Chapter 39. Complex Regional Pain Syndrome

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 periaquaductal gray matter of the midbrain (e.g., non-opioid analgesia).4,5 In contrast, rest and quiescence are represented in the ventrolateral periaquaductal 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 those 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, 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 suffered from 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 following 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, would influence 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. 39-1). 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.

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 regional application of guanethidine, bretylium, and systemic intravenous phentolamine.17–20

With regard to intravenous regional sympatholysis, placebo-controlled, double-blind studies have supported the use of this modality and method of inducing analgesia.21 Observations by Jänig and McLachlan,22 Blumberg and Jänig,23 Häbler and colleagues,24 Jänig and Koltzenburg,25 and Price and colleagues26 provide evidence in favor of a role for the sympathetic nervous system in the generation of pain in such patients. Likewise, Torebjörk and coworkers27 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, Roberts28 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) multi-receptive neurons, (lamina 5, dorsal horn), thereby maintain the status quo (Fig. 39-2). 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 Hallin29 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 following nerve injury (i.e., hyperalgesia was in this instance mediated by large, myelinated afferents).

Campbell and coworkers30 and Raja and coworkers31 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.32 However, studies by McLachlan33 in rats have demonstrated adrenergic sprouting at dorsal root ganglia within 2 weeks following 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 model34 of neuropathic pain (chronic constriction injury), 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 felt 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 an increased density of alpha-1 adrenoceptors are found in the epidermis of hyperalgesic skin of patients with CRPS.35

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,36 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 colleagues37 showed that hyperalgesia in association with SMP is mechanical (brush evoked) whereas 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 early stages of CRPS. The second study, by Schürmann and colleagues38 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.39 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 hypervigilence about their disease.40 In this regard positron emission tomographic studies reveal extensive cortical and subcortical activity in several neuropathic pain states.41 Rommel determined that in 24 patients with CRPS-1 were found to have hemisensory and motor impairment suggestive of supratentotial areas of central processing.42 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.43

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.”45 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 those 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, resulted in the development of a strict set of clinical descriptors to characterize features of these medical entities in order 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

Requirements for a New Taxonomy

• 1. 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.
• 2. A new taxonomy should improve the differential diagnosis from other medical entities that have features similar but not identical to those found in reflex sympathetic dystrophy.
• 3. A new taxonomy should suggest tests in support of a diagnosis of reflex sympathetic dystrophy.

New Taxonomy

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 following 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, which is evident as tremor, dystonia, or muscle weakness. 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 felt 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. It was agreed that experience with the new taxonomy may suggest a reappraisal and inclusion of staging in the future.

Although the epidemiology of CRPS has not been systematically studied, recent publications in relation to Colles fracture38 and statistics from Sweden (T. Gordh, 1998, personal communication) suggests a prevalence of about 10%. Also, a clinical study by Mailis and Wade51 concerning the development of CRPS types I and II in white women suggest genetically similar profiles, whereas Devor and Raber52 and Bhatia and colleagues,53 in two separate studies that demonstrated the predisposition for neuropathic pain behavior in genetically selected laboratory animals, provide support for this concept.

Motor symptoms and signs frequently are reported 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, although they are mentioned in the draft criteria of the taxonomy. Likewise, the response to sympathetic blockade is also removed from the taxonomy of CRPS types I and II but receives attention in the discussion of sympathetically maintained pain 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 lay 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 not associated with a particular injured nerve. Although these entities might be classified as a subset within the main definition, like 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 would, of necessity, satisfy the diagnostic criteria for CRPS.

Sympathetically Maintained Pain

SMP is defined as pain that is maintained by sympathetic efferent innervation or by circulating catecholamines.46 A positive response to sympatholysis (sympathetic block) historically was necessary before a diagnosis of CRPS could 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 following a positive response to sympatholysis can a diagnosis of CRPS be supported. The concept of sympathetically independent pain was introduced to explain those cases in which sympatholysis (either pharmacologic or nerve blockade) provides no pain relief. This concept4 is illustrated in Figure 39-3.

