Complex localized pain syndrome was previously known as Sudeck’s dystrophy, degenerative bone pain, burning neuralgia, or reflex sympathetic dystrophy. The syndrome is a multifactorial group of painful syndromes. The term “complex” refers to the variety of clinical symptoms associated with pain, such as abnormal sensory, motor and autonomic function.
The term “localized” refers to the focal distribution of symptoms and signs, often radiating distally to the affected limb, beyond the innervation of a particular nerve or nerve root. “Pain” is the core symptom of the disorder.
Primary CRPS is rare, and typical CRPS occurs secondary to minor tissue injury or limb trauma. The syndrome can be divided into two subtypes: CRPS type 1, which has no clear evidence of major neurological damage, and CRPS type 2, which has clear evidence of neurological damage. Therefore, by definition, CRPS type 1, without clinical evidence of major neurological injury, often does not fully meet the diagnostic criteria for neurogenic pain.
The sensory signs and symptoms of CRPS types 1 and 2 are almost identical, but because of the presence of major nerve injury, CRPS type 2 can present with more severe hyperalgesia to mechanical stimuli. In summary, CRPS type 1 and type 2 can exhibit the same disease spectrum and the pathophysiological manifestations remain consistent over a wide range. Therefore, the author does not differentiate between CRPS type 1 and type 2 to a large extent in this review when discussing clinical manifestations, pathogenic mechanisms, and the interaction between the two.
Clinical manifestations of CRPS
The existing diagnostic criteria for CRPS are based on its main signs and symptoms: sensory abnormalities, autonomic abnormalities, and motor abnormalities. Less specific symptoms of CRPS are the so-called “neglect phenomenon”, postural abnormalities and joint contractures, and sympathetic maintenance pain. The degree to which these signs and symptoms occur varies, and the clinical presentation of an individual patient may change over time.
One important clinical finding is the distal distribution of all signs and symptoms in the limb: symptoms spread from the injured area to the distal end in a glove-like or garter-like pattern, leading to the appearance of corresponding signs, as well as hand symptoms including all fingers and foot symptoms including all toes. Sensory deficits may extend to the proximal region of the affected limb and may also involve the healthy limb; hypokinesis may occur at the end of the limb that was not previously involved.
Another important factor in the diagnosis of CRPS is that the nature of the pain can change as the disease progresses: many patients describe a sudden change in pain sensation from typical injury pain shortly after injury or surgery to typical neurologic “burning” pain.
The existing diagnostic criteria for CRPS were established by the International Consortium for the Study of Pain in 1994. Therefore, it is difficult to compare the results of studies prior to this definition with those obtained under the same definition during the last 20 years. Some authors may mistake syndromes with similar symptoms for CRPS, and some findings on the treatment of CRPS may be based on different populations, thus limiting the applicability of these findings.
Somatosensory abnormalities and pain
Pressure hyperalgesia is the most common somatosensory symptom of CRPS, occurring in 66% of patients with CRPS type 1 and 73% of patients with CRPS type 2. In patients with CRPS of the upper extremity, spontaneous pain occurs in 55% of CRPS1 patients and 76% of CRPS2 patients. More than 60% of patients may have pain on movement; more than 50% of patients may have pain in the upright position.
Patients often describe the pain as “tearing,” “burning,” or “pins and needles”; it is often diffuse and deep in the extremity. Deep areas of the body may play an important role in the CRPS process (discussed below).
Some patients with CRPS present with SMP, a spontaneous or irritating increase in pain when the sympathetic nervous system is stimulated. However, it is important to understand that SMP is not a core symptom in all patients with CRPS, and that SMP should be treated as a potential sign of CRPS.
Autonomic abnormalities and edema
Vasodilator disturbances are common in patients with CRPS: differences in skin temperature and skin color between the affected and non-involved extremities are often seen, due to vasodilator disturbances in the affected extremity. Asymmetry in skin color between the involved and non-involved extremities is reported in 71-97% of patients, and differences in skin temperature between the two are reported in 79-98% of patients. About half of the patients report abnormal sweat production, mostly hyperhidrosis and occasionally oligohidrosis.
Edema is seen in 55-89% of cases, especially in acute CRPS, and similar to other autonomic disorders, edema can be triggered by external stimuli such as pain or uprightness, as well as by changes in vascular tone. Although 90% of patients report a tendency to develop localized swelling even after 15 years of disease, over the course of the disease, edema often becomes less frequent and/or less severe, and the tendency to develop edema may eventually disappear altogether.
Abnormalities in motor function and nutrition
Abnormalities in motor function are reported in 75-88% of patients with CRPS, which is consistent with abnormalities in motor function detected by clinical physical examination. Of these patients, 80% report decreased range of motion in the affected limb and 75% have weakness in the affected limb. Patients may have particular difficulty completing compound movements, such as clenching a fist and placing the thumb opposite the little finger.
In acute CRPS, decreased motor function can be explained to some extent by edema and increased muscle pressure; in chronic CRPS, contracture and fibrosis of the palm or finger tendons may limit hand muscle movement. Impaired central processing of proprioceptive information may also be involved in this pathological process. Although uncommon, patients with CRPS may also report the development of dyskinetic disorders such as bradykinesia, myoclonus, and tremor.
