Complex Regional Pain Syndrome Gabriel Mattei, MD Interventional Pain Fellow Hudson Spine & Pain Medicine 5/4/2017

In 1993, the IASP introduced the term Complex regional pain syndrome to describe all pain states that previously would have been diagnosed as RSD or causalgia-like syndromes

Defining CRPS: IASP Consensus Workshop Orlando, Florida, 1993 The term RSD was: Too over-used & non-specific to be of value Inaccurate CRPS type 1: (RSD) CRPS type 2: (Causalgia)

Defining CRPS: IASP Consensus Workshop Orlando, Florida, 1993 CRPS type 1 is a syndrome that usually develops after an initiating noxious event Not limited to the distribution of a single peripheral nerve Disproportionate to the inciting event

Defining CRPS: IASP Consensus Workshop Orlando, Florida, 1993 Defining CRPS type 1: IASP, 1993 May be associated with evidence of: Edema Changes in skin blood flow Abnormal sudomotor activity Allodynia or hyperalgesia The site is usually distal aspect of an affected extremity or with a distal to proximal gradient

IASP Did Not Include: The term sympathetic Response to sympathetic blocks Predisposing factors Psychological factors Stages Osteoporosis Impairment of motor function

Complex Regional Pain Syndrome: a variety of painful conditions following injury which appears regionally having a distal predominance of abnormal findings, exceeding in both magnitude and duration the expected clinical course of the inciting event, often resulting in significant impairment of motor function, and showing variable progression over time.

Epidemiology CRPS I: 21 per 100,000 CRPS II: 4 per 100,000 Female-to-Male ratio: 3:1 Any age, but middle age predominates Median 42 years Onset 9 – 85 years of age CRPS occurs in about 1-2% of patients who have had fractures and in approximately 2-5% of patients after peripheral nerve injuries

Differential diagnosis: Unrecognized local pathology (fracture, sprain) Traumatic vasospasm Cellulitis Lymphedema Raynaud’s disease Thromboangiitis obliterans Erythromelalgia DVT Also, nerve entrapment syndromes, occupational overuse syndromes, and diabetic neuropathy

A modified diagnostic criteria was proposed by the IASP in 2007 to increase specificity (the ‘Budapest criteria’): Continuing pain that is disproportionate to any inciting event Must report at least one symptom in three of the four following categories: Sensory: hyperalgesia, allodynia Vasomotor: temp. asymmetry, skin color changes or asymmetry Sudomotor/Edema: edema, sweating changes or asymmetry Motor/Trophic: decreased range of motion, weakness, tremor, dystonia, trophic changes Must display at least one sign at the time of evaluation in two or more of the following categories: No other diagnosis better explains the signs and symptoms

CRPS Types 1 and 2: Features in common Pain Spontaneous or evoked Allodynia and/or hyperalgesia Disproportionate pain to the inciting event Regional: not limited to a single peripheral nerve distribution Evidence of edema or abnormal sudomotor activity Diagnosis is excluded if other conditions could be account

Differentiating CRPS Types 1(RSD) and 2 (Causalgia) Type 1 occurs after an initial noxious event other than nerve injury Type 2 occurs after a nerve injury

Insults followed by CRPS 1 Trauma Stroke or other CNS disorders Shingles MI Shoulder disorders Malignancy Other precipitants Spontaneous

Pathophysiology Three main hypotheses Facilitated neurogenic inflammation Autonomic dysfunction Neuroplastic changes within the CNS

Neurogenic inflammation Classic inflammatory signs are present in CRPS: pain, swelling, erythema, hyperthermia and impaired function However, when clinical chemistry parameters for inflammation are evaluated, there are no differences between CRPS patients and controls With neurogenic inflammation, distinct classes of C-fibers called mechano-heat-insensitive C-fibers have both an afferent function in the mediation of pain and itch as well as an efferent neurosecretory function, releasing neuropeptides via ‘axon reflex’ Action potentials in these fibers can be conducted retrogradely to terminal branches via axon collaterals where neuropeptides such as substance P and calcitonin-gene-related peptide (CGRP) are released Substance P provokes plasma protein extravasation (edema) and appears to have a role in osteoclastic activity CGRP induces vasodilation (hyperthermia and erythema), increases sweating, and appears to be involved in hair growth

