Complex Regional Pain Syndrome
Redefining Reflex Sympathetic Dystrophy and Causalgia
Salim M. Hayek, MD, PhD; Nagy A. Mekhail, MD, PhD
THE PHYSICIAN AND SPORTSMEDICINE - VOL 32 - NO. 5 - MAY 2004
In Brief: Complex regional pain syndrome (CRPS) is the new nomenclature that encompasses the older diagnostic entities of reflex sympathetic dystrophy (now CRPS 1) and causalgia (CRPS 2). CRPS arises after injuries such as sprains, strains, or fractures, but in some patients the cause is unknown. Although a perennial suspect in the pathogenesis of this entity, the sympathetic nervous system's role in CRPS remains unclear. New studies provide insight into the contribution of the sympathetic nervous system to CRPS and allow reevaluation of clinical features, diagnostic criteria, testing methods, and treatment modalities.
Physiologists have long recognized that the sympathetic nervous system has a central role in protective and adaptive reflexes and adjustments in response to acute stress and impending pain. These normal protective responses are essential for survival and for coping with environmental challenges. However, only in the mid-20th century has the role of the sympathetic nervous system in generating and maintaining pain states been acknowledged.1 Despite considerable focused research, the exact mechanisms underlying pain syndromes with sympathetic nervous system involvement are not totally clear.
Redefining the Nomenclature
Complex regional pain syndrome (CRPS) is the new terminology proposed by the International Association for the Study of Pain (IASP) to replace the old names (reflex sympathetic dystrophy [RSD] and causalgia).2,3 Features usually include burning pain, hypersensitivity, allodynia, edema, and, sometimes, muscle spasms and dystonias.4,5 However, to simplify CRPS and develop a rational diagnostic and therapeutic approach, the pain patterns in CRPS can be divided into two states: sympathetically maintained pain (SMP) and sympathetically independent pain (SIP).
Sympathetically maintained pain. This term describes pain that is dependent on and maintained by sympathetic input. Two particular features distinguish SMP: The pain is accompanied by signs of autonomic dysfunction, and sympathetic blockade generally relieves pain. The response to sympathetic blockade is generally good and was the rationale for the original designation of RSD.1 How the sympathetic blocks work is not exactly known, and, unfortunately, no well-controlled studies assess the efficacy of the sympathetic blocks. Many uncontrolled studies, however, reveal excellent initial pain relief and long-term pain relief in more than 50% of patients.6-9
The goal of treatment is to break the cycle of the pain state while the patients engage in progressive rehabilitation programs.10 Occasionally, a single blockade can stop the process, especially if it is given early in the course of the disease. Many patients will have progressively prolonged symptom improvement following subsequent blockades. However, in some cases, the effectiveness of blockade is brief, and sometimes as the disease progresses the sympathetic blocks become less effective. This diminution may arise from decreased contribution of the sympathetic system to the pain or from the development of fibrosis around the sympathetic ganglion that shields it from the injected local anesthetic.11 Physicians must recognize that the term "sympathetically maintained pain" describes a mechanism by which pain occurs and is not limited to CRPS. SMP also occurs in various other neuropathic pain conditions, such as neuralgias, diabetic neuropathy, ischemic peripheral vascular disease, postherpetic neuralgia, neuroma pain, and phantom limb pain.12,13
Sympathetically independent pain. This term describes the pain state that occurs most often in treatment-resistant cases of CRPS, in which sympathetic blockade or sympathectomy yields no clinical reduction in pain. The pain characteristics of this clinical subgroup suggest the involvement of other neuropathic mechanisms. The relative contribution of SIP and SMP to CRPS determines the therapeutic response to sympathetic blockade, and response can vary within a particular patient at different times and between patients.
