Basiskurs Schmerztherapie A Poertschach Juni 24- 29, 2013

Michael StantonMichael Stanton--HicksHicksMB;BS Dr. med, FRCA, ABPM, FIPPMB;BS Dr. med, FRCA, ABPM, FIPP

Department of Pain ManagementDepartment of Pain ManagementInstitute for Neurological RestorationInstitute for Neurological Restoration

Shaker Pediatric Rehabilitation ProgramShaker Pediatric Rehabilitation ProgramCleveland ClinicCleveland Clinic

Morbus Sudeck

• A 67 yo female presents to the emergency room with a right Colle’s fracture. Which of the following interventions decreases this patient's risk for developing CRPS?

A.A corticosteroid taper course

B.Piroxicam

C.Gabapentin

D.Vitamin C

E.A stellate ganglion block

Ambroise ParAmbroise Paréé an earlyan earlydescription of CRPS description of CRPS in a wounded soldierin a wounded soldier 15521552

MILESTONESMILESTONES

Weir Mitchell symptom Weir Mitchell symptom amplification in wounded amplification in wounded during American Civil Warduring American Civil War

TTerm Causalgia 1872erm Causalgia 1872

epidemiology

• Complex regional pain syndrome 1 (CRPS 1): prospecti ve study omplex regional pain syndrome 1 (CRPS 1): prospecti ve study and laboritory evaluation and laboritory evaluation

Sandroni et al, Clin J Pain 1998: 14; 282Sandroni et al, Clin J Pain 1998: 14; 282

•• The Incidence of Complex Regional Pain Syndrome: a The Incidence of Complex Regional Pain Syndrome: a populationpopulation --based Studybased Study

deMos M, de Bruijn, Huygen FJ, Dielman JP, deMos M, de Bruijn, Huygen FJ, Dielman JP, Stricker BH, Sturkenboom MC. Pain 2007; Stricker BH, Sturkenboom MC. Pain 2007; 129(1129(1--2):122):12--2020

epidemiology

• A web-based cross-sectional epidemiological survey of complex regional pain syndrome

Sharma A, Agarwal S, Broatch MSW, Raja, SN

2009; 34: 110-115

epidemiology

de Mos et de Mos et al 2007al 2007**

Sandroni et al Sandroni et al 19981998

Sharma et Sharma et al 2009al 2009

IRIR 26.226.2 5.465.46(25.2) prevalence(25.2) prevalence ??

Gender F:MGender F:M 3:13:1 4:14:1 5:15:1

Peak AgePeak Age 6161--7070 5050--7070 3535--5252

IE IE F/SF/S F/SF/S F/SF/S

* per 100,000 (n=190,102)* per 100,000 (n=190,102)

Cause(s) ofCause(s) ofCRPS?CRPS?

Inflammatory AspectsInflammatory Aspects

•• Biological markersBiological markers––ProPro --inflammatory cytokines in CSFinflammatory cytokines in CSF––Alexander et al Pain 2005; 116; 213Alexander et al Pain 2005; 116; 213

––Local inflammation Local inflammation -- cytokinescytokines––Huygen et al Mediators Inflamm 2002; 11: 47Huygen et al Mediators Inflamm 2002; 11: 47

––Uceyler et al Pain 2007; 132:195Uceyler et al Pain 2007; 132:195

Inflammatory AspectsInflammatory Aspects

The first scintigraphic detection of tumor necrosis The first scintigraphic detection of tumor necrosis factorfactor --alpha in patients with complex regional pain alpha in patients with complex regional pain

syndrome type Isyndrome type IBernateck, M et al Anesth Analg 2010; 110: 211Bernateck, M et al Anesth Analg 2010; 110: 211 --55

TcTc--labelled antilabelled anti --TNFTNF--αα antibody infliximab was positive in antibody infliximab was positive in early but not late CRPS Iearly but not late CRPS I

TNFTNF--αα only found in affected handsonly found in affected hands

Eberle et al. Warm and cold complex regional pain syndromes: differences beyond skin temperature? Neurology 2009; 72(6)

•• Dystonia exclusive to cold allodynia Dystonia exclusive to cold allodynia –– central effectcentral effect

•• CNS changes in pain processing in cold CRPS CNS changes in pain processing in cold CRPS

•• Loss of nonLoss of non --painful sensitivity painful sensitivity –– more frequent in more frequent in cold allodynia: altered sensory processing in braincold allodynia: altered sensory processing in brain

•• Cold CRPS vs. warm CRPS have risk of chronic Cold CRPS vs. warm CRPS have risk of chronic pain pain

.