Autonomic dysfunction Pathological sympatho-afferent coupling: Peripheral nociceptors develop adrenergic sensitivity (mainly alpha-2 receptors) such that tonic sympathetic efferent activity leads to their activation Painful impulses via these nociceptors maintain the central nervous system in a sensitized state Painful and non-painful stimuli to the affected limb result in hyperalgesia and allodynia, respectively Catecholamine levels, however, are actually lower in the affected extremity, thus, it is not a problem of excessive sympathetic nerve output

Neuroplastic changes within the CNS Studies using functional brain imaging in patients with CRPS have found a significant degree of cortical reorganization in the central sensory and motor cortices The amount of reorganization positively correlates with the extent of pain intensity The areas of reorganization were found to be reversible in adequately treated patients

Clinical Presentation PAIN, PAIN, PAIN Spontaneous, constant, burning, aching, throbbing Disproportionate to the injury and persists beyond normal or expected recovery period Asymmetrical and not in the distribution of a peripheral nerve. Worst distally. Severe mechanical and thermal allodynia, hyperalgesia, and hyperpathia

Clinical Presentation Autonomic (Sympathetic) Abnormalities Vascular Hot, swollen, erythemetous Cold, blanched Mottled Sudomotor Hyperhydrosis Hypohydorosis

Clinical Presentation Motor Diffuse weakness of the extremity, but normal EMG/NCS until late in the course of the disease. Tremor Dystonia occasionally

Clinical Presentation Trophic Changes Nail growth Loss of function: muscle, joint and tendon atrophy, contractures and fibrosis Hair changes (coarse hair, loss of hair) Skin--thin and glossy, loss of elasticity, ulceration. Osteoporosis

Clinical Presentation Time Course Three stages: Stage 1 (acute) Stage 2 (dystrophic) Stage 3 (atrophic)

Stage One: Initial Phase MOST LIKELY TO BE REVERSED AND CURED Duration: weeks to months Limb pain Skin is variable: cold/cyanotic/sweaty or warm/red/dry Hair and nail growth may be increased Swelling with associated decreased range of motion or stiffness

Stage 1 (Acute)

Stage Two: Dystrophic Phase Duration: 3-6 months Limb pain spreads diffusely, but may decrease overtime Brawny edema: swelling evolves into thickened dermis and fascia Nails show ridges, splits, and decreased growth Early signs of muscular atrophy and osteoporosis

Stage 2 (Dystrophic)

Stage 2 (Dystrophic)

Stage Three: Atrophic Stage Pain persists, but may be less intense Muscle atrophy and osteoporosis may worsen Irreversible trophic skin changes: smooth glassy skin, tapered digits, contractures. Skin is pale, cyanotic, & cool

Atrophic Stage 3 Severe Mottling

Atrophic Stage 3 Contractures Skin Ulceration Migratory/progressive

Diagnosing CRPS CRPS is a clinical diagnosis There is no gold standard for diagnosing CRPS

Diagnostic Tests Plain Radiographs Bone scans Skin temperature and thermography Sweat tests EMG/NCS Response to sympathetic blockade

Plain Radiographs Sudeck’s atrophy- patchy osteopenia, ground glass appearance Osteopenia is more than expected from disuse alone Nonspecific Osteopenia occurs in a small % of cases

Plain Radiographs Atrophic stage Late findings only showing bone loss and patchy osteoporosis

Triple-Phase Bone Scan First two phases are nonspecific Third phase bone scan-abnormal, with enhanced uptake in the periarticular structures. Hyperperfusion Suggestive and supportive of the diagnosis of CRPS, but not diagnostic

Skin temperature Two degrees side to side difference in limb skin temperature Temperature may be variable and inconsistant, limiting it’s usefulness

Diagnostic Tests Skin Temperature Thermography may show asymmetry. Affected limb is warmer than normal in acute stage and later becomes cooler. Subject to many variables.