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 sympathetic blockade. This example illustrates the poor diagnostic specificity when sympathetic blockade 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.54–56 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 laminar-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. 39-4).

Musculoskeletal Disorders and Pain Dysfunction Syndromes

Those medical entities that do not satisfy specific diagnostic criteria for a specific condition are described in the International Classification of Diseases (ICD-9) 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)57 (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,58–61 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 hyper-responsiveness, associated headache, fatigue, sleeplessness, depression, and other subjective symptoms may occur in conjunction with CRPS or these musculoskeletal entities.61

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.

Differential Diagnosis

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 sympathetic dystrophy (see Fig. 38-3) 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 39-1 is a list of conditions that should be considered in the diagnosis of CRPS.

Motor dysfunction, although not an inclusion criterion of CRPS, is found sufficiently frequently for its mention in the classification. In fact, recent papers have all identified motor dysfunction as an independent and almost invariable finding.62–64 Dystonia, limitation of movement, and weakness must be carefully distinguished from a lack of voluntary effort or dystrophic changes in joint components.

The differential diagnosis of CRPS II can be distinguished from a nerve injury in which neurogenic inflammation is associated with pain and by symptoms that are out of proportion, as described in the new taxonomy. The additional criteria are edema, skin temperature, color changes, and sudomotor changes that also are out of proportion to those that would be found in association with a painful nerve injury. Although one or more of these signs and symptoms may dominate, all should be found at some time during the course of the disease. The pain, including allodynia and hyperalgesia, without vasomotor changes by itself would not satisfy the criteria for CRPS. Only rarely do patients present with all or most of the clinical features of CRPS, but without pain. Although the temporal course and response to treatment modalities may be identical with that of CRPS, the taxonomy requires that such patients should remain outside the CRPS umbrella.

A few patients with CRPS types I and II may have premorbid psychological or psychiatric disturbances, the occurrence of which does not exclude their primary diagnosis. Likewise, malingering and factitious disease are well-recognized clinical entities that are separate from a diagnosis of CRPS but must be included in the differential diagnosis. Conversion disorders and somatization, well recognized in association with chronic pain, have their own specific criteria and may occur independently or in association with CRPS types I and II.65 Occasionally, the diagnosis of these conditions is difficult and may only be determined after medical treatment is instituted. In the final analysis, pain that is neuropathic and out of proportion to that occurring as a symptom of many other medical conditions is required for a diagnosis of CRPS. SMP is neuropathic pain that is associated with many conditions; for example, postherpetic neuralgia, diabetic neuropathy, and most cases of CRPS types I and II early in the course of the disease.

Diagnostic Tests

Although no diagnostic tests specifically support a diagnosis of CRPS, a number of measurements and laboratory tests may contribute to the clinical diagnosis.

Temperature Measurement

Temperature change that is reflective of changes in the cutaneous blood flow66 may be measured by thermometry, telethermometry, passive infrared methods, or thermography. For these measurements to have any relevance, they should also be taken on corresponding sites or areas of the contralateral extremity. At least 1.5°C is required for the difference to be significant. Thermography in conjunction with cold physiologic stress testing of an unaffected independent extremity is a useful test of autonomic function in the ipsilateral extremity. This test should be undertaken only in a thermostable, and preferably comfortable—about 22°C—environment. Either the failure to respond to cold stress or the delay in rewarming, particularly when the contralateral temperature side differences are 1.5°C or greater, does this test indicate dysfunction of the autonomic nervous system.

