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10 Articles in Volume 10, Issue #2
Introduction to a Referred Sympathetic Pain Map
Deconstructing Complex Regional Pain Syndrome
Feedback and Response Regarding ACOEM’s Practice
Psychologists as Primary Care Providers
FDA’s Risk Evaluation and Mitigation Strategies Program
Avoiding Complications From Interventional Spine Techniques
Laser Therapy in the Management of Fibromyalgia
Expanding Ellipsoidal Decompression (EED®) of the Spine
Neurotechnology, Evidence, and Ethics
Sphenopalatine Ganglion Neuralgia Diagnosis and Treatment

Deconstructing Complex Regional Pain Syndrome

Progress in understanding the pathophysiology of CRPS is leading to new and more effective treatments.

Dr. Robert Schwartzman is internationally known and respected for his work in studying Complex Regional Pain Syndrome (CRPS) and helping patients who suffer the pain and distress of the disease. It is through Dr. Schwartzman’s efforts to understand the pathophysiology of CRPS that we are closer to referring to this troublesome syndrome (a collection of symptoms and signs) as a disease. Control of the disease, rather than just symptom control, depends on this knowledge and understanding.

Complex regional pain syndrome (CRPS) results from damage to C-fibers and A-delta fibers that innervate soft tissue and bone in the great majority of instances. It may also occur after direct nerve injury and in approximately 10% of patients after damage in CNS pathways (stroke, head and spinal cord trauma, and multiple sclerosis).

Nociceptive pain occurs from potential or tissue destructive stimuli. It is mediated by high threshold unmyelinated C-fibers or thinly myelinated A-delta fibers whose primary neurons reside in the dorsal root ganglion.1 As pain is signalled through specific afferent nociceptive pathways, direct projections of these fibers activate: 1) the discriminative pain system (location, intensity and quality of stimulus); 2) the affective system (the unpleasantness of the stimulus); 3) the autonomic nervous system (sympathetics); 4) the motor system (nocifensor reflexes); and 5) the immune system.2

Approximately 50% of patients have been casted and CRPS is rarely seen following complete nerve transection.3 Harden and Bruehl applied factor analysis to 123 patients with CRPS who met International Association for the Study of Pain Criteria (IASP) and determined that signs and symptoms cluster into four distinct subgroups: 1) abnormalities in pain processing (allodynia, hyperalgesia and hyperpathia); 2) skin color and temperature changes (differential blood flow); 3) edema (neurogenic), vasomotor and sudomotor dysregulation; and 4) a motor syndrome.4

Incidence of CRPS

The incidence of CRPS after injuries varies in different studies, but the most recent representative population based study shows an incidence of 40.4 for females and 11.9 for males per 100,000 person years at risk.5 The female to male ratio is approximately 4:1; the average age at onset is between 37 to 64 years of age. Bone fractures, sprains, soft trauma and surgical procedures are the most common initiating events.6,7 After one year, most of the signs and symptoms are well established and only increase moderately with disease duration.8 There is an increase in many of the discriminative components of the McGill Pain Questionnaire but no change in affective pain measures. Dynamic and static mechanoallodynia, loss of surround inhibition, after discharge, cold allodynia, as well as skin color and temperature change, were prevalent within the first five years and significantly worsened over time. Neurogenic edema occurred in 75% of patients within one year and in 90% by 15 years. Hyperhidrosis was very variable and increased from 33% during the first five years to 44% after 15 years. The movement disorder—or at least one component of it (difficulty with initiation and maintenance of posture)—was seen in virtually all patients by five years. Other aspects of movement disorders in CRPS included weakness, tremor, spasms, dystonia, myoclonus and parietal-like kinesthetic deficits.9-11

Visceral pain occurred in 47% of patients during the first five years and was reported by 62% of patients at 15 years. Prominent other symptoms reported were difficulty sleeping (prolonged latency and multiple awakenings), cognitive dysfunction (decreased short term memory and dysexecutive syndrome), gastroparesis, difficulty swallowing (cricopharyngeus spasm), loss of voice (paralysis of posterior cricoarytenoid muscle), inability to initiate micturition, presyncope (vasodepressor), rash, pruritus, headache (migraine), and blurred vision.

