AS THE NAME INFERS, COMPLEX REGIONAL PAIN syndrome (CRPS) is a multifarious, painful condition that most commonly affects an extremity following a noxious event. Management of this complicated disorder is typically challenging, as the pathogenesis and natural history of CRPS are incompletely characterized, and a multifaceted biopsychosocial process is invariably involved. Subsequently, an interdisciplinary treatment approach among qualified specialists is mandatory to thoroughly address all aspects of this disease. A coordinated approach targeting biomedical and psychosocial rehabilitation has been shown to augment outcomes. This chapter will review the diagnostic criteria and pathogenesis of CRPS and focus on the multimodal, evidence-based treatments shown to optimize functional restoration.

CRPS is a chronic and often disabling neuropathic pain syndrome that presents with classic neuropathic pain symptoms in conjunction with a combination of vasomotor effects, including skin color and temperature changes, tissue edema, sensory allodynia or hyperalgesia, decreased range of motion, and motor dysfunction. CRPS manifests itself in two primary forms with the vastly more common subtype CRPS type 1 (formerly known as reflex sympathetic dystrophy) diagnosed without any obvious or known neuronal injury. The much less common CRPS type 2 (formerly known as causalgia) is associated with an identified nerve lesion. CRPS is usually preceded by trauma, with the most common culprits being fractures, sprains, crush injuries, and surgery. Insults including stroke, myocardial infarction, injections, and spinal cord injuries are much less commonly the cause. Occasionally in CRPS type 1, the patient is unable to identify the initiating trauma. CRPS type 2 is usually caused by nerve injury during a procedure such as during an injection or neuronal transection.^1,2 Ultimately the signs and symptoms of both CRPS subtypes are nearly indistinguishable, and there is no evidence that they differ in pathophysiology and even treatment.

Determination of the true incidence of CRPS has been hindered by the absence of definitive diagnostic tests. Two retrospective studies using the 1994 International Association for the Study of Pain (IASP) criteria have demonstrated an incidence of 5 per 100,000 person-years for CRPS type I and 0.8 per 100,000 person-years for CRPS type II. However, the more recently established Budapest criteria have been shown to decrease the diagnostic incidence by 50%. Additionally, the National Order for Rare Disorders has distinguished CRPS as a “rare” disease, which reflects less than 200,000 cases in the United States. Population-based studies do demonstrate a higher preponderance in females with a 4:1 ratio compared to men and a peak incidence at 50 to 70 years of age. There appears to be an increased propensity for involvement of the upper limbs with a ratio of 3:2 compared to the lower limbs in adults. Risk factors for this condition include individuals with a history of migraine, osteoporosis, asthma, and angiotensin-converting enzyme (ACE) inhibitor therapy and individuals with an elevated intracast pressure or extreme extremity positions. Pediatric population reviews show a mean onset of around 12 years of age with 75% involving females and a history of trauma in about 70% of adolescent patients. Nevertheless, exclusionary diagnostic criteria continue to obscure reliable statistics in this rare condition.^3,4

Complex regional pain syndrome manifests as regional pain, allodynia, hyperalgesia, swelling, vasomotor and sudomotor abnormalities, motor impairment, and trophic changes. Typically, patients present after minor trauma or surgery with the injured limb feeling very painful, erythematous, swollen, and temperature change (warm or cold).

Occasionally, no specific event can be identified as the cause of the pain. Pain, sensory, autonomic, and other symptoms usually start in a single limb (upper more often than lower extremities) but can also begin in two limbs simultaneously or in other areas of the body. These symptoms usually develop distal to the site of the injury but can travel proximally. The severity and nature of the pain do not correlate with the severity of the trauma. Onset of symptoms typically occurs within a few days to a month after the initial injury, but some patients will have immediate onset of symptoms. CRPS occurs mainly in adults but has been reported in patients as young as 2.5 years of age. Common clinical manifestations in children include a cool extremity, lower limbs affected more frequently than upper limbs, and neurologic and sympathetic symptoms are less pronounced. CRPS can vary from self-limiting to a chronic disease that is debilitating, and remission with relapse can commonly occur.^1–6

