Ever since Claude Bernard implicated the sympathetic nervous system in sensation, its role in nociception has been the subject of debate.1 No one would argue with the fact that the sympathetic nervous system is intimately involved with the preservation of homeostasis and noxious challenges in humans, although the manner in which it influences the sensation of pain has, until recently, escaped explanation.2 Anatomically, the sympathetic nervous system constitutes a highly complex arrangement of preganglionic and postganglionic neurons that subserve specific and diverse functions of target organs, including enteric neurons, smooth muscle, syncytial muscle, and striated muscle.3 Physiologically, the sympathetic nervous system is associated in some way with both systemic and specific local reactions, which are expressed by supratentorial and confrontational aspects that are represented in the periaqueductal gray matter of the midbrain (e.g., nonopioid analgesia).4,5 In contrast, rest and quiescence are represented in the ventrolateral periaqueductal gray matter, being associated with endogenous opioid analgesia.
The stress response described by Selye,6 “fight or flight,” involves both spinal levels of integration, with hypothalamo-mesencephalic centers, but is associated with adrenocortical and hypothalamo-hypophyseal responses designed to protect the organism under normal biologic conditions. A secondary set of responses to sympathetic activity that can be considered pathophysiologic and occur with or without obvious nerve injury are changes in blood flow, sudomotor and muscle activity, with subsequent trophic changes and abnormal sensation long after the noxious event.7,8 Sensory changes include allodynia, hypoalgesia, hyperalgesia, hyperesthesia, and hyperpathia. Why, and in what manner, the sympathetic nervous system is involved in these changes that occur in a small but readily identifiable group of patients is still unclear. However, recent research has clarified some of the previous misconceptions with regard to levels of sympathetic activity, involvement of the central nervous system (CNS), and the possibility of preexisting immunologic factors. Interestingly, similarities in the characteristics of complex regional pain syndrome (CRPS) are seen in other chronic pain states, such as irritable bowel syndrome, interstitial cystitis, nonulcer dyspepsia, and certain cases of angina pectoris.
During the Civil War, Weir Mitchell9 drew attention to the exaggerated response to nerve injury that was distinct from the neurogenic inflammation that is associated with most nerve injuries. These patients typically sustained a penetrating injury in the vicinity of a major nerve, in most cases without disruption, and typically caused by a musket shot. Mitchell called this causalgia because of the bizarre swelling, heat (causa), and pain (algia), which were out of all proportion to the signs and symptoms of most nerve injuries. Leriche,10 a French surgeon, also described similar syndromes in the lower extremities for which he developed the surgical procedure of stripping the sympathetic nervous plexus from the large vessels in the lower extremities. Sudeck, in a series of articles, provided similar descriptions with detailed observations of the bony and trophic changes after injury that came to be described in German-speaking countries as “morbus Sudeck” or “Sudeck’s atrophy.”11
Perhaps Livingston, more than any other individual, influenced contemporary thinking with regard to these CRPSs. Livingston12 proposed the concept of a vicious circle that involved the spinal cord at the level of sensory interneurons, which are maintained in a state of abnormal repetitive firing from the periphery (Fig. 48-1). In other words, Livingston proposed that a linkage existed between afferent nociception, and the efferent responses generated by spinal neurons in some manner contributed to an exaggeration of the nociceptive signals in the local injured tissue. This so-called sympathosomatic coupling suggested the genesis of a reflex mechanism that was fundamental to these disorders.
FIGURE 48-1.
Figure illustrates the concept of a vicious circle involving the spinal cord both at the level of the sensory disturbance and the temporal and spatial expansion that was proposed by Livingston in 1943. (Used with permission from Livingston WK. Pain Mechanisms: A Physiological Interpretation of Causalgia and Its related States. New York: Plenum; 1976.)
Obviously influenced by Livingston’s thinking, Evans13 coined the term reflex sympathetic dystrophy in a single stroke implying a mechanism that had not yet been scientifically validated. It is interesting to note that Lewis,14 also a contemporary, made the suggestion that secretory dysfunction might be responsible for the dystrophic changes and atrophy that are seen in integumentary structures, although he did not specifically imply that there was a disturbance of autonomic function. He suggested that the nocifensor nerves actually became irritated in causalgic states, thereby potentiating the clinical process.
