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CRPS: Epidemiology, Pathophysiology, Assessment, and Management Martin D. Cheatle, PhD Learning Objectives Describe the differential diagnoses when a patient presents with signs of possible CRPS Demonstrate effective pharmacologic and novel nonpharmacologic strategies to manage pain and improve functionality Examine the potential benefits and long term efficacy of interventional pain procedures in CRPS Silas Weir Mitchell Causalgia in soldiers suffering from bullet or shrapnel injuries during the civil war in the 1860s In combining the Greek terms for burning (“kausos”) and pain (“algos”) they coined the term “causalgia” "...a painful swelling of the joints....may attack any or all articulations of a member. It is distinct from the early swelling due to the inflammation about the wound itself, although it may be masked by it for a time:nor is it merely a part of the general edema....Once fully established, it keeps the joint stiff and sore for weeks or months. When the acute stage has departed, the tissues become hard and partial ankylosis results." Mitchell et al 1864 Evolution of CRPS 1900: Sudeck – variant of causalgia with bone demineralization 1940s: the term reflex sympathetic syndrome (RSD) was coined by Evans “The true diagnostic features are those disorders initiated by perversions of reflex sympathetic stimulation, namely increased rubor or pallor, sweating, edema, atrophy of skin, and spotty or even cystic atrophy of bone” (Evans 1946) Evolution of CRPS 1993: IASP Diagnostic criteria CRPS I (reflex sympathetic dystrophy) -- The presence of an initiating noxious event or a cause of immobilization -- Continuing pain, allodynia, or hyperalgesia with which the pain is disproportionate to any inciting event -- Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain -- This diagnosis is excluded by existence of conditions that would otherwise account for degree of pain, dysfunction Note: Criteria 2 through 4 must be satisfied CRPS II (causalgia) -- Presence of continuing pain, allodynia, or hyperalgesia after a nerve injury, not necessarily limited to the distribution of the injured nerve -- Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain -- This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction Note: All 3 criteria must be satisfied. CRPS 2003 Budapest criteria • Aimed to improve diagnosis and validity Other diagnostic criteria have been proposed but all of them are lacking – Unclear pathophysiology of CRPS – No gold standard diagnostic test for CRPS CRPS Epidemiology 2007 retrospective review in the Netherlands – Query of general practice database between 1996-2005 – Incidence rate of CRPS was 26.2 per 100,000 person years (95% CI: 23.0-29.7) – Females affected 3 times more often than males • Highest incidence in females ages 61-70 – Upper extremity affected more frequently than lower extremity • Fracture was most common inciting event (44%) de Mos, de Bruijn et al. The incidence of complex regional pain syndrome: a population-based study. Pain. 2007 May;129 (1-2): 12-20 Epidemiology Continued Population based study in Olmsted County Minnesota –Medical records from 1989 to 1999 with diagnosis codes for CRPS –74 cases of CRPS-1 identified • Incidence rate of 5.46 per 100,000 person years at risk –Female patients 4 times more likely to develop CRPS in comparison to males • Median age onset of 46 years –Upper limb affected twice more than lower limb • All cases reported antecedent event and fracture was most common trigger (46%) Sandroni et al. Complex regional pain syndrome type 1: incidence and prevalence in Olmsted county, a population-based study. Pain. 2003 May; 103(1-2): 199-207 Pathophysiology Proposed Pathophysiology Still being elucidated Common prevailing thoughts –Multifactorial routes all affecting CNS, PNS, and SNS –Could be genetic predisposition as well Putting it All Together A speculative mechanism currently postulated in the pathogenesis of CRPS – Tissue injury in the periphery leads to nerve injury that causes the release of cytokines that produce signs of inflammation and locally increased nociceptive responsiveness (peripheral sensitization) – These effects are maximized in patients who may be genetically susceptible to the disease As peripheral and central sensitization occur, trophic changes begin to appear in the periphery around the area of tissue injury After the inciting event, nociceptive fibers in the area begin to upregulate expression of adrenergic receptors, after which sympathetic nervous system activity and circulating catecholamines can directly trigger nociceptive firing – Reduced sympathetic outflow in the region after the initiating trauma produces signs of vasodilation and impaired thermoregulatory responsiveness • Diminished sympathetic outflow also contributes to upregulated sensitivity of local adrenergic receptors, leading to exaggerated vasoconstrictive responsiveness in the affected region in the presence of circulating catecholamines Bruehl. An update on the pathophysiology of complex regional pain syndrome. Anesthesiology. 