Sensory changesSensory changes

Sensory Changes in the Forehead of Patients Sensory Changes in the Forehead of Patients with Complex Regional Pain Syndromewith Complex Regional Pain SyndromeDrummond PD, Finch PM. Pain 2006; 123 (1Drummond PD, Finch PM. Pain 2006; 123 (1 --2): 832): 83--99

Sensory changes Sensory changes Drummond and Finch Drummond and Finch

•• PressurePressure --pain threshold pain threshold -- ipsi. foreheadipsi. forehead

•• P. Prick sharpness in UL mirrored in ipsi. P. Prick sharpness in UL mirrored in ipsi. foreheadforehead

•• sensitivity to light touch in limb corresponds sensitivity to light touch in limb corresponds with sensitivity to sharpness, cold & heatwith sensitivity to sharpness, cold & heat --pain pain in foreheadin forehead

•• Suggests disrupted central nociceptive Suggests disrupted central nociceptive processing in CRPS processing in CRPS -- thalamus and cortexthalamus and cortex

Nervous SystemNervous System

•• Spinal sensitization Spinal sensitization –– NMDA, NKNMDA, NK --1 receptors 1 receptors Ji RR Ji RR Trends Neurosci 2003; 26: 696Trends Neurosci 2003; 26: 696 --705705

•• Hypothalamic cerebral blood flow changesHypothalamic cerebral blood flow changesWu CT et al Wu CT et al Clin Nucl Med 2006; 31: 317Clin Nucl Med 2006; 31: 317 --320320

•• Post synaptic motor reflex inhibitionPost synaptic motor reflex inhibitionSchouten et al Exp Brain Res 2003; 151: 1Schouten et al Exp Brain Res 2003; 151: 1 --8 8

Somatosensory NSSomatosensory NS

•• Evidence of focal smallEvidence of focal small --fiber axonal fiber axonal

degeneration in complex regional degeneration in complex regional

pain syndromepain syndrome --1 (reflex sympathetic dystrophy)1 (reflex sympathetic dystrophy)

Oaklander et al. Pain 120 (2006) 235Oaklander et al. Pain 120 (2006) 235

Human sural nerve seenHuman sural nerve seenusing electron microscopyusing electron microscopy

Her hypothesis is that smallHer hypothesis is that small--fiber axon damage fiber axon damage

is key in CRPSis key in CRPS

HypoxiaHypoxia

–– Biological markersBiological markers–– Endothelial dysfunctionEndothelial dysfunction

Schattschneider et al Neurology 2006; 67: 673 Schattschneider et al Neurology 2006; 67: 673

–– Tissue hypoxiaTissue hypoxiaKoban et al Pain 2003; 104: 149Koban et al Pain 2003; 104: 149

–– Free radical involvement likelyFree radical involvement likely

–– Ludwig et al Eur J Pain 2007; 11: 677Ludwig et al Eur J Pain 2007; 11: 677

RenRenéé Leriche Leriche (1879(1879--1955)1955)

•• RRelated chronic pain to SNS dysfunctionelated chronic pain to SNS dysfunction

Like Weir Mitchell, saw this Like Weir Mitchell, saw this

as trigger for causalgia as trigger for causalgia

after acute injuryafter acute injury

CCriticized colleagues whose riticized colleagues whose

patientspatients ’’ were considered neuroticwere considered neurotic

•• CChronic pain as a disease: hronic pain as a disease: ““ douleur maladiedouleur maladie ””

Autonomic NS Symp. arousal provokes pain in CRPS Symp. arousal provokes pain in CRPS patientspatients ¹¹

Adrenergic receptor hypersensitivityAdrenergic receptor hypersensitivity ²²

density of density of αα--adrenoceptorsadrenoceptors ³³

1 Drummond P Finch P Neur, Neurol, Neurosurg 20041 Drummond P Finch P Neur, Neurol, Neurosurg 20042 Ali Z, Raja SN et al Pain 20002 Ali Z, Raja SN et al Pain 20003 Toda K et al Clin J Pain 20063 Toda K et al Clin J Pain 2006