Experiments by Walker and Nulsen,15 who were interested in autonomic physiology, determined that stimulation of the sympathetic trunk in patients who had undergone a thoracic sympathectomy for causalgia elicited burning and tingling paresthesias in the affected extremity. Twenty years later, these observations were confirmed by White and Sweet,16 who contended that a sympathetically dependent mechanism is responsible for the disturbance that is seen in patients with causalgia and reflex sympathetic dystrophy. Other clinical observations that support a role of the sympathetic nervous system in pain are the relief that frequently attends interruption of the paravertebral ganglia with local anesthetics, chemical or physical modalities, and surgery, as well as intravenous (IV) regional application of guanethidine, bretylium, and systemic IV phentolamine.17–20
Observations by Jänig and McLachlan,21 Blumberg and Jänig,22 Häbler and colleagues,23 Jänig and Koltzenburg,24 and Price and colleagues25 provide evidence in favor of a role for the sympathetic nervous system in the generation of pain in such patients. Likewise, Torebjörk and coworkers26 have demonstrated that α-adrenoceptor agonists that are applied by injection or iontophoresis in a previously affected extremity rekindle symptoms in patients who had been in remission for periods exceeding 15 years. Similar responses have been elicited by injection of epinephrine into a chronic neuroma.
In 1986, Roberts27 introduced the concept of sympathetically maintained pain (SMP), which he postulated accompanies CRPS at some point in the natural history of the condition. His suggestion that low-threshold mechanoreceptors types I and II (Aβ fibers) are induced by postganglionic sympathetic activity that, in turn, induces chronic firing in wide-dynamic-range (WDR) multireceptive neurons (lamina 5, dorsal horn), thereby maintain the status quo (Fig. 48-2). The hypothesis is supported by animal experiments that demonstrate an activation of mechanoreceptors by sympathetic postganglionic sympathetic efferents. Although there is a qualitative difference from the proposal by Livingston12 some 40 years earlier, there are striking parallels between the two hypotheses. Indeed, Torebjörk and Hallin28 were unable to demonstrate any lowering of nociceptor mechanical threshold nor the relief of pain by C-fiber block but did demonstrate analgesia by pressure (differential) ischemic block induced by tourniquet in patients who exhibited hyperalgesia after nerve injury (i.e., hyperalgesia was in this instance mediated by large, myelinated afferents).
FIGURE 48-2.
This figure illustrates the hypothesis of Roberts, introduced in 1986, to explain the phenomenon of sympathetically maintained pain (SMP). (A) Initiation of C-nociceptor response to injury with excitation of the wide-dynamic-range (WDR) neurons and spinothalamic transmission. (B) WDR neurons now become sensitized to activity in large-diameter A-mechanoreceptors, which respond to light touch (allodynia). (C) Increased WDR response to A-mechanoreceptor activity resulting from sympathetic efferent action at the nociceptor. Note: This last phase represents SMP and requires no further cutaneous stimulation. DRG, dorsal root ganglion; CPN, C-polymodal nociceptor; SG, sympathetic ganglion. (Used with permission from Torebjork HE, Wahren LK, Wallin G, et al. Noradrenalin-evoked pain in neuralgia. Pain. 1995;63:11-20.)
Campbell and coworkers29 and Raja and coworkers30 believe that the genesis of SMP results from an expression of additional α1-adrenoreceptors on primary afferent nociceptors that, in turn, are stimulated by postganglionic sympathetic efferents (i.e., physiologic and not a result of sympathetic dysfunction). This theory would imply a peripheral and not central cause for the clinical syndrome.