2010; 113: 713-25 Pathophysiology Conclusion Complex and multifactorial –Enhanced peripheral sensitization –Enhanced central sensitization Up regulation of pro inflammatory cytokines Altered sympathetic and catecholamine function Genetic susceptibility Psychophysiological interactions Clinical Manifestations Clinical Manifestations Pain out of proportion to what is expected Allodynia Hyperalgesia Clinical Manifestations Temperature changes Skin changes Trophic changes –Hair/nails Clinical Manifestations Edema Sweating changes Clinical Manifestations Bony changes Limb contractures CRPS in a Nutshell Painful neuropathic condition – Distinguishes itself from other neuropathies by sympathetic symptoms that accompany it Symptoms usually present after trauma – Not always the case In addition to classic neuropathic complaints – – – – – Allodynia, hyperalgesia Swelling/edema Skin color changes, temperature differences Trophic changes to hair/nails/skin End stage-altered motor function Type 1—absence of nerve injury Type 2—nerve injury present Stages of CRPS 3 Stages of CRPS Acute Phase Stage-1 (days to weeks) –Burning pain out of proportion to initial injury –Pain increases with emotion and physical contact –Temperature and color variations –Edema usually present – 3-Phase bone scan may show increased periarticular uptake in late phase –Also may start to see hair and nail changes 3 Stages of CRPS Dystrophic Phase Stage II (several weeks to months) –Affected limb becomes • Indurated • Hairless • Cyanotic • Mottled • Nails can become cracked and brittle 3 Stages of CRPS Atrophic Stage 3 (6 months to years) Defined as irreversible tissue damage –Skin is thin and shinny –Pain spreads proximal and can migrate to other extremities –Anxiety leads to sympathetic discharge which can lead to worsening pain –Many patient develop emotional disorders 2ndary to intractable pain Diagnosing CRPS Diagnosis Long standing continued pain Pain that is disproportionate to any inciting event All other etiologies have been excluded Budapest Criteria-2010 –Categorizes various clinical markers –Must report at least 1 sign/symptom in 3 of 4 categories Diagnosis Budapest Criteria-2010 Diagnosis Signs and Symptoms Sensory: hyperalgesia and/or allodynia Vasomotor: temperature asymmetry and/or skin color changes Sudomotor/edema: symptoms of edema and/or sweating changes and/or asymmetry Motor/trophic: decreased range of motion and/or motor dysfunction Radiological Imaging Three-phase bone scan –Accelerated blood flow and/or increased periarticular uptake –Non-specific and can occur late in disease progression X-ray and X-ray bone densitometry – Not been shown to be helpful in early stages of CRPS • Osteoporosis can be seen later in progression and may help clinical diagnosis MRI has not been shown to be useful in diagnosis Radiological Imaging Quantitative Sensory Testing –Provides information about the function of afferent nerve fibers Quantitative Sudomotor Axon Reflex Test –Provides information about the sudomotor reflex loops Thermography –Measures heat emissions from the body using special infrared technology Management of CRPS Pharmacological Management of CRPS Evidence based medications are few and far between –Due to rarity of diagnosis Most practitioners treat as a neuropathic pain condition –Antiepileptic Ca channel blockers –TCAs –SNRIs –Antiepileptic Na channel blockers –Opioids –NSAIDs Management Continued Since the data is lacking regarding medication therapies for CRPS –Expert panels agree that a multimodal treatment plan should be incorporated into patient care • Panels also believe that first line therapies should include trials of an anticonvulsant (ie, gabapentin), TCA, NSAID and possibly opioids for refractory pain Stanton-Hicks MD, Burton AW et al. An updated interdisciplinary clinical pathway for CRPS: report of an expert panel. Pain Pract. 2002;2(1):1 Bisphosphonates 3 RCTs on use of bisphosphonates – Placebo controlled trials with intranasal calcitonin, iv clodronate, and iv alendronate – 118 patients total Primary outcomes were active movement and motor function All 3 studies showed statistically significant improvement with therapies – Given paucity of data available, bisphosphonates have been only well documented medications that work Gobelet C, . The effect of adding calcitonin to physical treatment on reflex sympathetic dystrophy. Pain. 1992;48:171–175. 