–

(Chronic post ischemia(Chronic post ischemia pain(CPIP) model)pain(CPIP) model)

Role of NFRole of NF κκB in an animal model of chronic regional B in an animal model of chronic regional pain syndromepain syndrome -- type I (CRPStype I (CRPS --I)I)de Mos M et al The Journal of Pain 2009; 10: 1161de Mos M et al The Journal of Pain 2009; 10: 1161 --11691169

•• nuclear factor kappa B (NFnuclear factor kappa B (NF κκB) is associated B) is associated with allodynia after ischemic injury with allodynia after ischemic injury –– without without nerve injury nerve injury

•• ? role in human CRPS ? role in human CRPS -- in spinal cord & in spinal cord & peripherallyperipherally

•• activated by UV, free radicals, cytokinesactivated by UV, free radicals, cytokines

Regulation of peripheral blood flow in Complex Regional Pain Syndrome: clinical implication for symptomatic relief and pain management

Groenweg G, Huygen FJPM, Coderre TJ, Zijlstra FJ BMC Mus c Dis 2009; 10: 116

Stewart J. Tepper, MD

imaging studiesimaging studies•• Cortical changes in complex regional pain syndrome Cortical changes in complex regional pain syndrome

(CRPS)(CRPS)Svart CMA, Stins JF, Beek PJ ESvart CMA, Stins JF, Beek PJ E ur J. Pain, 2009;13: 902ur J. Pain, 2009;13: 902 --907907

MISLOCATION OF TACTICAL STIMULIMISLOCATION OF TACTICAL STIMULI

BODY PERCEPTION DISTURBANCESBODY PERCEPTION DISTURBANCES

CHANGE IN SIZE AND SOMATOSENSORY MAPPINCHANGE IN SIZE AND SOMATOSENSORY MAPPIN GG

VALUE OF MIRROR THERAPY AND MOTOR IMAGEVALUE OF MIRROR THERAPY AND MOTOR IMAGE RYRYMcCabe et al 20McCabe et al 20 03, Moseley 200503, Moseley 2005

Cortical reorganizationCortical reorganization

•• Patterns of cortical reorganization Patterns of cortical reorganization in complex regional pain syndromein complex regional pain syndromeMaihofner C, Handwerker H, Birklein F Neurology 2003: Maihofner C, Handwerker H, Birklein F Neurology 2003: 61; 170161; 1701--1717 1717

––Possible mechanism sustaining an Possible mechanism sustaining an interaction between autonomic, afferent interaction between autonomic, afferent sensory and motor systems in CNSsensory and motor systems in CNS

Cortical reorganizationCortical reorganization

•• Cortical reorganization during recovery Cortical reorganization during recovery from complex regional pain syndromefrom complex regional pain syndrome

• Maihofner C, Handwerker, H, Neundorfer B, Birklein F. Neurology 2004: 63; 693-701

–– Targeted neuromodulation MAY promote unwinding of Targeted neuromodulation MAY promote unwinding of centralcentral --peripheral dysfunction peripheral dysfunction –– so called so called ““ neural switchneural switch ””

Proposed New Diagnostic Criteria for Proposed New Diagnostic Criteria for Complex Regional Pain SyndromeComplex Regional Pain Syndrome

R. Norman Harden, MD, Stephen Bruehl PhD,R. Norman Harden, MD, Stephen Bruehl PhD,Michael StantonMichael Stanton--Hicks, MB,BS, Dr med, FRCA, ABPM,Hicks, MB,BS, Dr med, FRCA, ABPM,

Peter R Wilson, MB,BS, PhD. Pain Medicine Vol 8, 4, 326Peter R Wilson, MB,BS, PhD. Pain Medicine Vol 8, 4, 326--331, 2007331, 2007

••

Emphasis on 4 categories Emphasis on 4 categories -- SENSORYSENSORY-- VASOMOTORVASOMOTOR-- SUDOMOTOR / EDEMASUDOMOTOR / EDEMA-- MOTOR / TROPHICMOTOR / TROPHIC

Minimum number of Minimum number of -- -- -- -- -- SIGNS & SYMPTOMSSIGNS & SYMPTOMS