Defining Complex Regional Pain Syndrome
CRPS better describes the disorder than did the older terms. The word complex describes the condition's varying clinical features. Pain is the sine qua non of the clinical entity and is usually regional. CRPS is further divided into CRPS type 1 and 2, with type 1 now defining what was formerly called RSD, and type 2 encompassing causalgia as well as posttraumatic neuralgias. Unlike CRPS 1, CRPS 2 occurs after an injury to a specific nerve.3 Although CRPS tends to affect an extremity in most cases, it may occur elsewhere in the body. CRPS is not limited to adults; cases have been described in children, in whom prognosis is more favorable.10
CRPS 1 is characterized by:
CRPS 2 displays the following characteristics:
Incidence data for CRPS are sparse. Approximately 10% of patients referred to multidisciplinary pain clinics are diagnosed with CRPS. The condition typically follows some trauma or surgery, but in a few patients the etiology is unknown or spontaneous.5 Although no clear sex prevalence exists for SMP, CRPS occurs more often in women than in men (3:1), and the mean age of patients is between 36 and 42. Several studies have reported that the incidence of causalgia (now called CRPS 2) following peripheral nerve injury varies between 2% and 14%.14
Among adolescents, girls seem to be more frequently affected than boys, and the lower limbs are more frequently affected than the upper limbs. Pediatric patients with CRPS are usually high achievers and are active in sports.15 However, a high degree of family dysfunction has also been described in these children.10
The Clinical Presentation
History. Most patients with CRPS have a history of soft-tissue, bone, or nervous system trauma that may stem from accidental injury, such as a sprain, fracture, dislocation, crush injury, or blunt trauma.5 Surgical or other iatrogenic injuries, or even vaccinations, have been reported to produce SMP. Additionally, SMP has been associated with neurologic diseases such as diabetic neuropathy, strokes, postherpetic neuralgia, and herniated disk lesions. The unanswered question remains: Why, following apparently identical injuries, do only a small proportion of patients develop the pain and associated trophic changes? Recent studies16,17 suggest a possible genetic predisposition in individuals experiencing CRPS.
Physical exam clues. The clinical signs and symptoms of CRPS 1 are variable. The characteristic triad of signs and symptoms includes sensory abnormalities and autonomic and motor disturbances. These signs and symptoms may be present in varying combinations and intensities, depending on disorder severity and duration.
Sensory abnormalities. Pain after trauma that persists beyond the expected normal healing process is an early warning sign of CRPS 1. Spontaneous burning pain and pain to light mechanical stimuli are prominent signs of the disorder. Pain is typically not limited to the distribution of a specific peripheral nerve. These sensory abnormalities are most pronounced distally in the affected limb; however, symptoms of CRPS often extend beyond the involved extremity. Indeed, recent studies have shown hemisensory impairment in one third of CRPS patients that manifested as decreased temperature and pinprick sensation in the part of the body corresponding to the affected limb.18 These patients, moreover, displayed increased frequency of allodynia and hyperalgesia, suggesting that, in addition to peripheral upregulation in alpha-adrenoceptors, central mechanisms enter into play in the pathophysiology of CRPS.
Autonomic dysfunction. Altered skin temperature on the hyperalgesic region is often noted in patients with CRPS 1.19,20 Autonomic dysfunction can also be demonstrated by abnormal responsiveness in the cold pressor test. Such abnormalities may be easily demonstrated by skin temperature measurement, or, more accurately and quantitatively, by thermographic imaging. Trophic changes such as local edema, abnormal hair and nail growth, and patchy osteoporosis may occur from altered microcirculation.20-22 Because of their responsiveness to sympathetic blocks, these changes may arise from the hypersensitivity of affected organs to the sympathetic outflow.23
Motor dysfunction. Not uncommonly, dystonia affecting movement in the distal extremity is noticed in patients with CRPS 1. Muscle strength is reduced and may be lost. However, this phenomenon is mostly from disuse atrophy or limited use from the pain state.24 Joint stiffness occurs in both CRPS 1 and CRPS 2. The dystonia may be focal, multifocal, or diffuse and is notoriously resistant to treatment. Of note, motor signs and symptoms were not included in the IASP diagnostic criteria, because these symptoms were sporadic.
