Deconstructing Complex Regional Pain Syndrome
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