““ BudapestBudapest ”” CriteriaCriteriaat least I SYMPTOM and 1 SIGN in 2 or more at least I SYMPTOM and 1 SIGN in 2 or more categories. (SENS. 0.99: SPEC. 0.68) categories. (SENS. 0.99: SPEC. 0.68)

Harden et al. Pain (2010);150: 268Harden et al. Pain (2010);150: 268 --274274

CATEGORY SYMPTOM SIGN

SENSORY Hyperesthesia, allodynia

hyperalgesia (PP)allodynia – mech. /

thermal / deep

VASOMOTOR ∆ skin / color∆ temperature

> 1˚ C / ∆ skin color

SUDOMOTOR EDEMA

∆ sweating / edema ∆ sweating / edema

MOTOR TROPHIC

motor dysfunction ROM

∆ trophic

motor function ROM (weak,

dystonia, tremor) / trophic

Rx

• Pharmacotherapy is problematic – most meds. are “off label’

• Most interventions support functional restoration o nly

• Levels of Evidence will be used to determine effica cy

• Most cases of CRPS remit spontaneously or with simp le measures, corticosteroids.

• About 20% cases need aggressive interdisciplinary c are

• Many of these require lifelong support

Stewart J. Tepper, MD

Learning Objectives

• Evidence Matters in CRPS– Staging

– Management

–Rehabilitation

–Psychological

–Pharmacologic

– Interventional

Levels of Evidence

• Level 1: Meta-analysis or systematic reviews.

• Level 2: One or more well-powered randomized, controlled trials.

• Level 3: Retrospective studies, open-label trials, pilot studies.

• Level 4: Anecdotes, case reports, clinical experien ce, etc.

Harden RN et al., Complex regional pain syndrome: practical diagnosti c and treatment guidelines, 4th edition . Pain Med. 2013 Feb;14(2):180-229.

• CRPS: 3 stages originally proposed–Inflammatory: early–Dystrophic: 3-6 months–Atrophic: Late

• INACCURATE! (Level 4)

Bruehl S. et al., Pain. 2002 Jan;95(1-2):119- 24 Maleki J. et al., Pain. 2000 Dec 1;88(3):259-66

� Most cases No progression of sxs� Sxs actually remain stable or improve with time (“spread” in 10%)

CRPSCRPSmild severe

Rehabilitation Pathway

ReactivationDesensitization

Isometrics Flexibility

Edema Control Peripheral E-stim

Treat Secondary MFP

ROM (gentle!) Stress Loading

Isotonic StrengtheningAerobic Conditioning

Postural Normalization

ErgonomicsMovement TherapiesNormalization of Use

Vocational/Functional Rehab

Pharm. Pain managementPsych Rx with

educational focus

Progress P

rogr

ess

Fai

lure

to

Pro

gres

s in

Reh

abF

ailure toP

rogress in Rehab

InterventionalPain Management

PsychologicalTreatment

MINIMALLY INVASIVE�Sympathetic Blocks�IV Regional Blocks�Somatic Nerve Blocks

�Assess for Axis Idisorders

�Pain Coping Skills�Biofeedback /

relaxation training�Cognitive

behavioral Rxof Axis disorders

~�Increase

frequency /intensity of

psychotherapy

Surgical or Experimental Therapies

�Sympathectomy�Motor Cortex

Stimulation

~

MORE INVASIVE�TEC & Plexus

catheter blocks�Neurostiimulation�IDT: baclofen,

prialt

~

Exellent response

Follow Up

Relapse

Repeat Pathway

AlgorithmCRPS

Stanton-Hicks M et al., Pain Pract 2002;2:1–16

McCabe CS et al., Rheumatology (Oxford). 2003 Jan;4 2(1):97-101 Daly AE, Bialocerkowski AE. Daly AE, Bialocerkowski AE. Does evidence support physiotherapy management of adult complex regional pain syndrome type one? A systematic review. Eur J Pain 2009;13:339–53.

