Complex Regional Pain Syndrome History and Nomenclature

Complex regional pain syndrome (CRPS) is the newer nomenclature encompassing the clinical entities of reflex sympathetic dystrophy (RSD) and causalgia. It is characterized by intractable pain usually affecting one or more extremities. Even though it was originally described over a hundred years ago, much debate lingers over the clinical and basic pathophysiological characteristics of this condition. Named as causalgia (from Greek, kausos [heat], algos [pain]), it was initially described in 1864 during the American Civil War by Silas Weir Mitchell from the observation of soldiers developing chronic pain following traumatic nerve injuries. Since its original description, it has been given a number of different names such as algodystrophy, posttraumatic dystrophy, sympathetic-maintained pain syndrome, hand-shoulder syndrome, Sudeck atrophy, and other names. Early in the twentieth century Paul Sudeck described a syndrome with predominantly trophic symptoms that developed following distal bone fractures not affecting directly peripheral nerves. Patients experiencing Sudeck syndrome obtained significant pain relief by sympathetic block, thus suggesting at the time a central role for the autonomic nervous system in the pathophysiology of the condition. An articulation of the belief in a central role of sympathetic system was the term reflex sympathetic dystrophy (RSD) , coined by Evans in 1946 to label all syndromes characterized by excessive chronic pain following injury, responsive to sympathetic blocks and as such driven by the sympathetic system. As understanding of the condition evolved, it was clear that sympatholytic interventions and sympathetically maintained pain (SMP) were not specific to RSD but common in other neuropathic pain disorders. In addition, dystrophic changes were not always observed, and there was no evidence that the condition was a reflex. As such, a working group of the International Association for the Study of Pain (IASP) developed a consensus definition in 1994 and proposed a new terminology reflecting a more accurate description of the condition. The term CRPS type I replaces RSD; the term CRPS type II , which requires demonstrable peripheral nerve injury, replaces the term causalgia . Various diagnostic tests have been proposed (without much success) to confirm the diagnosis of CRPS, including among others radiological studies, triple-phase bone scans, quantitative sensory testing, quantitative sudomotor axon reflex test (QSART), and limb thermography with or without sympathetic block. However, diagnosis of CRPS remains a clinical process relying mostly on history and potentially on physical examination. The current IASP diagnostic criteria define CRPS type I as a syndrome that usually develops following a trauma, fracture, surgery, or immobilization, with pain that is disproportionate to the inciting event in a regional/nondermatome pattern (not limited to the distribution of a single peripheral nerve or nerve root). CRPS II requires the same set of descriptive criteria; however, an identifiable nerve injury is required for diagnosis. Although these diagnostic criteria had a high sensitivity (98%), their specificity was poor (36%), resulting in a correct diagnosis in as few as 40% of patients. The lack of an objective test that serves as a gold standard for diagnosis has led to extensive efforts to validate a set of bedside diagnostic criteria to improve the accuracy of CRPS diagnosis. The new proposed diagnostic criteria ( Box 9-1 ) do not imply at all the pathogenesis of the disease; however, they supply a set of descriptive signs and symptoms that are adequately sensitive and specific in diagnosing CRPS ( Table 9-1 ). The same set of criteria would be applied with varied stringency, depending on the intent, and thus defined as research criteria or clinical diagnostic criteria. These newer criteria have not yet been ratified by the taxonomy committee of the IASP and will undergo further validation studies before full adoption.

Patient Demographics and Risk Factors

There are only two population-based epidemiological studies of CRPS in the general population. One reported the population-based incidence rate in North America, and the other in Europe (Netherlands). The reported incidence rates are different; the U.S. study reporting an incidence of 5.6 per 100,000 person-years; the more recent European study reported a rate of 26.2. The inclusion criteria for both studies were different, which could be one of the factors accounting for varying results. CRPS affects females more than males at a ratio almost 4 : 1, and the majority of CRPS cases in females occur in the postmenopausal stage of life, suggesting a potential hormonal etiological role in CRPS. The observed mean age of diagnosis in these studies of CRPS is 50 to 70 years old with a mean of 52.7 years old. This age peak is higher than is generally expected and observed in some nonpopulation-based investigations. Before the mid-1980s there were only scattered case reports of RSD in children. However, over the last 10 to 15 years it has become apparent that CRPS does occur in children, with a mean age of onset of about 12.5 years (range 3 to 18 years), particularly following sports injuries.

No single causative factor has been found that explains the development of this complex disorder, but an inciting event often precedes the onset of CRPS. Initial observations correlated CRPS with wounds and crushing limb injuries. Fractures are the most common trigger, wrist fractures in particular. Cast immobilization appears to be another condition associated with development of CRPS. During cast immobilization increased pressure and early complaints of tightness are predictive risk factors for the onset of CRPS. On the other hand, CRPS cases developing as a consequence of remote processes such as stroke, spinal cord injury, and myocardial infarction have been reported. The risk for developing CRPS may depend on susceptibility to exaggerated responses, probably through genetic predisposition to basic pain-related mechanisms such as inflammation and sensitization. This has led to a search for gene polymorphisms that could predict development of CRPS. In a study from Herlyn and colleagues a single nucleotide polymorphism within the α-adrenoceptor appears to be a risk factor for the development of CRPS I after distal radius fracture. Polymorphisms in the human leukocyte antigen (HLA) system have been studied, and loci from all three HLA classes reportedly have been associated with CRPS onset. Studies on co-occurrence of disorders such as migraine, osteoporosis, menstrual cycle–related problems, and neuropathies with CRPS can potentially give clues to shared etiologic factors and reveal risk factors.