Caution is necessary when interpreting temperature changes as has been demonstrated by Wasner, et al.32 When whole-body temperature changes were induced, three distinct vascular patterns were identified, namely inhibition of cutaneous sympathetic vasoconstrictor neurons as characterized by a warmer affected limb early in the disease. In chronic CRPS, sympathetic vasoconstrictor neurons are still inhibited, but secondary changes in neurovascular transmission caused the skin changes to remain cold, and an intermediate change characterizes the dynamic vascular abnormalities that depend on the specific activity of sympathetic vasoconstrictor neurons at the time. These authors noted that the maximal difference in skin temperature during induced thermo-regulatory changes is a reliable means of distinguishing CRPS from other extremity pain syndromes.67

Peripheral Blood Flow

This measurement may be made by laser Doppler flowmetry. As already mentioned, Schürmann and colleagues have clearly demonstrated that this test is an early predictor of sympathetic dysfunction and, therefore, supportive of a diagnosis of CRPS.38,39

Quantitative Sweat Testing

The quantitative sudomotor axon reflex test (QSART) is another clinical laboratory test that focuses on abnormalities of evoked sweat production. Taken together with the resting sweat output (RSO) and alteration in vasomotor activity, QSART provides a good laboratory correlation with the clinical features of CRPS.66,68

Quantitative Sensory Testing

This test is a useful evaluation of vibratory, thermal, and cold responses that, although not specific for CRPS, may contribute to the clinical picture and support a differential diagnosis of CRPS.69

Sympathetic Skin Response

This response may be used to identify increased conductance when comparing the ipsilateral with the contralateral extremity.55

Bone Scan

Three-phase bone scintigraphy with technetium diphosphonate usually demonstrates a reduction in flow during the early phase of CRPS but increased periarticular uptake during the third phase. Sensitivity is approximately 60%, and specificity of 86% has been claimed, but many reports describe 30% false-positive and 30% false-negative responses.70

Muscle Strength and Joint Testing

The measurement of muscle strength depends on patient cooperation, psychological factors, and pain. Nevertheless, grip strength with thumb adduction and opposition, along with pinch testing and goniometry, may be important measurements both as baseline and as prognostic indicators. Joint mobility, including range of motion (ROM), although subjective, may be obtained most reliably by a therapist who works frequently with orthopedic patients.

Psychological Tests

The most useful instruments for psychological testing are the Beck Depression Inventory and the McGill Pain Questionnaire.

Physical Therapeutic Algorithm

If early diagnosis is crucial to the institution of an appropriate treatment plan, incorporating a graduated and stepwise approach to treatment using modalities that experience has shown to be most effective is a natural corollary.

Until a mechanism for CRPS is established, functional restoration using physiotherapeutic methods is regarded as essential to providing a remission in most cases. Three requirements are necessary if physical therapy is to be successful.

• 1. Pain control
• 2. “Turning off” the disturbance
• 3. Development of patient rapport and confidence in the requirements of a treatment program

Depending on the complexity or fulminant nature of the disease in a particular patient, it may be necessary to increase the proposed time for each step in the physical therapeutic algorithm.71 This point is arbitrary and serves two purposes: (1) to prevent the patient who, because of symptoms, may no longer progress with a particular treatment modality, and (2) to reassess the disease process and introduce measures of symptom control that will permit exercise therapy to continue.

Initially, it is important to gain rapport with the patient so that he or she will develop confidence in the planned investment of effort and time using the various therapeutic modalities that will be necessary, in most cases, to achieve a remission. Once each patient buys into this approach, the business of motivation, mobilization, and desensitization are introduced. It is important at each step to rapidly achieve increments of symptomatic improvement using non-narcotic or narcotic analgesics,72 while at the same time addressing the disturbances of sleep, anxiety, depression, and motor dysfunction.73,74 Some patients with recent onset of CRPS may respond well with a reduction in pain to anticonvulsants or antiarrhythmic medications.75–79 Unacceptable side effects, together with the length of time (3 to 4 weeks) to realize any efficacy, may preclude their use. Further deterioration in functional integrity, failure to improve, or an increase in symptoms should trigger the use of a therapeutic and prognostic sympathetic block.