In fact, the studies already referred to by Torebjörk, using microneurography in the 1970s, and an analysis of catecholamine levels in affected extremities have never reflected any increase in sympathetic activity. To the contrary, in many cases, sympathetic activity in patients with CRPS was actually found to be less than normal.31 However, studies by McLachlan and colleagues32 in rats have demonstrated adrenergic sprouting at dorsal root ganglia within 2 weeks after complete sciatic nerve transection, suggesting functional adrenergic change in response to injury. These investigators were able to demonstrate evoked activity in primary sensory neurons that were blocked by α-receptor antagonists when the postganglionic sympathetic fibers were stimulated. Using the Chung model33 of neuropathic pain (spinal nerve ligation), they found accelerated sympathetic sprouting at the dorsal root ganglion of segmental nerves within 4 days of this injury. They noted a reduction in mechanosensory threshold that preceded changes in the thermal threshold. These authors believed that the more rapid manifestation of changes in the sympathetic nervous system could be attributed to the influence of nerve growth factor expressed by the damaged axon. Drummond et al. had produced evidence that increased density of α1-adrenoceptors are found in the epidermis of hyperalgesic skin of patients with CRPS.34
All of the foregoing observations do not support the previously held opinion that sympathetic hyperactivity is necessary to explain the clinical features of CRPS. In fact, an alternate theory, and one whose origins go back to Sudeck, suggests that local inflammatory mediators with changes in vascular hydrostatic pressure resulting from dorsal root reflexes may amplify inflammatory responses and pain in the periphery. Wall,35 in a recent editorial, has drawn attention to the current understanding of neuropathic pain mechanisms and relationship, if it exists and in what manner, by which the sympathetic nervous system might be involved. Two recent important communications underscore a possible central origin for the expression of CRPS, whether of clinical nerve injury or tissue damage. Sieweke and colleagues36 showed that hyperalgesia in association with SMP is mechanical (brush evoked), but thermal hyperalgesia is not present. This finding, together with the ineffectiveness of acetylsalicylic acid in treatment, strongly supports a major central component that contributes to pain, at least in the late stages of CRPS. The second study, by Schürmann and colleagues37 using laser Doppler flowmetry found that a loss of the normal sympathetic control of the microcirculation in an ipsilateral extremity of patients with CRPS was also a systemic-wide phenomenon, a finding that strongly supports a central foundation for CRPS. In fact, this study corroborates earlier observations by Schwartzman and McClellen.38 Although predisposing psychological characteristics have not found support in numerous studies, there has been some suggestion that patients who developed CRPS may acquire an excessive preoccupation with or hypervigilance about their disease.39 In this regard, positron emission tomographic studies reveal extensive cortical and subcortical activity in several neuropathic pain states.40 Rommel and colleagues determined that 24 patients with CRPS-1 were found to have hemisensory and motor impairment suggestive of supratentorial areas of central processing.41 Likewise, it has not been possible to distinguish between the protective response behavior that occurs in association with these diseases as being merely a response to the excessive pain or an abnormal psychological response that is seen only in patients with these syndromes.42
In sum, the pathophysiology of CRPS remains unclear; however, recent advances in both preclinical and clinical research, particularly, research in genetics and in biochemical as well as biophysical changes in the peripheral nervous system (PNS) and CNS, help to enrich our understanding that multiple mechanisms might be involved in the pathogenesis of CRPS. Currently, it is widely accepted that there are three concepts that define the pathogenesis of CRPS, namely, neurogenic inflammation, abnormal efferent sympathetic and afferent sensory nerve coupling, and neuroplasticity of the CNS.43 Additionally, it is believed that genetic factors might be involved in the pathogenesis of CRPS based on a small number of studies.
The foundations for a new taxonomy had their origins in a meeting that was held in 1988 at Schloss-Rettershof, Germany.44 A consensus statement describing reflex sympathetic dystrophy in the following terms was presented at a meeting of the Special Interest Group (SIG), Pain and the Sympathetic Nervous System of the International Association for the Study of Pain (IASP) at the Sixth World Congress on Pain in Adelaide, Australia, in 1990. This statement read:
Reflex Sympathetic Dystrophy is a descriptive term meaning a complex disorder or group of disorders that may develop as a consequence of trauma affecting the limbs, with or without an obvious nerve lesion. RSD may also develop after visceral disease, central nervous system lesions, or rarely without an obvious antecedent event. RSD consists of pain and sensory abnormalities, abnormal blood flow, decreased or increased sweating, abnormalities of the motor system, and changes in the structure of both superficial and deep tissues (trophic changes). It is not necessary that all components be present. The name “Reflex Sympathetic Dystrophy” is used in a descriptive sense and does not imply any specific underlying mechanisms.5
As would be expected, making a change in concepts that had been introduced to characterize certain aspects of reflex sympathetic dystrophy and causalgia such as SMP and sympathetically independent pain tended to complicate rather than improve the level of understanding, at least by practitioners of whichever discipline who are faced with the diagnosis and treatment of these syndromes.