Complex Regional Pain Syndrome Pathophysiology

The pathophysiology of CRPS is not fully understood; however, based on animal and human studies several hypothesized mechanisms appear to play an important role. In the acute (early) stage as described by Veldman and associates CRPS presents with skin discoloration, edema, increased nail or hair growth, temperature difference, limited movement, or reported sweating. Traditional sequential staging of CRPS into acute inflammatory, subacute dystrophic, and chronic atrophic stages has been largely supplanted by classifying the condition based on limb appearance and warmth. Thus CRPS has been more recently subdivided into a “warm and a cold form.” The difference in temperature between affected and unaffected extremities has led to the use of thermography, albeit with low specificity for either diagnosis or prognosis. Symptoms such as edema, trophic changes, sweating, and vasomotor-related changes have been considered signs of autonomic system dysregulation (sympathetic); pain responding favorably to sympathetic blocks is considered sympathetically maintained pain (SMP). However, the role of the sympathetic system in CRPS has been debated since the vasomotor instability can be explained by other mechanisms such as abnormal sensitivity of adrenergic receptors to normal sympathetic outflow. Moreover, α-adrenoceptors appear to be overexpressed in hyperalgesic skin from CRPS-affected limbs. The reverse hypothesis of diminished sympathetic stimulation has been postulated as an underlying cause of adrenergic receptor up-regulation and sensitization in CRPS patients. A generally acknowledged view today is that SMP and sympathetic dysregulation can be important but not obligatory components of CRPS.

Aseptic neuroinflammation may be a mechanism that is active early in the establishment of CRPS. Trauma-related events could lead to activation and sensitization of primary neuronal afferents to cytokines and neuropeptides released in the affected body region, mainly substance P (SP) and calcitonin gene-related peptide (CGRP). Evidence of a neuroinflammatory process is also obvious from analysis of fluid derived from artificially produced blisters on CRPS-affected extremities. Analysis of blister fluid with a multiplex array testing for 25 different cytokines revealed a strong proinflammatory expression profile, with increased markers for activated monocytes and macrophages. Recently neuropeptide Y and angiotensin-converting enzyme (ACE) have been also suggested as potential modulators of neuroinflammatory responses. Despite the commonly found increase in proinflammatory cytokines in human studies, there is a lack of correlation between cytokine expression and severity and duration of CRPS, suggesting that neuroinflammation is only partly involved in the pathophysiology of CRPS.

Pain and hyperalgesia are the predominant symptoms in CRPS. Persistent peripheral nociceptive input in CRPS results in spinal cord central sensitization with features of mechanical hyperalgesia and allodynia. A hallmark of central sensitization is spreading of hyperalgesia, which goes far beyond the initial site of injury. This expansion of nociceptive receptive fields occurs as a result of neuroplasticity changes in the central nervous system (CNS) between the dorsal horn (DH) of the spinal cord and the somatosensory cortex. At the spinal level DH central pain-projecting neurons are pathologically activated by N- methyl- d -aspartate (NMDA) receptor–mediated processes, which leads to hyperexcitability and central sensitization. Furthermore, changes in central representation of somatosensory input in the thalamus and cortex have been found by various studies. This cortical reorganization correlates linearly with the amount of CRPS pain and is reversed following pain relief as confirmed by magnetoencephalography (MEG) studies.

Recently the hypothesis of progressive small-fiber degeneration as the basis for CRPS has gained some ground. This has primarily resulted from the work of Oaklander and Fields. Oaklander and colleagues demonstrated for the first time through a morphometric analysis performed on skin biopsies that CRPS I is associated with small-fiber axonal degeneration.

Since CRPS is a heterogeneous disorder, multiple mechanisms, including inflammatory and neuropathic, are likely involved in complex interactions, resulting in this chronic painful and potentially debilitating disorder.