Differential Diagnosis and Diagnostic Procedures
Many disorders have symptoms that mimic CRPS, and several modalities can be employed to differentiate these from CRPS and diagnose the condition. Differential diagnoses include posttraumatic vasoconstriction from thrombophlebitis, arthritis, infection, soft-tissue damage, tenosynovitis, fasciitis, fracture, and radiculopathy.
Thermography. Infrared thermographic imaging employing quantitative temperature difference has been used to confirm CRPS 1, but the quantitative temperature difference has inherent problems, because skin temperature asymmetry may be present in neuropathic abnormalities, focal inflammation, or vascular disease. Gulevich et al25 used computer-generated side-to-side quantitative and qualitative temperature differences as well as functional autonomic responses to cold water stress testing (cold pressor test) to diagnose CRPS 1. The authors showed that stress infrared thermography helps confirm the diagnosis of CRPS 1, with 93% sensitivity and 89% specificity. The technique produces serial thermographic images of the affected area (figure 2).
Triple-phase bone scan. Bone scintigraphy has some role in patients with CRPS 1 who are within the first year of onset of symptoms, but the sensitivity is only around 50%.26,27 Triple-phase bone scanning usually reveals hypervascularity in the affected extremity on early images, followed by diffusely increased uptake in distal joints on delayed images.28 The modality can sometimes be used to eliminate other conditions in the differential diagnosis.
Quantitative sensory testing. In patients with CRPS, the mean threshold for pain to mechanical29 and thermal30 stimuli is dramatically decreased on the affected side. Even stimuli that are innocuous on normal skin, such as stroking with a camel hair brush, applying a vibrating tuning fork to a bony prominence outside the hyperalgesic area, or moving a single hair follicle, can cause profound pain.
Sympathetic blockade. This modality is still a very important intervention in the management of CRPS patients, especially if pain is mediated through the sympathetic nervous system. However, lack of pain relief does not exclude CRPS. (See "Diagnosing Sympathetically Maintained Pain") Pain relief that outlasts the duration of the injected local anesthetic is an important diagnostic feature of SMP.10 However, it is important to note that significant placebo response can occur with sympathetic blocks as manifested by early pain relief following stellate ganglion blocks without sympathetic blockade31 and by similar analgesic effects from saline or local anesthetic injection in sympathetic ganglia.32 However, unlike saline, local anesthetics produced long-lasting relief.33
Many therapeutic modalities exist for patients with CRPS and provide physicians with different avenues for individualizing treatment, depending on the condition of the patient at evaluation.
Physical therapy and rehabilitation. These are the mainstays in treating CRPS. Aggressive physical therapy and rehabilitation programs should be individually designed with the ultimate goal of regaining function of the affected extremity. Rehabilitation starts with desensitization and reactivation of the disabled extremity and progresses as tolerated to isometrics, stress loading, and increased endurance and functional restoration of the affected limb.5,10 Psychological and pain management interventions can be incorporated when pain hinders progress.5
Addressing psychological factors. Severe pain engenders emotional suffering and behavioral changes that can be misinterpreted. The behavioral response to CRPS ranges from fully preserved function to complete disability. Behavioral responses may be especially important in CRPS because of disuse, overprotection, and immobilization of the affected limb. These behaviors may exacerbate edema, vasomotor changes, and demineralization that can accompany CRPS. Furthermore, major psychiatric illnesses could both exacerbate and reduce the ability to cope with CRPS-associated pain. For example, depression occurs in CRPS as in other chronic pain syndromes, and it also exacerbates overall patient suffering. For these reasons, it is very important to address the potential psychological issues, psychiatric illnesses, and personality disorders in individual patients as part of a multidisciplinary program of treatment.34
Adjuvant medications. Pharmacologic treatment of neuropathic pain, including CRPS, is notoriously difficult, and very few well-designed trials have addressed this issue. In acute cases of CRPS, a course of systemic corticosteroids is useful.35,36 Numerous medications have been used to treat CRPS, including tricyclic antidepressants, alpha-adrenergic blockers, calcium channel blockers, membrane stabilizers, and alpha-2 agonists.5,10 Confirming efficacy of these agents, however, will require larger randomized controlled trials.