In November, 1993, under the auspices of the SIG, Pain and the Sympathetic Nervous System, another closed workshop convened in association with the annual scientific meeting of the American Pain Society in Orlando, resulting in the development of a strict set of clinical descriptors to characterize features of these medical entities to distinguish them from other diseases, the mechanism for which, or their pathophysiology, is well known. These recommendations were made to the Committee on Taxonomy of Chronic Pain Conditions of the International Association for the Study of Pain and formed the basis for the term complex regional pain syndromes that was published in the second edition of the Classification of Chronic Pain: Description of Chronic Pain Syndromes and Definition of Pain Terms, published by the IASP Press in 1994.46,47
Any new taxonomy for reflex sympathetic dystrophy should suggest areas of basic research and development of animal models that identify how the sympathetic nervous system is involved and should promote clinical investigation or corroborate hypotheses born out of the basic research.
A new taxonomy should improve the differential diagnosis from other medical entities that have features that are similar but not identical to those found in reflex sympathetic dystrophy.
A new taxonomy should suggest tests in support of a diagnosis of reflex sympathetic dystrophy.
The term complex regional pain syndrome was chosen to replace the former terminology of reflex sympathetic dystrophy and causalgia.47 Acknowledging that at the time, no mechanism was available to explain the clinical features of these disorders and using a linguistic convention adopted by the Subcommittee on Taxonomy for inclusion in the classification of chronic pain, the term allows for the later inclusion of a variety of painful conditions that may occur after injury. These conditions are manifested regionally, mostly in an extremity, predominantly distal, and with findings that exceed in magnitude and duration the expected course after such an inciting event. The taxonomy also acknowledges that in some cases, these disorders may occur on the trunk or face and spread to other body areas. Frequently, there is impairment of motor function (especially as the disease progresses), which is evident as tremor, weakness, dystonia, or muscle atrophy. Because a temporal sequence is variable, the terms complex and regional were used to distinguish this from other syndromes. The taxonomy emphasizes that the clinical features tend to commence in the distal part of an extremity and tend to extend proximally, involving the musculature of the shoulder or pelvic girdles, respectively, but in a small percentage of cases, the syndrome may emanate proximally.
The order of classifying these conditions was changed, with the term CRPS type I (RSD) being the generic disease and CRPS type II (causalgia) being applied to conditions in which there is obvious nerve injury. The previous listing in the first edition of the IASP classification was historical in deference to the description by Mitchell.9 Causalgia is well described by both Richards48 and Bonica49 and requires no elaboration here.
The terminology for CRPS types I and II acknowledges that both spontaneous and touch-evoked (allodynia or hyperalgesia) pain may be concurrent in the affected region. Pain of either nature is regarded as a cardinal symptom in these medical disorders, although in rare cases, pain in association with all other clinical features that satisfy the diagnosis may be absent.
In patients who do not fulfill the criteria for a diagnosis of CRPS type I or II, allowance was made in the taxonomy for a third type of CRPS, not otherwise specified (NOS). With this instrument, the taxonomy encourages the clinician to identify specific types or subgroups of CRPS types I and II. For example, one patient group may meet all the criteria specified for CRPS type I but uniformly have in addition another specific symptom or clinical finding. The temporal course of their disease process follows a uniformly different course or their response differs from that of the main type I group, in which case the classification could be changed to include this as a specific subgroup within the main CRPS type I group. Bonica50 introduced the concept of staging, which he believed was important to the description of these diseases, but experience has questioned the utility of this in diagnosis or treatment and, as a consequence, it was eliminated from the taxonomy. As a result of internal and external validation studies, a statistically derived revision of CRPS criteria was achieved. For research purposes, the criteria were tightened to achieve a sensitivity of 0.70 and specificity of 0.96. In 2004 at a closed-consensus workshop in Budapest, the foregoing criteria were codified and formally adopted by the IASP Committee for Classification of Chronic Pain in 2012, to be subsequently included as the “Budapest criteria” in the next revision of the Taxonomy of Chronic Pain Terms.51
The epidemiology of CRPS has now been systematically studied in one prospective and two retrospective studies.52–54 The earlier publications in relation to Colles fracture38 and statistics from Sweden (T. Gordh, 1998, personal communication) suggest a prevalence of about 10%. Also, a clinical study by Mailis and Wade55 concerning the development of CRPS types I and II in white women suggests genetically similar profiles, but Devor and Raber56 and Bhatia and colleagues,57 in two separate studies, demonstrated the predisposition for neuropathic pain behavior in genetically selected laboratory animals, providing support for this concept.