Management of Complex Regional Pain Syndrome

A number of treatment approaches are available for CRPS. These approaches can be categorized as pharmacological, interventional, physical/occupational therapy, and psychological techniques. Physical therapy is the first-line and the mainstay treatment for CRPS. However, it is often limited by the pain itself, and pain-control interventions are often essential to enable full patient participation. Interventional approaches are very useful and are applied usually in combination with pharmacological measures to enhance patient compliance with physical therapy (PT). Various sympathetic blocks, intravenous regional blocks, and epidural blocks can be provided on an outpatient basis. However, the response to sympathetic blocks varies and appears to be more effective than placebo in duration but not magnitude of pain relief. In general, pharmacological pain treatment is similar to that of managing neuropathic pain and would include antidepressants (particularly tricyclics and serotonin-noradrenalin reuptake inhibitors), antiepileptics (e.g., gabapentin), and occasionally muscle relaxants and topical analgesics. Opioids may have a limited role in refractory CRPS patients. Steroids, given their anti-inflammatory function, may be effective in improving inflammatory signs, especially early on. Antioxidants and free radical scavengers may be effective given that hypoxic phenomena in the affected limb can enhance the production of free radicals. In the Netherlands free radical scavengers such as dimethylsulfoxide (DMSO) and N -acetylcysteine (NAC) are widely applied in the treatment of CRPS. Bisphosphonates have shown promise to significantly improve symptoms of CRPS in randomized clinical trials. By reducing local acceleration of bone remodeling, bisphosphonates may alleviate pain by effects on nociceptive primary afferents in bone. Psychological treatment in CRPS involves cognitive behavioral techniques and biofeedback and relaxation training. Even though there are no studies to support its use in CRPS, in the general chronic pain population psychological treatment is an effective treatment modality, and it may be used in CRPS to improve coping skills and facilitate rehabilitation.

Electrical Neurostimulation for Complex Regional Pain Syndrome

The idea of electrical stimulation for pain control was based on the initial description of the gate control theory by Melzak and Wall whereby electrical stimulation of Aβ (A beta) fibers in dorsal columns would result in closing the “gate” and obliterating onward central transmission from peripheral nociceptors (C fibers). Varying methods of neurostimulation have been developed, depending on target tissue. In CRPS there is solid evidence for effectiveness of spinal cord stimulation (SCS) and to a lesser extent for peripheral nerve stimulation (PNS) and motor cortex stimulation (MCS).

Spinal Cord Stimulation for Complex Regional Pain Syndrome

Dorsal column electrical stimulation or SCS has been applied to a variety of pain disorders. The mechanism of action of SCS is described elsewhere in this volume. However, focusing on CRPS, SCS theoretically could act on various pathogenetic mechanisms such as (a) direct inhibitory actions on central sensitization mechanisms, (b) restoration and sustainability of blood flow (microcirculation) to the affected extremity by increasing the release of vasoactive mediators such as CGRP and SP, and (c) decreasing sympathetic output by antidromic effects. Even though there are no firm data to support these hypotheses, some recent animal data and clinical observation are emerging that could indicate how SCS could influence various biological functions in CRPS.

Evidence of Spinal Cord Stimulation Effectiveness in Complex Regional Pain Syndrome

A plethora of reports supports the use of SCS in treating neuropathic pain conditions in general and CRPS in particular. Of note, the Neuromodulation Therapy Access Coalition found substantial evidence to recommend the use of SCS for treatment of CRPS. However, as of early 2010, literature search reveals only one SCS randomized controlled trial (RCT), three prospective long-term trials ( Table 9-2 ), and 12 retrospective studies and multiple case reports and case series.

Table 9-2

Summary of Prospective Studies on Spinal Cord Stimulation for Complex Regional Pain Syndromes

Study Type (Reference Authors)	No. of Patients Enrolled	Indication	Length of Study (Follow-up)	Devices Used	SCS Outcomes/Complication Rate
RCT SCS + PT vs. PT (2 : 1 randomization; intent to treat analysis)
Kemler et al , 2000	54 (24 implants)		6 months		Significant improvement of VAS score (3.6 mm) compared with 0.2 cm increase of control; significant improvement in HQOL Nottingham Health Profile; complication rate 25% at 6 months (most caused by unsatisfactory position of the electrodes)
Kemler et al , 2002 (follow-up)	51 (24 implants)	CRPS I (duration ≈40 months)	24 months	Medtronic electrodes; IPG	Significant improvements in SCS+PT group in pain intensity and global perceived effect; no improvement in functional status; HQOL improved only in SCS group; 2-year complication rate 38%
Kemler et al , 2008 (follow-up)	44 (20 implants)		60 months		Pain score not significantly different; patient satisfaction significantly higher with SCS; no difference in QOL measures; 5-year complication rate 42% (Two explants)
Prospective studies (nonrandomized)
Harke et al 2005, SMP	29	SMP CRPS I (RSD) (median duration 3 years)	35.6 months (mean)	Medtronic quadripolar leads; IPG	VAS significantly improved; excellent improvement in allodynia and deep pain; significant improvement in PDI and grip strength (functionality of the limb); excellent improvement in analgesic consumption; psychological screening; generator changes in 16/29 caused by exhaustion
Oakley et al , 1999	16	CRPS I (average duration 7.5 months)	7.9 months	Medtronic Pisces-Quad or Quad Plus four contacts; IPG/RG	VAS, QOL measures (sickness impact profile) all significantly improved; BDI trending toward significance; rate of revision 4/19 (lead adjustment or receiver change; one patient accounted for 50% of revisions)
Clavillo et al , 1998 SIP	36 (implants; 24 SCS; 7 SCS+PNS; 5 PNS)	CRPS I CRPS II	36 months	Medtronic Pisces II/IPG	Significant improvement in pain intensity; significant decrease in narcotic intake; significant improvement of QOL and 41% return-to-work rate; psychological screening; SIP is an inclusion criterion

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