Subject viewing non-reflective surface with painful limb hidden

Subject viewing non-painful limb in mirror with painful limb hidden

• Daly and Bialocerkowski: meta-analysis�good quality level 2 evidence

Rehabilitation PathwayReactivation/MVF/GMI 2

Desensitization 3

Isometrics 3Flexibility

Edema Control 4Peripheral E-stim

Treat Secondary MFP

ROM (gentle!) 4Stress Loading 3

Isotonic StrengtheningAerobic Conditioning

Postural Normalization

ErgonomicsMovement TherapiesNormalization of Use

Vocational/Functional Rehab

Pharm. Pain managementPsych Rx with

educational focus

Progress

Pro

gres

s

Fai

lure

toP

rogr

ess

in R

ehab

Failure to

Progress in R

ehab

InterventionalPain Management

PsychologicalTreatment

Minimally Invasive�Sympathetic Blocks�IV Regional Blocks�Somatic Nerve Blocks

�Assess for Axis I Disorders�Pain Coping Skills�Biofeedback/Relaxation training�Cognitive Behavioral Therapy for Treatmentof Axis Disorders

~�Increase frequency/intensity of Psychotherapy

Surgical or Experimental Therapies

�Sympathectomy�Motor Cortex Stimulation

~

More Invasive�Epidural and Plexus Catheter Blocks�Neurostimulation�Intrathecal Drug Therapy (e.g. Baclofen)

~

Excellent ResponseFollow Up

Relapse

Repeat Pathway

AlgorithmCRPS

3Stanton-Hicks M et al., Pain Pract 2002;2:1–16

Hyperbaric Oxygen (level 2)

• DBRCT, 15 x 90-minute sessions, 5 d/wk– 37 patients HBO vs.

– 34 patients room air (2.4 Atm. P)

Kiralp MZ et al., Effectiveness of hyperbaric oxyge n therapy in the treatment of complex regional pain syndrome.J Int Med Res. 20 04 May-Jun;32(3):258-62

Pharmacotherapy for CRPS• Inference from neuropathic pain trials

• Complex pathophysiology ���� unlikely one medication will control all pain

• Rational polypharmacy: often necessary

• Specifically trialed in CRPS:–Calcitonin and bisphosphonates

–Corticosteroids

–intravenous immunoglobulin (IVIG)Harden RN et al., Complex regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition. Pain Med. 2013 Feb;14(2):180-229.

Anti-inflammatories• NSAIDs: level 4

–Anecdotal +

–Small CRPS trial naproxen not effective

• Oral Corticosteroids: level 2

–High dose: ~30 mg/day

–Long duration: ~12 weeks–Use when inflammation present

–Beware of contraindications

• TNF-αααα: Anecdotal case reports (level 4)Rico H et al., Clin. Rheumatol 1987 Jun;6(2):233-7Christensen K et al., Acta Chir Scand 1982;148:653–5Braus DF et al., Ann Neurol 1994;36:728–33

Free Radical Scavengers--Vitamin C (level 1) for Prevention

• 4 RCTs, 3 UE (wrist) and 1 LE (ankle)

• One systematic review

• Vitamin C prevents CRPS (level 1)

–A minimum dose of 500 mg/day is recommended

• Limited to prophylaxis immediately after fx

Zollinger PE et al., Lancet 1999; 354:2025-8Cazeneuve JF, Acta Orthop Belg 2002; 68:481-4Zollinger PE et al., J Bone Joint Surg Am. 2007 Jul;89(7):1424-31Besse JL et al., Foot Ankle Surg. 2009;15(4):179-82Shibuya N et al., J Foot Ankle Surg. 2013 Jan-Feb;52(1):62-6

Free Radical Scavengers--DMSO and N-acetylcysteine (level 2-3)

• DMSO (50% cream 5 x/day for 2 months) signific ant pain vs. placebo (level 2)

• It is likely that 600 mg tab of N-acetylcysteine TI D the symptoms of CRPS-I (level 3)

Perez RS et al., Pain 2003, 102:297-307Zuurmond WW et al., Acta Anaesthesiol Scand 1996, 40:364-367Fourouzanfar T et al., Eur J Pain 2002;6:105–22

Anticonvulsants

• Gabapentin: mild effect (level 2)– Adult case series and pediatric case report

– 1 DBRCT: mild effect with improvement in sensory de ficits

• Carbamazepine: RCT>placebo (level 2)

van de Vusse AC et al., Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1 [ISRCTN84121379]. BMC Neurol. 2004 Sep 29;4:13

