simple and cost effective way of limiting the incidence of CRPS and can be considered in at-risk patients 1: Besse JL. Foot and Ankle Surgery; 2009; 15: 179-82.

2: Zollinger PE. J Bone Joint Sugery Am; 2007; 89: 1424-31

Interventional Pain Therapy  Minimally Invasive Therapies

– Sympathetic / Somatic nerve blocks – IV Regional nerve blocks

 More Invasive Therapies

– Epidural / Plexus Catheter Blocks – Neurostimulation – Intrathecal Drug Infusion

 Surgical Therapies

– Sympathectomy – Motor Cortex Stimulation Burton A. Interventional therapies. Complex Regional Pain Syndrome: Treatment Guidelines. RSDSA press. 2006:51-62..

Velasco F. Pain, 2009, Volume 147, Issue 1, Pages 91-98

Central Sensitization: Cerebral Pre SGB (+thermal stim)

Post SGB (+thermal stim) SI/MI

AC PF

AC PF

Intrathecal Baclofen  Dystonia in CRPS that cannot be treated by more conservative measures can be alleviated through intrathecal Baclofen  In patients with dystonia baclofen possibly improves pain, disability and quality of life from Van Rijn. Pain, 2009; 143:41-47

Van Hilten BJ et al. N Engl J Med. 2000 Aug 31;343(9):625-30.

Van Rijn MA et al. Pain. 2009; 143: 41-47.

Intravenous Ketamine High dose

Anesthetic doses of Ketamine have been used anecdotally in the treatment of CRPS. However, these findings have not been tested in randomized trials Kiefer RT. Pain Med. 2008 Nov;9(8):1173-201

Low dose

Intravenous Ketamine at low doses (25-30 mg/hr in 70kg adult) was reported to yield significant pain relief but no functional improvement (level 3 evidence). Also, SQ dosing has been tried Sigtermans MJ. Pain, 2009; 145: 304-11.

Schwartzman RJ. Pain, 2009; 147: 107-115

Spinal Cord Stimulation  Spinal cord stimulation (SCS) may have a modest, time limited effect on pain scores but no effect on health-related quality of life (level 3 evidence)

Kemler MA. N Engl J Med. 2006 Jun 1;354(22):2394-6.

Kemler MA. J Neurosurg 108:292–298, 2008

Surgical Therapies: Sympathectomy  Controversial procedure  In carefully selected patients, may result in reduction in pain severity and disability (level 4 evidence) – Patients with SMP who respond to repeat selective-sympathetic blockade – Patients who are refractory to other therapies

 Radiofrequency and neurolytic techniques are anecdotal alternatives to a surgical sympathectomy Stanton-Hicks M et al. Pain Practice. 2002;2:1-16.

Bandyk DF et al. J Vasc Surg. 2002;35:269-277.

Today’s dogma will be tomorrow’s heresy D J Dalessio