Figure 39-5 is an updated clinical pathway illustrating the main domains of rehabilitation, pain management and psychological treatment that are fundamental to regaining function and, ultimately, a remission of CRPS.67,120 The new clinical pathway (guideline) emphasizes an intra-disciplinary, time-contingent guidance that incorporates the recently published treatment options. These are addressed simultaneously and will vary according to the patient’s response to treatment. Important to the use of this clinical guideline is the recommendation to use whichever treatment modality, when a patient fails to respond to whatever level of treatment after 12–16 weeks. The clinical pathway focuses on quality of life, as well as function.

A word should be said about joint movement, and particularly ROM, in patients with these syndromes. Orthopedic experience in particular has shown that the use of aggressive or passive ROM, or both, may be deleterious for progress or worse, because mechanoreceptor stimulation in the joint structures can cause a dramatic worsening of both pain and the inflammatory response.80 This is evident by immediate increase in edema, allodynia or hyperalgesia, and hyperpathia.

The technique of so-called stress loading with isometric exercises and gentle ROM has been found most effective.80 It may be necessary to use cognitive behavioral methods to assist the patient against pain avoidance, kinesophobia, bracing, and overprotection, all of which may develop in a patient in whom previously inappropriate exercise therapy may have been employed.81–83 Treatment of the nociceptive and neuropathic generators is required using the following pharmacologic, regional anesthetic, and neuromodulation techniques. In fact, a combination or sequence of these modalities may, in some cases, be required to ultimately achieve a return of function.

Pharmacologic Management

The following section summarizes drugs that have been found useful in the treatment of CRPS. Although none is specific for the disease, each has a place in managing an aspect of the clinical presentation.

Nonsteroidal Anti-Inflammatory Drugs

These agents are most successful in the treatment of early or very late CRPS types I or II. Their use should be tempered by the development of gastrointestinal or renal side effects.71 If one member is without effect, then others with a better side effect profile should be chosen. It may also be worth using one of the cyclooxygenase-2 (COX-2) agents. Topical use of these drugs has also been suggested. It should be remembered that these agents have a tendency to cause water retention, with edema, a side effect that may interfere with rehabilitation.

Opioids

Although opioids are more effective in the treatment of nociceptive pain, they have a place in treatment of pain of a neuropathic nature.72 If tolerated by the patient, the use of slow-release opioids on a round-the-clock basis is preferable to as-needed dosing. The side effects of one class of opioid do not preclude use of another class. It is important to remember that abrupt discontinuation of opioids may lead to an extreme exacerbation of a patient’s symptoms, as well as other signs and symptoms of withdrawal. It should be noted that there is a greater acceptance in the use of opioids for neuropathic pain, such as CRPS.

Anticonvulsants and Antiarrhythmics

Agents generally classified as so-called membrane stabilizers include anticonvulsants, local anesthetics, and antiarrythmic agents. Drugs that are the most effective for neuropathic pain are carbamazepine, gabapentin, lamotrigine, phenytoin, and valproic acid.75–79 Recent studies with gabapentin, a selective voltage-gated Na2+ channel blocker, have demonstrated some efficacy in the treatment of CRPS pain. The oral antiarrhythmic lidocaine analogue, mexiletine, may prove quite effective in a small but significant number of patients with CRPS.78 The drug has been found effective in the treatment of diabetic neuropathy in a dose of 10 mg/kg. An intravenous bolus and infusion of lidocaine can be used to predict the response to oral analogues.84 In addition, transdermal lidocaine, which has been shown to be quite effective in the treatment of postherpetic neuralgia, can in some patients reduce the touch-evoked allodynia of CRPS.85 The conotoxin SNX-111 (Ziconitide), infused intrathecally, may be successful in the treatment of long-standing CRPS that has proved refractory to all other treatment.86

Tricyclic Antidepressants

The serotonin and norepinephrine reuptake blocking agents, amitriptyline, desipramine, maprotiline, have all demonstrated efficacy in the treatment of neuropathic pain syndromes, including CRPS.87–89 These agents are much more effective than the selective serotonin reuptake inhibitors (SSRIs), suggesting that it is the catecholaminergic aspect of the former three agents that is therapeutic. These agents are also particularly useful in providing sedation and reducing nocturnal symptoms. They should, therefore, be prescribed for use at night.