Motor symptoms and signs are frequently reported (>75%) in patients with CRPS types I and II. During preparation of the new taxonomy, a lack of scientific evidence in support of this being a specific movement disorder resulted in the exclusion of these findings from the standard clinical criteria, but they are now formally a part of the “Budapest criteria.”54 Likewise, the response to sympathetic blockade (SNB) is also removed from the taxonomy of CRPS types I and II but receives attention in the discussion of SMP and other neuralgias.
Specific exclusion criteria for the definition of CRPS types I and II were necessary to prevent the inclusion of other clinical entities and syndromes in which the findings are consistent with a particular injury but resemble those of CRPS types I and II. One example might be a patient who met the criteria for causalgia but whose signs and symptoms lie outside of the territory of the injured nerve. If the clinical findings were to occur within the regional territory of that nerve, however, they would then satisfy inclusion criteria under this definition. Another exception might be a patient in whom the clinical findings are localized to the trunk or face but are not associated with a particular injured nerve. Although these entities might be classified as a subset within the main definition, similar to the primary classification, they must have signs and symptoms that are completely disproportionate in both nature and severity to the injury.
Signs of vasomotor instability may not be present at the time of clinical examination. However, a patient history of swelling, sweating, color, and temperature changes, if presenting with motor weakness and dystrophic features, would, of necessity, satisfy the new diagnostic criteria for CRPS.
Sympathetically maintained pain is defined as pain that is maintained by sympathetic efferent innervation or by circulating catecholamines.46 A positive response to sympatholysis (sympathetic block) historically is necessary before a diagnosis of CRPS can be made. Given the current ignorance of the manner in which the sympathetic nervous system is involved in the pathophysiology of these conditions and the contradictory literature in this regard, it has been necessary to abandon the convention that only after a positive response to sympatholysis can a diagnosis of CRPS be made. The concept of sympathetically independent pain was introduced to explain cases in which sympatholysis (either pharmacologic or nerve blockade) provides no pain relief. This concept4 is illustrated in Figure 48-3.
FIGURE 48-3.
Illustration of the relative contribution of sympathetically maintained pain (SMP) to overall pain. Whereas the symbolic patient A would demonstrate maximum response to sympatholysis (i.e., demonstrating a large component of SMP), patient B would have almost no response to sympathetic block, therefore exhibiting sympathetically independent pain. It should be noted that points A and B may also represent the same patients at different times in the course of these patients’ diseases.
In this figure, a symbolic patient (A) may be seen at one time in the course of his or her disease in which most of the patient’s pain is sympathetically maintained (i.e., it responds to sympatholysis) but temporarily becomes less responsive to blockade and ultimately is composed mostly of sympathetically independent pain. Similarly, A and B may be two separate patients who, at the time of their physical examination, exhibit these distinguishing characteristics of pain by their response to SNB. This example illustrates the poor diagnostic specificity when SNB is used for this purpose and is the reason for which a positive response to sympathetic block is no longer regarded as being necessary for a diagnosis of CRPS to be sustained.
However, the response to sympatholysis may contribute to other clinical signs and symptoms that support the diagnostic criteria for CRPS. This and other tests, including temperature measurement, sudomotor function, skin blood flow, and skin resistance, have been developed to assess sympathetic activity.58–60 The hypothesis for SMP already discussed may be as important to treatment as it is to diagnosis. The sensitization of C-polymodal nociceptors and sensitization of WDR neurons in lamina-5 fibers of the dorsal horn may, as a response to sympatholysis, subside but can only be regarded as a contributory phenomenon or symptom in CRPS or, for that matter, in many other conditions (Fig. 48-4).