Harke H et al., The response of neuropathic pain and pain in complexregional pain syndrome I to carbamazepine and sustained-r elease morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth Analg 2001;92:488–95

Antidepressants: ���� Monoamines

• NNT = 3 for TCA in neuropathic pain

• There is no evidence that antidepressants are effective in reducing pain in patients with CRPS-I (level 4)

Perez RS et al., Evidence based guidelines for complex regional pain syndrome type 1. BMC Neurol. 2010 Mar 31;10:20

Opioids

• Historically effective

• There is insufficient evidence for the effects of o ral opioids in CRPS patients on pain (level 4)– One poorly designed study no effect @ 8 days

Perez RS et al., Evidence based guidelines for complex regional pain syndrome type 1. BMC Neurol. 2010 Mar 31;10:20Harke H et al., The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patie nts pretreated with spinal cord stimulation: a double-blinded randomize d study. Anesth Analg 2001;92:488–95

NMDA Antagonists:Ketamine -Subanesthetic (level 2)

• N=19: 4 h (25 ml/h) daily for 10 days–100 ml of NS –100 ml NS +Ketamine (max 25 mg/hr)

• Clonidine and Midazolam to both groups

• 3 month follow upSchwartzman RJ et al., Pain. 2009 Dec 15;147(1-3):1 07-15

Schwartzman RJ et al., Pain. 2009 Dec 15;147(1-3):1 07-15

• DBPCRT

• 66 patients

• 7.4 y median disease duration

• 4.2 days infusion– Low-dose S(+) Ketamine (22 mg/h/70kg)

– Saline

Sigtermans MJ et al., Pain 145 (2009) 304–311

Sigtermans MJ et al., Pain 145 (2009) 304–311

Sigtermans MJ et al., Pain 145 (2009) 304–311

Ketamine -Anesthetic (level 3)

• 20 CRPS patients, ASA I-III x 5 days

• Significant pain relief was observed at 1, 3, and 6 months following Rx (94%, 89%, 79%; P < 0.001)

• Complete remission from CRPS: – @ 1 month in all patients– @ 3 months in 17 patients– @ 6 months in 16 patients

Kiefer RT et al., Pain Med. 2008 Nov;9(8):1173-201

Antihypertensives and αααα-Adrenergic Antagonists

• Clonidine:–Systematic review: no evidence (level 1)

• Nifedipine:–2 uncontrolled case series found doses of up to 60

mg/day useful for CRPS (level 4)

• Phenoxybenzamine:–2 case series ���� seems to work best for syndromes

of less than 3-month duration (level 4)

Kingery WS et al., Pain 1997;73:123–39Muizelaar JP et al., Clin Neurol Neurosurg 1997;99:26–30Prough DS et al., Anesthesiology 1985;62:796–9Ghostine SY et al., J Neurosurg 1984; 60:1263–8

Bone Pain: Bisphosphonates

• Inhibiting active bone resorption (3-phase bone sca n) may improve pain for select CRPS pts

• 3 + DBRPCT bisphosphonate studies (level 2)–2 alendronate (up to 4 x osteoporosis dose)

– 1 clodronate (not approved in USA)

Adami S, et al., Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis 1997, 56:201-204.Varenna M, et al., Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized, double blind, placebo controlled study. J Rheumatol 2000, 27:1477-1483.Manicourt D et al., Role of alendronate in therapy for posttraumatic complex regional pain syndrome type I of the lower extremity. Arthritis Rheum 2004, 50:3690-3697

Bone Pain: Calcitonin (thyroid h)

• Antinociceptive independent of bone effect

• Conflicting evidence re efficacy of calcitonin for CRPS-I based on systematic reviews

Perez R, Treatment of reflex sympathetic dystrophy (CRPS type I): A research synthesis of 21 randomized clinical trials. J Pain Symptom Manage 2001;21:511–26Berg P van den et al., Therapy for Reflex Sympathetic Dystrophy [Dutch]. Huisarts Wet 2002, 45:166-171

Emerging Rx: IVIG

• One small DBPCRT

• 12 /13 pts completed the study

• VAS ���� by 1.55 on average IVIG>placebo

• Only 0.5 g/kg used (customary for neuro disorders 2 g/kg)

Goebel A et al., Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med. 2010 Feb 2;152(3):152-8

Pharma Rx: General Recommendations

Harden RN et al., Complex regional pain syndrome: p ractical diagnostic and treatment guidelines, 4th edition. Pain Med. 20 13 Feb;14(2):180-229.