Adrenergic Drugs

The α1-adrenoceptor blocking agents (terazosin, prazocin, and phenoxybenzamine) may be strikingly effective in patients with SMP.90 They do, however, have a poor side effect profile—with tachycardia, chest pain, gastric symptoms, and, in some cases, sedation that preclude their use. However more than 30% of patients with SMP respond dramatically to these agents. The α2 agonist, clonidine, is most effective when introduced by the epidural or intrathecal route of administration.91 It may be tried topically and, in some cases, it may be dramatically effective when applied to a discrete area of hyperalgesia.92,93

Corticosteroids

Corticosteroids have been successful in the treatment of early CRPS when the acute inflammatory response may be most pronounced.94,95 It is during this phase that intraosseous plasma extravasation can be demonstrated scintigraphically by labeled immunoglobulins. It should be noted that corticosteroids are most successful when sympathetic blocks are completely effective in relieving the continuous pain.

Regional Anesthesia

Regional anesthetic techniques have two purposes: firstly, the relief of symptoms otherwise not controlled by pharmacologic means; and secondly, the demonstration of pain that is sympathetically maintained (SMP).31,66 Traditionally, this approach has been used in the treatment of CRPS involving both the upper or lower extremities. Significantly, when used early in the course of the disease, pain relief that is either partial or complete, depending on the degree of SMP, may be realized. Blocks of the sympathetic nervous system interrupt efferent vasomotor, sudomotor, and visceromotor fibers as well as visceral afferents, somatic afferents, and nociceptor fibers.

For sympatholysis in the upper extremity, the paratracheal technique of stellate ganglion block at the level of C6, with the development of Horner’s syndrome (myosis, ptosis, and enopthalmos), has been a standard approach for many years. However, as has been pointed out by many authors, including Bonica, Kuntz, and others, the anatomic position of the stellate ganglion anterior to the costovertebral articulation and neck of the first rib makes it more amenable to block at the lower portion of the C7 vertebral body.96–98 In addition, the local anesthetic has a greater chance of diffusing on the longus colli muscle to reach the T2 through T4 ganglia, thereby providing a more effective sympathetic blockade to the upper extremity. Signs of a successful sympathetic block include a temperature rise to 35°C, measured at the finger pulp. Supplementary tests of sympathetic function are the sympathetic skin response using a modified electrocardiogram and cold pressor test to demonstrate that this response has been disabled when a noneffected extremity is placed in ice-cold water. Laser Doppler flowmetry is an excellent noninvasive measurement of changes in skin blood flow, the loss of which is clearly evident.

In the same manner, lumbar sympathetic blockade can be realized using a single needle under fluoroscopic guidance at the lower third of the body of L3.99 The correct anatomic site is clearly demonstrated by the flow of radiocontrast in the gutter formed by the fascia overlying the psoas muscle and its continuation as the periosteum overlying the vertebral bodies of L2 through L4. Verification of effective sympatholysis can be demonstrated by using one of the previously described measurements.

If sympathetic blockade completely eliminates the patient’s symptoms, consideration should be given to effecting a prolonged block by neurolysis, using either an agent such as phenol, which may be prepared with radiocontrast material (e.g., Meglumine [Conray 420, Malingkrodt, St. Louis, Mo.]) or radiofrequency lesions.100 A duration of effect lasting up to 6 months may be achieved by these methods. Demonstration of SMP by sympathetic blockade also should trigger the use of an α-adrenoceptor blocker, such as terazosin. A good pharmacologic response with these agents may preclude further sympathetic blockade, which in any case should be discontinued if the symptomatic relief fails to outlast the duration of local anesthesia.