A recent study37 evaluated the efficacy of intrathecal baclofen in CRPS 1 patients with multifocal or generalized dystonias. Intrathecal baclofen provides substantial therapeutic value in patients with CRPS 1, especially when the dystonia involves the upper extremities.
Sympathetic blockade. The goal of sympathetic blockade is to arrest the cycle of sympathetic hypersensitivity and to relieve pain, which in turn facilitates rehabilitation. Various methods can be used: (1) stellate ganglion blocks for upper-extremity CRPS, (2) lumbar sympathetic blocks for lower-extremity CRPS, and (3) intravenous (IV) regional blocks or repeated IV phentolamine infusion if more than one extremity is involved or when sympathetic blocks are contraindicated (eg, anticoagulation).10
Continuous infusion of drugs. Continuous infusion of epidural opioids and local anesthetics has shown good outcomes in affected patients, with acceptable rates of complications and side effects over weeks to months. Favorable results were mainly noticeable when the technique was initiated within 1 year of the onset of symptoms.10,38,39 For surgery on an extremity affected by CRPS, physicians should implant an epidural catheter to provide surgical anesthesia and maintain postoperative epidural analgesia for a period commensurate with the extent of the procedure and the severity of the illness. Failure to do so can markedly exacerbate CRPS symptoms.40
Peripheral nerve stimulation. Peripheral nerve stimulation (PNS) has been used in the treatment of severe, intractable CRPS 2 (causalgia). Criteria for patient selection include severe intractable symptoms that are entirely or mainly in the distribution of one major peripheral nerve. In one study,41 significant decreases in spontaneous pain as well as allodynia were noted up to 4 years following PNS placement, with 20% of patients returning to part-time or full-time employment. Unlike earlier cases, more recent studies42,43 indicate a more consistent response to PNS.
Spinal cord stimulation. Studies33,44-51 have shown that spinal cord stimulation (SCS) has a proven value in the management of refractory CRPS. It is worth noting that in these patients all other modalities had failed. These patients had improvements in visual analog pain scale and perception of pain, improvements in daily living and quality of life, and substantial decreases in analgesic consumption (figure 3). The SCS-induced pain relief in CRPS is independent of sympathetic or vasodilatory effects.52 In these studies,44,46,49 no significant improvement was observed in trophic alterations, such as musculoskeletal changes, or in functional status of patients, but a clear propensity to return to work and productivity was evident in patients who received SCS implants.
A randomized, prospective trial44 in 54 patients with CRPS tested SCS and physical therapy against treatment with physical therapy alone. Patients in the combination therapy had significantly lower pain scores and significantly higher global perceived effect than those assigned to the physical therapy-only group. In addition, the combination therapy-group had health-related quality of life improvement. Reduction in pain was not dependent on the type of the extremity involved, age, gender, duration of pain, overall distress, or health-related quality of life.44 Similarly, in a retrospective analysis of 196 patients who received neurostimulation for chronic pain, 54% of whom had CRPS, Mekhail et al53 showed significant savings from decreased healthcare use after stimulation.
A Clearer Path to Pain Relief
The IASP has redefined the nomenclature of pain syndromes to reflect more accurately the actual basis of the disorder and explain the role of pain and the sympathetic nervous system. Physical therapy and rehabilitation remain the mainstays of treatment, but other modalities, such as psychological and pharmacologic measures and invasive techniques, will aid treatment strategies. Further research will enhance the overall development of better regimens.
Dr Hayek is an associate staff member, and Dr Mekhail is associate professor and chairman of the department of pain management at the Cleveland Clinic Foundation in Cleveland. Address correspondence to Nagy A. Mekhail, MD, PhD, 9500 Euclid Ave, C25, Cleveland, OH 44195; e-mail to [email protected].
Disclosure information: Drs Hayek and Mekhail disclose no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.