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

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

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

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

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

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

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

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. 

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.

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.

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.

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.

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

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

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

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

Muscle symptoms in CRPS Muscle spasms Dystonia Tremors Myoclonus

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)

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

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

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

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

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

Epidemiology CRPS Type I incidence: 5.5 per 100,000 person-years prevalence: 21 per 100K fractures: prospective studies: 26-39% retrospective studies: 1-2 % ?? CRPS Type II incidence: 0.8 per 100,000 person-years prevalence: 4 per 100K peripheral nerve injury: 1-5%

Incidence and Demographics Olmsted county, Minnesota (2003) 5.5/100,000 person/years incidence 20.7/100.000 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

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

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

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

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

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

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 1-2-3 and no fixed time course Ryan P. Calfee, MD, MSc, Comprehensive Review Course, 2014

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

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

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

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)

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

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 www.radiopaedia.com

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

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

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

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

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 200 and 400 mg daily

Vitamin C use In a study by Taylor and Curhan, participants consuming 1000 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.

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 1000 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.

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

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

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

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

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.

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)

Ketamine

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.

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

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

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

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?

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

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

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.

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

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

Thank you !