The pain associated with CRPS is out of proportion in intensity and duration to the initial trauma. It is also not limited to a single nerve territory. The pain can be continuous or episodic and can often be caused by physical or emotional stimuli. Type 1 patients often complain of dull, aching, or tearing sensations. Type 2 patients often complain of burning pain, although this can also be seen in type 1 CRPS. Patients with either type of CRPS will typically have increased sensitivity to painful and often non-noxious stimuli. Sensory disturbances can be confined to a glove or stocking distribution in the affected extremity. The area of pain tends to extend to the whole extremity or further in those with longer disease duration. As the disease progresses, negative sensory signs such as hypoesthesia, hypoalgesia, and hypothermesthesia can develop.^1,2 Autonomic disturbances can include warm, erythematous, and swollen extremities in 90% of patients, whereas the other 10% can present with a cold extremity. Edema is seen in most patients, regardless of skin temperature, but the severity decreases as the disease progresses. There is no standardized definition as to what constitutes a temperature deviation between extremities, but a commonly used number is ≥1°C. Many adult and pediatric patients experience sudomotor disturbances such as hyperhidrosis or hypohidrosis. Vasomotor and sudomotor symptoms tend to be most common in the early stages of the disease and have the greatest likelihood of resolving. Trophic changes can be manifested as thin skin, changes in nail growth, brittle nails, and atrophy of muscle and bones^1,2 (Fig. 36–1).

Nearly all patients with both CRPS 1 and 2 will have some motor disturbance, which is typically weakness or limited range of motion. Reflexes tend to be exaggerated but can also be diminished. They also tend to be less accurate and slower in executing specific movements. Studies have shown varied frequencies of abnormal movements such as dystonia, spasms, and postural tremors. However, these motor symptoms tend to persist in the long term in those who experience them.^2,3 With time, the disease can significantly decrease strength and range of motion in the affected limb, subsequently decreasing function (Fig. 36–2).

CRPS is often informally categorized into “warm” or “cold,” although both subtypes can be seen in any stage of patients. “Warm CRPS” is typically associated with the acute phase of CRPS and is manifested with a warm, erythematous, and edematous extremity. A prospective study of proinflammatory cytokines suggests the inflammatory response underlying warm CRPS largely resolves within 12 months of onset in patients actively receiving treatment. Alternatively, “cold CRPS” typically reflects the more chronic phase of CRPS and presents with a cool, mottled extremity, and the long-term prognosis may not be as favorable.⁴ As mentioned, reports suggest that CRPS can spread to alternative extremities in a significant proportion of cases. A large systemic study (n = 185) suggests that contralateral spread is most commonly followed by ipsilateral spread, usually developing over 18 months following onset of symptoms. All four limbs were affected in more than 29% of cases. Although mechanisms of spreading are not well understood, Van Rijn and colleagues’ results indicated a significant proportion of cases of spreading CRPS occurred in the context of a second trauma.⁷ Although the natural history of CRPS remains poorly understood, existing evidence supports a high rate of spontaneous resolution (26 of 30) in patients with post-traumatic CRPS.⁸ Further, Sandroni et al found that 74% of CRPS cases diagnosed with the 1994 IASP criteria resolved with conservative modalities.⁹

Despite attempts to simplify CRPS to a single pathophysiological mechanism, it is arguably a multifactorial disorder that involves complex interactions between peripheral, central, and autonomic nervous systems in an individual with strong genetic and psychological inclinations that predispose the patient to develop CRPS.