Clinical Aspects of CRPS Pain and Related Neurochemistry

The pain of CRPS is spontaneous, burning, associated with a deep ache in muscles and joints, and often punctuated by lancinating jolts. It is often exacerbated by a dependent position and activity and may be relieved by rest and heat. It is out of proportion to the initial injury, does not respect a dermatome or root distribution, and spreads in characteristic patterns. It is often maintained by neuromas, poorly healed fractures, brachial plexus traction injuries and chronic root irritation.12-14 The extraterritoriality of the pain may be due to the products of Wallerian degeneration and inflammatory cells (cytokines) on commingled uninjured nerve afferents as well as failure of inhibition at the dorsal horn (DH) level.15,16 Activated microglia and astrocytes have been demonstrated segmentally at the level of injury (most prominently) as well as in a mirror distribution and throughout the spinal cord in an autopsied longstanding CRPS Patient.17 These nerve injury-activated microglia and astrocytes secrete the inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) in conjunction with nerve growth factor, which sensitize and discharge pain transmission primary neurons.18,19 Other important molecules of the ‘inflammatory soup’ at the site of injury that derive from the blood or invading immune cells are protons, prostaglandin E2, serotonin, bradykinin, epinephrin, lipoxygenase, brain-derived neurotrophic factor (BDNF), adenosine, neurotrophin 3, substance P and calcitonin gene-related peptide (CGRP). All of which induce peripheral nociceptive terminal membrane sensitization.2 These molecules activate intracellular phosphokinase A and C that phosphorylate tetrodotoxin (TTX) resistant sensory neuron specific (SNS) sodium ion channels that lowers their activation threshold and enhances their sodium current.20

The spontaneous pain suffered by CRPS patients may occur from discharge of nociceptive afferents, the cell bodies of injured dorsal root ganglion (DRG) neurons, as well as from low threshold mechanoreceptors in the injured nerve.21-23 Voltage-gated sodium channels, hyperpolarization-activated cyclic nucleotide-modulated channels (HCN), as well as voltage-gated potassium channel subfamily Q (KCNQ), all play a role in ectopic activity after nerve injury.24,25 A retrograde signal from the damaged nerve that involves Ras GTPase activates the transcriptional regulation of these ion channels in injured neurons.26

Molecular Basis of Activity-Dependent Neuroplasticity of Pain Transmission Neurons

Patients with CRPS have both enhanced and decreased sensation in areas of injury.7,27 These sensory abnormalities are a reflection of activity-dependent neuroplasticity and are similar to long term potentiation (LTP)—an increase in synaptic efficacy and long term depression (LTD) in which an afferent barrage is less effective in depolarizing a post synaptic neuron. These processes have been demonstrated in nociceptive neurons of pain models and are clinically relevant in patients.28-30 Post synaptic Ca2+ influx through the NMDA (N-methyl-D-aspartic acid) receptor of pain transition neurons (PTN) is critical for LTP induction after removal of its Mg2+ block by high frequency firing of mechano-heat insensitive C-fibers (i.e., the injury barrage). Blockade of the NMDA receptor with ketamine has cured severe longstanding CRPS patients.31-33

A major mechanism underlying LTP and LTD is the number, position, type and conductance of AMPA (A-amino-3hy-droxy-5methly-4isoxazolepropionate) re-ceptors at the post synaptic density (PSD) which opposes the afferent nociceptive axon. The induction and maintenance of LTP or LTD is dependent on the source (NMDA receptor; endoplasmic reticulum or voltage gated calcium channel) of the calcium concentration increase in the PTN.34 The greater the number of synaptic AMPA receptors, the more effective the transmission of the nociceptive barrage. Extra synaptic dispersal and internalization of AMPA receptors decreases synaptic transmission and causes LTD.15,35 LTP and LTD also are modified by increased transmitter release, dendritic, neuronal and post synaptic density structural alterations, activation of metabotropic glutamatergic receptors and nonspecific voltage-dependent cation complexes.36-38

A high frequency afferent barrage generated by mechano-heat insensitive C fibers, and maintained by sensitized peripheral nociceptors or unresolved nerve pathology, co-releases the neuroactive peptides substance P and calcitonin gene related peptide (CGRP). This causes temporal summation in DH nociceptive neurons that releases the Mg2+ block of the glutamatergic NMDA receptor. The subsequent increase of Ca2+ concentration activates multiple enzymatic cascades (CaMKII, serine and threonine kinases, phosphatases) which, if prolonged, in-duces the transcription of new proteins, ion channels, receptors and induces novel genes.15,38 Chronic pain results in structural change of the pain matrix. A dynamic interplay between the site of injury and DRG primary neurons is maintained by orthograde and retrograde axonal transport. Growth factors derived from immune cells at the site of injury modulate peripheral and central NMDA receptors, G-protein coupled receptors, synaptic transmitters and modulators, while new sodium channels are upregulated on primary nociceptive afferents in the DRG and damaged nociceptive afferents.2