Mixed conduction block of peripheral nerves or the brachial or lumbar plexus, or in the form of a central neural block, are useful alternatives to the use of sympatholysis. They should be employed only when analgesia by pharmacologic means is insufficient to support exercise therapy. Although intermittent blocks are helpful to initiate therapy, in some cases it is necessary to use continuous conduction analgesia.101 A catheter implanted in the brachial or lumbosacral plexus allows infusions for 1 to 2 weeks but is subject to technical failure or infection when used for longer periods. The epidural route with a tunneled catheter offers the greatest utility and enables the long-term administration of local anesthetics and adjuncts for many months. This facilitates exercise therapy,102,103 although technical failure with dislodgment, breakage, and infection, mostly at the skin entry site and less frequently in the deeper tissues, will require removal, treatment, and replacement of the catheter.

A word of caution with regard to implanted catheters is in order. Because these devices may be used for long durations, they should be treated as minor surgical procedures and can only successfully achieve their purpose if placement is made under strict asepsis using fluoroscopic guidance to ensure that the epidural infusion is ipsilateral, or if the contralateral extremity is also involved, that bilateral spread can be assured.

In a few cases, a long-acting local anesthetic such as bupivacaine or ropivacaine may be sufficient to provide analgesia commensurate with exercise therapy. However, it is frequently necessary to add an opiate, such as fentanyl, or other agents, including morphine, hydromorphone, sufentanil, or buprenorphine, to achieve a sufficient level of “working” analgesia. Occasionally, it may be necessary to consider the use of an α2-adrenoceptor agonist, clonidine, when hyperalgesia or allodynia prevent effective physical therapy. A short, 2- to 5-day hospital admission is required to determine the clinically most effective infusion in each case.

From this account, it should be clear to the reader that where once regional anesthetic techniques such as sympathetic blockade were necessary to support a diagnosis of CRPS, their conventional application is primarily to determine pain that is modified by sympathetic block (SMP) and as a means of supporting exercise therapy and other treatment modalities that will ensure the return of function.

Neuromodulation

Neuromodulation incorporating either spinal cord stimulation or peripheral nerve stimulation aims to change or modify function of the central or peripheral nervous systems. Although neuromodulation has been in use since its introduction by Shealy104 in 1967, it is the past 10 years that have seen such a dramatic increase in its use for the treatment of neuropathic and vasculopathic pain.105–108 Although the posterior columns were thought to be the primary target for spinal cord stimulation, stimulation of the descending inhibitory pathways and the dorsal root fibers are now recognized as being equally important for modulating nociception.109

Computer modeling of spinal cord stimulation has helped to determine the putative clinical response that could be achieved by electrode geometry and the ratio of dorsal column to dorsal root fibers.110 The pain in CRPS tends to be more global than dermatomal, and electrodes that have a longitudinal and central disposition tend to have greater spatial selectivity and are likely to be more efficient in providing pain relief to the affected extremity.

If, as has already been mentioned, CRPS is a neurologic disease, it should be amenable to treatment by neurostimulation. Perhaps one of the best indications for either spinal cord or peripheral nerve stimulation is injury to a peripheral nerve. Similarly, CRPS with its altered cutaneous sensibility, tactile allodynia to cold, and mechanical stimuli, is also likely to respond well to spinal cord stimulation. The autonomic effects of spinal cord stimulation, with improvement in both the micro- and macrocirculation in the stimulated region, appear to be a result of preganglionic modification of the autonomic nervous system function.111

Although there have only been two prospective studies describing the successful use of neuromodulation in the treatment of pain resulting from CRPS, a number of clinical retrospective case studies support use of the modality.112,113 Functional restoration is central to the treatment of CRPS, and adequate relief of pain and correction of the autonomic disturbance positions this modality well among other modalities in achieving this end.

Because time is of the essence in the treatment of CRPS, any failure to progress through the therapeutic algorithm, must be regarded as a trigger to introduce regional anesthetic or neuromodulatory methods to support progressive rehabilitation. The temporal introduction of the different treatment modalities must be seen only as a guide, and their order does not constitute priority (see Figure 39-5).