FIGURE 48-4.
Revised therapeutic pathway with emphasis on the therapeutic modalities that are used in response to the patient’s clinical progress in the rehabilitation algorithm. Adapted from the 1998 guidelines. (Used with permission from Swerdlow M. Anticonvulsants in the therapy of neuralgia pain. Pain Clin. 1986;1:9-19.)
Those medical entities that do not satisfy specific diagnostic criteria for a specific condition are described in the International Classification of Diseases (ICD-10) as NOS codes. The diagnostic criteria for CRPS types I and II use a similar device. As an example, pain in a limb without the other characteristics of CRPS is defined as limb pain, NOS type III. The IASP classification of chronic limb pain conditions provides a code for such instances: X1.19 pain in the limbs, NOS: upper limb (S) 2XX. XXZ, and lower limb (S) 6XX. XXZ. Pain in the hand (musculoskeletal disorder) that does not meet the criteria for CRPS might be diagnosed as pain dysfunction syndrome (a nonstandard classification)61 (see the discussion of differential diagnosis later in this chapter). Several medical conditions that have been described using nonstandard terminology, including cumulative trauma disorder, repetitive strain injury, overuse syndrome, and tennis elbow,62–65 are included under the umbrella term pain dysfunction syndrome. The International Coding Diseases Manual classification of such conditions is musculoskeletal disorders, which includes a large number of diseases and syndromes such as carpal tunnel syndrome. Many of these conditions that are associated with mechanical hyperalgesia, pain that is out of the ordinary, temperature changes, and myofascial pain syndrome might be considered as CRPS type III. However, the differential diagnosis, depending on tenderness and hyperalgesia that is found specifically over a particular muscle group or epicondylar region, would favor occupational overuse, bursitis, a nerve entrapment, or tennis elbow, for example. Often a long antecedent history of fibromyalgia with hyperresponsiveness, associated headache, fatigue, sleeplessness, depression, and other subjective symptoms may occur in conjunction with CRPS or these musculoskeletal entities.65
It also should not be forgotten that the specialty of the physician may influence the primary or secondary diagnosis, particularly its differential, if sufficiently stringent criteria do not satisfy a diagnosis of CRPS.
Many medical entities have characteristics that are similar to the clinical features of CRPS. Although many of these conditions are frequently found in the distal part of an extremity, they must be distinguished from other musculoskeletal and neuropathic pain conditions. As already discussed, their clinical presentation may suggest SMP; however, its interpretation, at least early in the course of the disease, must be circumspect. Pain relief after sympatholysis is not specific for reflex CRPS (see Fig. 48-3) but may merely reflect an altered response to physiologic sympathetic activity.
Patients with myofascial dysfunction, a frequent accompaniment, may present with regional temperature differences and mechanical hyperalgesia yet still not satisfy all of the criteria for a diagnosis of CRPS. The broad group of musculoskeletal disorders that have been described as pain dysfunction syndromes may have some clinical signs and symptoms but are insufficient in number or character to satisfy a diagnosis of CRPS. Table 48-1 is a list of conditions that should be considered in the diagnosis of CRPS.
Conditions to Be Considered in the Differential Diagnosis of Complex Regional Pain Syndrome
Musculoskeletal disorders |
Pain dysfunction syndrome |
Cumulative trauma disorder |
Repetitive strain injury |
Overuse syndrome |
Tennis elbow |
Shoulder–hand syndrome |
Nonspecific thoracic outlet syndrome |
Fibromyalgia |
Posttraumatic vasoconstriction |
Undetected fracture |
Peripheral vascular disease |
Myofascial pain dysfunction (MFD), a frequent association with CRPS, must be distinguished from primary MFD that may have been present before the onset of CRPS. Because of its prevalence, its recognition is essential not only as a diagnostic sign but also as a target for therapy.66–68 Dystonia, limitation of movement, and weakness must be carefully distinguished from a lack of voluntary effort or dystrophic changes in joint components.