Intrinsic plasticity, the probability that a post-synaptic neuron will be depolarized by a presynaptic input, is dependent on changes in the synthesis, insertion, density and functional properties of voltage-gated ion channels. Intrinsic plasticity of the PTN determines dendritic excitability and signal integration at the soma (i.e., its propensity to depolarize).39 These changes of excitability lend to plasticity of the firing mode of the PTN whereby a normally firing neuron is converted into a burst firing neuron that, when depolarized, fires a high frequency all or non-burst of action potentials. This plasticity of firing mode occurs in epilepsy, stress and pain models.40-42

Central Sensitization

The physiologic and clinical results of the above described processes lead to amplification of evoked pain and an increase in spontaneous pain. In the majority of patients it is secondary to facilitation of synaptic transmission in PTN43 in concert with disinhibition. Central sensitization is manifest by: 1) a lower threshold to fire PTNs; 2) an increase in their receptive field size; 3) dynamic tactile allodynia; and 4) secondary hypersensitivity. Presynaptic change in nociceptor afferents include: 1) an increase in the synthesis of neurotransmitters and neuromodulators as well as enlarged axons and pore release sites; 2) calcium channel density (necessary for the release of neurotransmitter).44,45 Prominent post-synaptic changes on PTNs are phosphorylation of the NMDA receptor that induces an increased Ca2+ concentration and increased post- synaptic AMPA density, as well as enhanced synthesis of ion channels and scaffold proteins in the post synaptic density.46,47 A lack of inhibition both at the DH level and from the descending nociceptive inhib-itory control system, as well as structural modifications and immune neural interaction, contribute to the hyperexcitability throughout the pain matrix that is the hallmark of central sensitization.2,43

“Most often the diagnosis is delayed. The source of the maintaining nociceptive barrage from traction injuries on plexi, recurrent disc disease, poorly healed fractures, neuromas is not addressed and treatment is not aggressive enough.”

Sympathetically-Maintained Pain

The anatomical and chemical connections between the sympathetic and nociceptive systems occur at the site of injury, the DRG and at almost all levels of the nervous system. Following peripheral nerve injury, sympathetic fibers that innervate blood vessels in the DRG sprout to form basket-like terminals around large DRG neurons (mechanoreceptors) and small PTNs (nociceptors). There is some evidence that high frequency firing of nociceptive afferents upregulate α2 adre-noreceptors on their axons. Experimental studies demonstrate: 1) adrenoreceptor activation of nociceptor afferents; 2) denervation adrenergic hypersensitivity of vascular smooth muscle; 3) adrenergic effects on nociceptor afferents sensitized by bradykinin, prostanoids, and neuro-trophic factors; 4) adrenal epinephrine that sensitizes mechanosensitive afferents and nociceptors.48,49 In conjunction with sympathetic nociceptive coupling in the periphery, descending adrenergic afferents are an important component of the DNIC (Difuse Noxious Inhibitory Con-trol) system that modifies pain transmission. There are multiple instances in which early sympathetic denervation has cured CRPS.50

Role of the Immune System in the Pain of CRPS

Chronic pain states and CRPS can result from interactions between the immune and nociceptive systems.51,52 Microglia and astrocytes are the primary immune competent cells in the CNS and are activated following nerve, tissue damage or inflammation. Activated glia have been shown to be both necessary and sufficient for enhanced nociception and their activation is an early feature of most neuroinflammatory disorders.53 Neurogenic inflammation and neuroimmune activation act in concert in persistent pain states and are a major component of CRPS.54-56

Activated glia and astrocytes secrete proinflammatory cytokines, nitric oxide, excitatory amino acids, prostaglandins and ATP.51,57 CRPS patients have elevated cerebrospinal fluid levels of proinflammatory cytokines as well as elevated glutamate and nitric oxide metabolites.58,59 We have shown in an autopsied patient with longstanding CRPS significant activation of both microglia and actrocytes as well as neural loss in the posterior horn (inhibitory neurons).17

Treatment of CRPS

At present, standard therapy for CRPS is limited. Most often the diagnosis is delayed. The source of the maintaining nociceptive barrage from traction injuries on plexi, recurrent disc disease, poorly healed fractures, neuromas is not addressed and treatment is not aggressive enough. Early sympathetic blockade is essential, while the patient is sympathetically maintained. The overwhelming majority of longstanding patients are sympathetically independent. After sympathetic blockade has been successful, patients require intense physical therapy to abrogate fear-avoidance of movement, block abnormalities of pain processing in the motor cortex, and perhaps stop the retrograde transport of neurotrophic factors that alter ion channels at the DRG and spinal levels.