Sweat Test May be variable and inconsistant, limiting it’s usefulness

EMG/NCS Are essentially normal in CRPS-1

Response to Sympathetic Blockade For diagnosing RSD, the IASP ignores the response to sympatholytic procedures

Quantitative Studies Quantitative Sensory Testing: Rarely available and no specific profile for CRPS QSART: Quantitative Sudomotor Axon Reflex Test of autonomic function. Rarely available

Treatment Early recognition and treatment of CRPS has a much favorable prognosis if <6months Dumitru 1991 Multimodal treatment is recommended

Treatment Goals = Relief of pain Return of function Prevent or slow progression EARLY TREATMENT IMPROVED OUTCOME =

Treatment Physical Therapy Physical Agents Pharmacology Sympathetic blockade Surgical Sympathectomy Psychological aids Other

Physical Therapy In the acute stage PT is the most important factor in reversing the syndrome. Later, it can improve pain & function and help prevent progression and migration. Aggressive PT may only be possible with treatment of pain: pain meds, sympathetic and/or somatic blockade.

Physical Therapy Prevents disuse atrophy Usually requires analgesia Start with gently active exercise, progressing to active-assistive Stress loading techniques

Physical Agents TENS Electro-acupuncture Ultrasound Heat or cold

Pharmacology Drugs demonstrated to be effective for CRPS based on randomized controlled trials, and their proposed mechanism of action: Prednisone (oral): anti-inflammatory, neuronal membrane stabilizer Vitamin C (oral): antioxidant Alendronate (IV): osteoclast inhibitor Bretylium (IV): Autonomic ganglia blocker Ketansarin (IV): serotonin and alpha receptor antagonist Phentolamine (IV): alpha-1 receptor antagonist Lidocaine (IV): sodium channel blocker DMSO (topical): free radical scavenger Calcitonin (intranasal): osteoclast inhibitor Clonidine (epidural): alpha-2 receptor agonist Baclofen (intrathecal): GABA-B receptor agonist

Pharmacology NSAIDs-Mild to moderate pain Opioids-potential benefit for severe neuropathic pain. Beware of all issues related to chronic opioid use. Steroids-Proven effective in acute (inflammatory) stage. Gabapentin and Pregabalin-Effective

Pharmacology Tricyclics-Effective for a variety of neuropathies Sodium channel blockers-IV lidocaine, Lidoderm, mexilitene, lamotrigine. NMDA blockers-Ketamine, dextromethorphan Topical Clonidine- 2-agonist: prevents release of catecholamines? Maybe helpful.

Sympathetic Blockade Lumbar sympathetic block Stellate ganglion block Guanethidine test If effective, sympathetic blockade often gives relief well past the duration of the block. Repeated blocks can be reverse the course of the disease. Very helpful in facilitating PT.

Sympathetic Block Local anesthetic is injected at the stellate ganglion (UE) or the lumbar paravertebral ganglion (LE) If relief, then suspect sympathetic etiology Proper response to a stellate ganglion block: Ipsilateral Horner’s Syndrome-Anhidrosis, conjunctival injection, nasal congestion, vasodilation and increased skin temperature.

Surgical Sympathectomy If block beneficial but transient Only for profoundly disabled patients who have responded positively to sympathetic blockade and have no other treatment options. Pain commonly recurs within 6-12 months after procedure. Pittman DM, 1997

Other treatment/procedures Implantable pumps Spinal cord stimulators Botox

Prognosis Remains guarded No single definitive treatment Early intervention Pain often continues

Summary CRPS has an extremely complex pathophysiology involving sensory, motor and autonomic abnormalities It is unknown as to how the autonomic abnormalities and inflammatory processes affect the pain and sensory/motor abnormalities It is unknown if and how the syndrome can be prevented

References Baron R, Raja SN. Role of adrenergic transmitters and receptors in nerve and tissue injury related pain. Malmberg AB, Chaplan SR (eds.). Mechanisms and Mediators of Neuropathic Pain. 2002, Birkhauser Verlag Basil/Switzerland. 153-174 Sommer C. Cytokines and Neuropathic Pain. Hansson PT, Fields HL, Hill RG, Marchettini P. (eds.) IASP Press,Seattle, 2001, 37-62 Baron R, Binder A, Schattschneider J, Wasner G. Pathophysiology and treatment of complex regional pain syndrome. Dostrovsky JO, Carr DB, Koltzenburg M. (eds.). IASP Press, Seattle, 2003, 683-704