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. Adami S, et al. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis. 1997;56: 201–204 Tran, Duong et al. Treatment of complex regional pain syndrome: a review of the evidence. Can Journal of Anaesth. 2010 Feb;57(2):149-66 Ketamine To help prevent or reduce central sensitization medications that target the NMDA receptor can be used –Placebo controlled trials show iv ketamine lowers pain scores in CRPS patients –However a recent systematic review concluded that there is no high quality evidence to support its use –No studies evaluating methadone yet Schwartzman, Alexander et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009 Dec 15; 147 (1-3): 107-15 Connolly SB, Prager JP et al. A systematic review of ketamine for complex regional pain syndrome. Pain Med. 2015 Jan 13 (epub ahead of print) Steroids Two small randomized trials showing beneficial effect –23 patients with post traumatic CRPS-1 • 13 patients randomized to receive 10 mg of prednisone three times a day vs a placebo group – Study group had up to 75% clinical improvement within a 12-week study period –36 patients with post stroke CRPS • 31 patients were nearly symptom free after a 10-day period of treatment with low dose steroids Christensen K, Jensen EM, Noer I. The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chir Scand. 1982;148(8):653 Braus DF, Krauss JK, Strobel J. The shoulder-hand syndrome after stroke: a prospective clinical trial. Ann Neurol. 1994;36(5):728 Interventional Approaches Lidocaine Infusions Lidocaine Infusions No numerical data provided in study Small n=16 ? Overstated effect: may suggest small benefit Interventional Approaches Epidural clonidine –Clonidine- α2-adrenergic agonist –May decrease sympathetic output when placed intraspinally –Catheter placed at C7-T1 for UE or L2-L3 for LE –Clonidine at 2 doses: 300 μg or 700 μg –Studied for a 6 hour period Rauch, R. et al., Epidural Clonidine treatment for refractory reflex symathetic dsytrophy, Anesthestiology 79;1163-69, 1994 Interventional Approaches Epidural clonidine –Decrease in VAS scores –+sedation, +hypotension, +decreased HR –Low sample size – 26 pts –No long term follow up after 6 hrs –No functional evaluation Interventional Approaches Intravenous regional blocks (Bier block) with: –Atropine, bretylium, droperidol, ketanserin Bottom line: –Low quality evidence of effectiveness –Very small sample sizes –Significant associated side effects O’Connell NE, et al. Interventions for Treating pain and disability in adults with complex regional pain syndrome- an overview of systematic reviews (Review), The Cochrane Collaboration, issue 4, 2013 Sympathetic Blocks Sympathetic Blocks Two studies looking at stellate or lumbar sympathetic blocks w/ local anesthetic for CRPS – Price 1998 and Verdugo 1995 Crossover study with saline Looking at >50% pain relief – no difference for immediate pain. Possibly some long term relief (48 hrs) w/ LA Cepeda 2005 – statistical analysis: not significant Sympathectomy Study looking at RFA of the lumbar sympathetic chain vs chemical neurolysis (Manjuanth 2008) –RFA- 80°C for 90 sec –Phenol –Both group reported pain relief –No difference btn groups at four months –“These techniques should be use cautiously in clinical practice in carefully selected pts.” Botulinum Toxic Type A Botulinum Toxic Type A Inhibits release of Ach from nerve terminals This works at the preganglionic sympathetic nerves and can prolong a sympathetic block Botulinum Toxic Type A (cont’d) Carroll et al – Sympathetic blocks with botulinum Crossover study using bupivacaine + botulinum toxic type A or bupivacaine Median return of pain time was 71 days in botulinum toxic type A group vs 10 days in bupivacaine group Low quality study and small sample size Requires further investigation Spinal Cord Stimulation Spinal Cord Stimulation Kemler et al, 2008 54 pts, randomized to SCS+PT or just PT Significant pain reduction in SCS+PT group At 2 yrs, no difference in QOL or function ? Diminishing effectiveness of SCS over time At 5 yrs, higher patient satisfaction in SCS group Surgical Sympathectomy Bandyk 2002–reported good pain relief with high patient satisfaction ~20-30% showed no improvement Very limited data or evidence Dennis F. Bandyk et al, Surgical sympathectomy for reflex sympathetic dystrophy syndromes, Journal