The sympathetic drive from the injured area is important and an attempt to break it should be done early. The usual diagnostic mistakes are calling clear CRPS fibromyalgia (which I think is a combination of brachial plexus injury and spreading CRPS) and not realizing that the arm, shoulder, scapular and chest pain (intercosticobrachial nerve) is from the brachial plexus. The face pain seen in many patients is from the cervical plexus which derives from C2-C4. Most of these patients have suffered whiplash injuries from motor vehicle accidents or falls. The most important clinical clues to CRPS are the associated neurogenic edema, autonomic dysregulation and movement disorder. With time, the process spreads in characteristic patterns.

Avoidance of opioids as much as possible is helpful, as they are ineffective for CRPS, activate microglia that secrete proinflammatory cytokines, and induce sympathetic withdrawal. If an opioid is to be used, methadone at 10 mg t.i.d. is the best choice. Dorsal column stimulation for one extremity is often effective early but loses effectiveness with time. GABAb agonists (baclofen) are effective for severe dystonia, spasms and myoclonus but most often require intrathecal pump placement. At times, they also give pain relief.2 High doses of neurontin (900mg to 2400mg) as well as Cymbalta® give about 30% relief in early patients but are ineffective in those suffering for greater than one year. Sleep is a major problem for all CRPS patients and no medications are particularly helpful. Amitriptyline at doses of 75 to 100mg at times gives the advantage of sleep and pain relief.


Ketamine produces effective and long term pain relief in all stages of CRPS,32,60,61 Prior to patients receiving ketamine, they undergo EKG, 2-D ECHO and tilt table evaluation. They also undergo extensive neuropsychiatric evaluation. Patients with a schizoid profile, manic depressive illness or a history of drug abuse are excluded. The outpatient ketamine protocol con-sists of ten 4-hour infusions. Each patient has continuous blood pressure, pulse oxygenation and EKG monitoring during the course of the infusion.

Patients receive 2 mg of midazolam, 0.1 mg of clonidine and 200 mg of ketamine IV over 4 hours. At the end of the infusion, patients receive another 2 mg of midazolam. They are required to stay in the infusion suite for one hour after treatment and are taken home by a relative or friend. Patients are given 2 mg of Ativan® p.o., if needed for sleep or agitation. At the end of ten infusions, most patients (80%) attain 60-80% pain relief. They are given boosters at 2 weeks (200 mg of ketamine), one month and three months.

The protocol usually provides clinically significant relief for 3-6 months. More severe patients receive the inpatient protocol in which up to 40 mg of ketamine/hr is administered around the clock together with 2-6 mg of midazolam and 0.1 mg of clonidine over 5 days. This protocol is often effective for severe longstanding patients. During both the inpatient and outpatient protocols, opioids are tapered off or main-tained at as low a level as possible. Anesthetic doses, given in conjunction with large doses of midazolam have been dramatically effective in 50% of generalized severe longstanding patients that have failed all conventional therapies.32 Detailed psychologic testing in the first nine of these patients demonstrated no cognitive impairment.62


In a subset of CRPS patients who have failed subanesthetic ketamine protocols, intravenous lidocaine has been successful and provides long lasting relief.63 Lido-caine blocks the upregulation of tetro-dotoxin resistant sodium channels on primary nociceptive neurons and afferents that increases their excitability.64 System lidocaine selectively blocks these channels and inhibits their depolarization in a use-dependent manner.65 Lidocaine: 1) decreases allodynia without blocking nerve conduction; 2) decreases the discharge rate of injured nociceptive afferent fibers; and 4) suppresses tonic A-delta and C-fiber depolarization initiated by acute injury.66

Patients have detailed cardiac evaluations prior to therapy. Important cardiac complications are heart block and hypo-tension. Patients with known seizure disorders should be excluded. All patients are EKG and blood pressure monitored while systemic lidocaine is continuously titrated to a final dose of 5 mg/liter. Other side effects at high doses were dizziness and nausea. Lidocaine is most effective in decreasing mechanical and thermal allodynia but also decreases all components of CRPS for 3 months, on average, with a subset of patients responding spectacularly for 6 months.

The Future of CRPS Treatment

A great deal of progress has been made in understanding the pathophysiology of CRPS that will lead to further advances in treatment. Propentofylline, a phosphodiesterase inhibitor can block microglial activation. Thalidomide and its analog lenalidomide are both effective in approximately one-third of severe CRPS patients. Ifenprodil blocks the subunit NR2B of the NMDA receptor and may be more effective than ketamine. Blocking the peripheral afferent barrage with topical agents while decreasing central sensitization has yet to be employed.

Cryoneurolysis of neuromas that can now be identified with MRI and ultrasound will lead to more effective treatment of this common local pain generator. Many more molecularly-targeted drugs are on the horizon for the treatment of this difficult syndrome.2

Last updated on: January 28, 2012
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