For patients with CRPS of either the upper or lower extremities, a single quadrapolar or octapolar lead is most effective. In cases where bilateral stimulation is required, it may be necessary to employ two electrodes to ensure adequate paresthesias (coverage) in both extremities. For CRPS II, selection of a peripheral nerve stimulator is more likely to provide stable and specific control of symptoms relative to the injured nerve.

All patients considered suitable for neuromodulation must first satisfy behavioral criteria and undergo a structured psychological examination.71,114 Self-report tests such as the Beck Disability Inventory and McGill Pain Questionnaire are suitable instruments.

It can be concluded that for cases characterized by failure to progress through the physiotherapeutic algorithm or an exacerbation of the patient’s symptoms, a trial of spinal cord stimulation may prove to be a most effective tool when other modalities have failed.

Psychological Aspects

Most studies in patients with CRPS have failed to show any correlation with a preexisting psychological disorder.115,116 However, a significant percentage of these patients develop behavioral abnormalities and require psychological support during treatment. Not uncommonly, 6 months into their disease, patients demonstrate varying degrees of depression manifested by disturbed sleep, anxiety, and despair that their disease is not improving. Measures such as biofeedback, relaxation, temperature control, and reduction in muscle tension are indicated. Group therapy, in which a spouse or family member is present, is sometimes helpful for CRPS patients, as for other patients with chronic pain. Use of a single antidepressant, particularly a tricyclic such as amitriptyline, is preferable to a combination of different antidepressants or the newer SSRIs.

Complex Regional Pain Syndrome in Children

It can be categorically stated that CRPS in children, particularly before puberty, and in adolescence, is a different disease from that in the adult.117,118 Although the same signs and symptoms constituting the clinical entity are present, the course of the disease and its response to treatment suggest early behavioral and psychological aspects that may require special skills in cognitive management. Because of their dependence on parents, children exhibit more behavioral aspects reflecting problems of enmeshment and bizarre responses to the slightest degree of family dysfunction.119 In fact, in many cases one sees a parallel in the adult with a conversion disorder.

Usually, children do not require the use of interventions and will respond appropriately to pharmacologic measures and good psychological support.120 Physical therapy should be presented either as a challenge or as a game, with goals being set to win and overcome the disability. Transcutaneous electrical nerve stimulation often provides sufficient analgesia (in over half the patients) to allow for their participation in physical therapy.120 It is preferable to avoid invasive therapies; however, a lumbar sympathetic block or an epidural catheter should not be withheld if there is failure to progress in exercise therapy or the disease process has remained refractory to conservative treatment. In rare cases, it may actually be necessary to use a spinal cord, or even peripheral nerve, stimulator, which in either case may be subsequently removed once the disease process is in remission. In principle, at least 60% of children will respond well to physical therapeutic measures and pharmacologic therapy, but almost all require strong support with these, or whichever additional psychological measures are used, to gain confidence in and increase compliance with their therapy.

CRPS is a disease, the pathophysiology and mechanism of which remain unknown. The disease is complex and generally commences in a particular region of the body, usually the distal aspect of an extremity. Sometimes it occurs in other parts of the body, and it may also spread to other areas. Pain is the sine qua non of CRPS but, in rare cases, may actually be minimal or absent. The diagnosis is one of exclusion after having eliminated, in the differential diagnosis, those other conditions for which the pathophysiology is well categorized. The treatment plan should be orderly, and one that uses a structured physiotherapeutic approach facilitated by pharmacologic, interventional, and behavioral components. Time is of the essence, and any delay or failure to progress with exercise therapy after 2 to 3 weeks of treatment should prompt the introduction of modalities that at the time seem most appropriate and more likely to facilitate therapy and achieve a remission. It frequently is necessary to make continuous adjustments in physical therapy commensurate with the clinical response. Such therapy, in each case, must be individualized to be successful.