Peripheral Nervous System

Local peripheral inflammation surrounding the initial tissue trauma is critical to the development of CRPS. Nociceptive neuropeptides such as substance P, bradykinin, neuropeptide Y, and calcitonin gene-related peptide (CGRP) are released after local tissue injury and cause vasodilation, warmth, redness, and local tissue swelling. ACE inhibitors, which alter the metabolism of bradykinin, have been associated with the development of CRPS. Despite the fact that local inflammatory mediators are increased, CRPS is not associated with the classical systemic markers of inflammation such as C-reactive protein. Furthermore, there is no elevation of leukocytes in serum and very few leukocytes in tissue biopsies obtained from CRPS patients. Collectively, there is a decreased firing threshold to thermal and mechanical stimuli that leads to allodynia and release of growth factors that contribute to skin thickening. Peripheral sensitization occurs via activation of intracellular phosphokinases A and C along with phosphorylation of tetrodotoxin-resistant, sensory-specific sodium ion channels on afferent nociceptors. This process along with central sensitization gives rise to local hyperalgesia with significantly reduced acute pain thresholds compared to the unaffected extremity.^2,10,11

Central Nervous System

The combination of the intensity and persistence of noxious excitability related to damaged tissue or injured nerve translates to alterations in nociceptive neurons throughout the spinal cord and has the potential to manifest into central sensitization. Repetitive stimulation of afferent neurons causes morphological and physiological changes in the spinal cord, and such changes in the central nervous system contribute to hyperalgesia with exaggerated responses to nociceptive stimuli and allodynia where usually nonpainful stimuli activate nociceptive pathways. Continuous release of neurotransmitters in the dorsal horn cause atrophic changes and a decrease in inhibitory neurons that culminate in both an excessive and inappropriate stimulation for a given stimulus. Maintenance of central sensitization of nociceptive neurons could be driven in part by the sympathetic nervous system, as pain relief commonly outlasts the duration of sympathetic blockade. Patients with CRPS also display significantly greater wind-up or increased excitability of the spinal cord neurons that is evoked by repeated stimulation similar in frequency to the rate of nociceptive firing.

Patients with CRPS have been found to have cortical reorganization of somatotopic maps; the affected limb has been found to have a reduced representation in the somatosensory cortex compared to the unaffected limb. The degree of somatotopic reorganization has been shown to correlate significantly with the degree of hyperalgesia and pain intensity. Similar reorganization of the motor cortex occurs with reduced muscle representation and plays a role in the motor disturbances so prominently observed in patients with CRPS. Despite these examples of brain plasticity, pathological changes in both the sensory and motor cortex of patients with CRPS has been shown to be reversible upon successful treatment of CRPS.^10,12–14

Autonomic Nervous System

Sympathetic dysregulation is thought to play a major role in CRPS pathophysiology and is likely manifested through changes in vasomotor tone reflected by temperature and skin color, hyperhidrosis, and edema. In particular, excessive sympathetic outflow has traditionally been considered a key characteristic of CRPS, which is why selective sympatholytic blocks have been one of the mainstays of CRPS treatment for pain relief. High sympathetic nervous system activity has been associated with increasing pain by 22% and hyperalgesia by 27% specifically in patients with sympathetically maintained CRPS pain.¹⁰ There are two probable mechanisms responsible for dysregulation of the sympathetic nervous system, with the first being that patients with CRPS have increased amounts of adrenergic receptors in the affected limb when biopsied. Second, studies have demonstrated increased expression of adrenergic receptors on nociceptive fibers both peripherally and centrally in the dorsal horn. This phenomenon has been described as sympatho-afferent coupling. Experimental models further support this anatomic connection as dorsal root ganglion sympathetic fibers sprout and form basket terminals around thinly myelinated A-delta fibers and large mechanoreceptive neurons.¹¹ Furthermore, there is an exaggerated vasoconstrictive response later in the disease process of CRPS that results in decreased blood flow to the affected areas despite patients exhibiting lower sympathetic outflow and lower norepinephrine levels. This paradoxical pattern may be due to receptor upregulation and resulting hypersensitivity to circulating catecholamines. These changes in blood flow contribute to trophic changes and local tissue hypoxia, which increases tissue exposure to reactive oxygen species and further enhances pain and inflammation.^10,11,15