of Vascular Surgery Volume 35, Issue 2, February 2002, Pages 269–277 Biopsychosocial Approach to CRPS Management Relieving Pain in America: Institute of Medicine June 2011 We believe pain arises in the nervous system but represents a complex and evolving interplay of biological, behavioral, environmental, and societal factors… http://www.nap.edu/catalog.php?record_id=13172 Biopsychosocial Approach to CPS Comprehensive pain management programs based on the biopsychosocial model of pain, typically emphasizing cognitive behavioral therapy, a graded exercise program and appropriate medication management have been shown to significantly improve treatment outcomes (return to work, pain reduction and increase in activity). Gallagher, 1999 Loeser & Turk, 2000 McCraken & Turk, 2002 Cheatle & Gallagher, 2006 Biopsychosocial Treatment Program for CRPS CBT Functional restoration Evidence-based rational pharmacotherapy Social support Graded motor imagery Cognitive Behavioral Therapy CBT focuses on maladaptive thought patterns (catastrophizing) and behaviors (kinesiophobia) that occur frequently in patients with CNCP The objective of CBT is to guide the patient in recognizing and reconceptualizing his/her personal view of pain, identifying their role in the process of healing and promoting the patient being proactive rather than passive, and competent rather than incompetent CBT include specific skill acquisition (relaxation therapy, stress management, cognitive restructuring) followed by skill consolidation and rehearsal, and relapse training (Turk, Flor, 2006) CBT (cont’d) CBT has been found to be efficacious for a number of chronic pain disorders including: –Arthritis (Keefe & Caldwell, 1997) –Sickle cell disease (Chen et al, 2004) –Chronic low back pain (Lamb et al, 2010; Glombiewski et al, 2010) –TMJ (Turner et al, 2006) –Lupus (Greco et al, 2004) –Pain in breast cancer patients (Tatrow et al, 2006) Functional Restoration Focus on improvement of functional restoration – Occupational and physical therapy • The most effective treatment option • Desensitization and resetting altered central processes of the brain – Aquatic therapy • Hydrostatic principles and buoyancy component • Mild compressive force around affective extremities – Decreases edema – Assist in weight bearing of the extremity Graded Motor Imagery (GMI) Pain is a Disease of the Brain Theory of pain modulation based on nociception Pain perception involves all areas of the brain Factors that Influence Nociceptive Inputs to Pain Perception Tracey, I. Neuron 55, August 2, 2007 CNS Plasticity in Pain CNS reorganization in a variety of chronic pain states: review. Henry, Chiodo, Yang. PM&R Vol 3 Dec 2011 CNS reorganization in response to sensory and emotional experiences Both structural and functional intrinsic changes are demonstrated Changes occur in number/ location of synapses Neuroplasticity changes in PLP Phantom limb pain – Remapping of somatosensory cortex – Brain activity changes in ipsilateral motor cortex, thalamus, insula, forebrain, ACC Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Gracely et al. Brain (2004) Increased activity in brain areas related to: –Anticipation of pain (FC) –Attention to pain (ACC, PFC) –Emotional aspects of pain (amygdala) What is Graded Motor Imagery (GMI)? Therapeutic techniques Began approximately 20 years ago Developed by a group of professional staff at the Neuro Orthopaedic Institute (NOI) group in Australia Lorimer Moseley credited with researching and progressing techniques Is progressively expanding and is taught internationally Research is ongoing GMI continued… Based on research, the brain is adaptable and changes over the course of our lives The brain can be “retrained” to help reduce pain GMI uses “brain exercises” to retrain how the brain processes pain “Graded Motor Imagery is the most up to date rehabilitation program – based on the latest science and clinical trials to treat many complex pain, and movement problems” (noigroup.com) How is GMI used in therapy? Three Phases: 1. Laterality training 2. Explicit motor imagery 3. Mirror therapy Laterality training Explicit motor imagery Mirror therapy Improved function Who is GMI used with? People with: Chronic pain Chronic regional pain syndrome (CRPS) Brachial plexus injuries Amputations Stroke/CVA Arthritis *GMI techniques can be individualized for any diagnosis, depending on the person’s needs* View Video: http://noijam.com/2014/10/31/what-is-graded-motor-imagery/ New Frontiers Multimodal Approach CBT Functional Restoration Interventions Pharmacotherapy Social Support CRPS GMI Thank you!!! [email protected]