PSYCHOLOGICAL INTERVENTIONS

• Psychological/social issues: Important

• Rationale– Utility in non-CRPS

– ? direct interaction with pathophysiological mechan isms

–Sympathetic/catecholamines

–Both anxiety and anger expressiveness have been fou nd to be significantly stronger in CRPS patients than in non -CRPS

– Inflammatory mediators

Harden RN et al., Complex regional pain syndrome: practical diagnosti c and treatment guidelines, 4th edition . Pain Med. 2013 Feb;14(2):180-229.

Psychological Interventions: Evidence ?

• Most studies: Level 4

• One level 2 study– prospective study: 18 pts

–Grp 1: Home PT

–Grp 2: Home PT + autogenic relaxation training 1/wk

–Equal improvement: Pain, ROM, edema

–Grp 2 > Grp 1 improvement in limb temp

• One level 3 Study:– Effective graded exposure for fear of movement

Fialka V et al., Complement Ther Med 1996;4:103–5de Jong et al., Pain 2005;116:264–75

Interventional Procedures Evidence

• Sympathetic Blocks

• Neurolytic sympathetic

• IVRA

• Somatic blocks/Infusions

• Neuromodulation

• Emerging therapies

Sympathetic Blocks

• First line treatment but poor quality studies

• DB cross-over study, 7 CRPS pts, SGB– Onset of analgesia: <30 min, both LA & saline

– duration of pain relief: LA > saline

• Testing for sympatholysis: CRUCIAL– Temperature >34 0C

– Within 3 0C from core temperature

Cepeda MS et al., Clin J Pain. 2002 Jul-Aug;18(4):2 16-33 Price DD et al., Clin J Pain. 1998 Sep;14(3):216-26Malmqvist EL et al., Reg Anesth 1992;17:340–7Tran KM et al., Anesth Analg 2000 Jun;90(6):1396-40 1

• One level 2 study–23 Children 10-18 yr. / unilateral LE CRPS

–GA ���� Lumbar sympathetic catheters

–IV lidocaine + saline (0.1 ml/kg; not > 6 ml)

–IV saline + lidocaine (0.1 ml/kg; not > 6 ml)

–Spontaneous and evoked pain ratings and sensory thresholds were assessed before and after

Meier PM et al., Anesthesiology. 2009 Aug;111(2):372-80

Meier PM et al., Anesthesiology. 2009 Aug;111(2):372-80

***

Meier PM et al., Anesthesiology. 2009 Aug;111(2):372-80

*

P = 0.05*

Sympathetic Contribution

• A favorable response to a sympatholysis is NOT required for the diagnosis of CRPS

Merskey H and Bogduk N eds. IASP Press 1994 Stanton-Hicks et al., Pain. 1995 Oct;63(1):127-33

SMP

SIPMagnitude of Pain

Sympathectomy

• Surgical: ~44% post-procedure neurlagia

• Neurolytic: not as controllable as RF

• RF (level 3)– Preferred

– Largest series for thoracic sympathetic RFA

–Less variable than lumbar

–>350 procedures

–Long lasting sympathectomy but ? analgesia

Wilkinson H. Neurosurgery 1996;38:715–25.

IVRA

•Level 1 evidence for lack of proven effect of IVRA

Perez R, Kwakkel G, Zuurmond W, de Lange J. Treatment of reflex sympathetic dystrophy (CRPS type I): A research syn thesis of 21 randomized clinical trials . J Pain Symptom Manage 2001;21:511–26.

Continuous Infusion Techniques

• When pain is not controlled by sympathetic blocks ���� Continuous somatic infusion techniques–Mostly by TEC, plexus or TAP–Limited data on efficacy or safety

• Goal: control pain to allow for functional rehabilitation–Usually 6 wks or longer–Best if Sx < 1 yr

Somatic Continuous Infusion Blocks

• Axillary catheters: level 4

• Epidural infusions: Level 2 & 3– Rauck et al., DBRCT epidural clonidine infusion vs . placebo

x 3 days

–17/19 pts on clonidine good relief

– Also efficacy of bupiv or bupiv/opioid

• However, high risk of infections

Rauck R et al., Anesthesiology 1993;79:1163–9Hayek SM et al. 2006, Clin. J. Pain 22(1): 82-89

Intrathecal Infusions• Bupivacaine

– Case series of 3 refractory CRPS patients

– All 3 patients had progression of CRPS despite IT b upivacaine

• Baclofen– DB prospective study, 7 pts with CRPS/dystonia

– Good analgesia and functional restoration

Van Hilten R et al., N Engl J Med 2000;343:625–30

Emerging: Botulinum Toxin

• DBRPCT, 25 pts– 0.2ml or 5 units per site– Limit: 40 sites or 200 U– spontaneous pain, brush allodynia, and cold pain th resholds

• LSB with BTx-A in 9 CRPS patients with SMP���� pain relief 71 days vs . <10 days for bupiv

Ranoux D et al., Botulinum toxin type A induces direct analgesic effe cts in chronic neuropathic pain. Ann Neurol. 2008 Sep;64(3):274-83Carroll I et al., Sympathetic block with botulinum toxin to treat comp lex regional pain syndrome. Ann Neurol 2009 Mar;65(3):348-51

SCS—CRPS Kemler et al.

Kemler MA et al., N Engl J Med. 2000 Aug 31;343(9): 618-24

SCS--CRPS

Kemler MA et al., N Engl J Med. 2000 Aug 31;343(9): 618-24

SCS--CRPS @ 2 years

Kemler MA et al., Ann Neurol. 2004 Jan;55(1):13-8

SCS--CRPS @ 2 years

Kemler MA et al., Ann Neurol. 2004 Jan;55(1):13-8

SCS--CRPS @ 5 years

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

SCS—CRPS Kemler et al.

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

Main Analysis Subgroup Analysis

SCS+PT PT P Implant P

# of Pts 31 13 20

Mean VAS

Change cm

-1.7±2.3 -1 ±2.9 0.25 -2.5±2.2 0.06

% Pts Much Improved GPE

23% 15% 0.24 35% 0.02

“18 (90%) of 20 patients with an implant indicated that they had positively responded to the treatment, and 19 patients (95%) reported that they would undergo the treatment again for the same result”

Comment: Possible failure of functional improvement

,

22 patients had a sympathectomy

Post-sympathectomy neuralgia: hypothesis on peripheraland central neuronal mechanisms.Kramis RC, Roberts WJ, Gillette RG Pain 1996; 64: 1-9

Hypothesis:1. Transection of somatosensory & visceral afferents2. Central deafferentation3. Pre-existing sensitization of spinal afferents

Rehabilitation PathwayReactivation/GMI

Desensitization

Isometrics Flexibility

Edema Control Peripheral E-stim

Treat Secondary MFP

ROM (gentle!) Stress Loading

Isotonic StrengtheningAerobic Conditioning

Postural Normalization

ErgonomicsMovement TherapiesNormalization of Use

Vocational/Functional Rehab

Pharma. Pain management

Psych.education

Progres

s

Pro

gres

s

Fai

lure

toP

rogr

ess

in R

ehab

Failure to

Progress in R

ehab

InterventionalPain

Management

PsychologicalTreatment

Minimally Invasive�Sympathetic Blocks�IV Regional Blocks�Somatic Nerve Blocks

�Assess for Axis I Disorders�Pain Coping Skills�Biofeedback/Relaxation training�Cognitive Behavioral Therapy for Treatmentof Axis Disorders

~�Increase frequency/intensity of Psychotherapy

Surg.or Experimental Therapies�Motor Cortex

Stimulation

~

More Invasive�TEC and Plexus Catheter Blocks�Neurostimulation�IDM(e.g.Baclofen,Prialt)

~

Excellent ResponseFollow Up

Relapse

Repeat Pathway

Interdisciplinary Management

Flor H et al., Pain 1992;49:221–30 Guzman J et al., BMJ 2001;322:1511–6

• A 67 yo female presents to the emergency room with a right Colle’s fracture. Which of the following interventions decreases this patient's risk for developing CRPS?

A.A corticosteroid taper course

B.Piroxicam

C.Gabapentin

D.Vitamin C

E.A stellate ganglion block