Altered nutritional status is also typical of CRPS, such as increased or decreased hair or nail growth and tissue dystrophy. Phyllodesis or mirror-like dystrophy of the skin, subcutaneous tissue, muscle and bone tissue are also common clinical manifestations.
Treatment based on pathogenic mechanisms
Both types of CRPS exhibit the typical signs associated with neurogenic pain: sporadic, burning pain, nociceptive hyperalgesia; and pain in areas of sensory abnormalities. Some of the pathological mechanisms known from other neurogenic pain can be temporarily “transferred” to CRPS to explain its pathophysiological properties, and the following hypothesis is made – different clinical signs reflect different underlying mechanisms.
The diverse and complex nature of the pathophysiological mechanisms of CRPS can be considered to be related to the heterogeneity of its clinical phenotype and may explain the difficulty in establishing evidence-based treatment options.
Evidence for CRPS-specific treatment strategies is scarce, as are treatments that directly target specific mechanisms rather than merely alleviate CRPS symptoms. Attempts to establish causative mechanism-based treatment regimens currently rely heavily on applying findings in other pain syndromes to explain CRPS.
However, the use of drugs that are effective in neuropathic pain for the treatment of CRPS is not trivial. Most randomized controlled trials studying neuropathic pain have included patients with postherpetic pain or diabetic peripheral neuropathy, with significant differences in experimental design, outcomes, number of patients included, and duration of treatment, in addition to the fact that most have a chronic course.
After taking these difficulties into account, the author reviews the pathophysiological mechanisms and possible treatment options for CRPS. Drug selection for specific patients depends on their comorbidities, drug interactions and tolerance to adverse effects, and risk of drug misuse and abuse; it is important to recognize these.
Peripheral nervous system mechanisms
Nerve injury alters the expression of neurotransmitters, neuromodulators, growth factors, receptors, and neuroactive molecules in primary afferent neurons, resulting in spontaneous ectopic firing and hyperexcitability of primary afferent nociceptive receptors. This process leads to sensitization of the peripheral nervous system, with subsequent enhancement of pain perception and resulting in a high degree of sensitivity to pain. Microphotography has demonstrated spontaneous lesional nerve impulse activity in injury receptor neurons in some patients with CRPS, supporting the idea that peripheral nervous system sensitization is associated with CRPS.
Peripheral nervous system sensitivity as a therapeutic target
Although modulation of peripheral nerve activity is one of the standard approaches to pain management, studies on the effect of inhibition of peripheral nerve activity in the treatment of CRPS are rare. NSAIDs, carbamazepine, and other commonly used sodium channel function modulating antispasticity drugs lack clinical studies with placebo controls to assess efficacy.
In a small clinical trial, intravenous application of lidocaine to patients with CRPS narrowed areas of thermal and mechanical nociceptive sensitization. However, the evidence on the use of lidocaine in the treatment of CRPS is generally rated low because of the lack of large sample studies and the lack of knowledge on the long-term effects of lidocaine for the treatment of pain and other symptoms of CRPS.
Sympathetically maintained pain
Inflammatory processes and sympathetic-afferent nerve coupling desensitize the peripheral nervous system in patients with CRPS, implying that corticosteroid or sympathetic blocker treatment may desensitize the peripheral nervous system. Intradermal injection of norepinephrine exacerbates the condition in some patients with CRPS, showing that norepinephrine sensitization of peripheral nociceptive afferent sensory fibers is associated with CRPS and that there is a pathogenic interaction between the efferent sympathetic and afferent systems.
This efferent afferent nerve coupling can occur directly through activation of norepinephrine-releasing sympathetic efferent fibers and alpha-adrenergic receptor-expressing nociceptive afferent nerves, indirectly through vasoconstriction affecting the nociceptive receptor microenvironment, or indirectly through macrophage activation leading to the release of inflammatory mediators. All of these direct or indirect mechanisms lead to activation and further sensitization of nociceptive sensory fibers.
Sympathetic ganglion blockers
Norepinephrine-induced sensitization of afferent nerve fibers can be treated by blocking norepinephrine release from sympathetic fibers locally or at the nearest sympathetic ganglion. Although there are encouraging results in clinical practice and many positive results in uncontrolled studies in patients with CRPS, it should be noted that many of these studies lack specificity, long-term follow-up results and evaluation of different interventions. Therefore, the efficacy of sympathetic blockade in CRPS remains controversial.
One controlled trial of sympathetic ganglion blockers showed equal immediate pain relief after administering local anesthetic injections and saline injections, respectively, but re-evaluation 24 hours later found that local anesthetics were more effective than placebo. This result suggests that the effect of sympathetic blockers should be evaluated after 24 hours of administration.
In contrast, no significant pain reduction was found after 1 month of repeated astroglottic blocker add-on treatment. These conflicting results suggest that uncontrolled studies should be interpreted with caution, and only a few of these studies evaluated the long-term effects of anti-sympathetic drugs.
Norepinephrine release inhibitors
A meta-analysis assessing the efficacy of IVRS by the norepinephrine release inhibitor guanethidine showed no superiority of IVRS over placebo for pain relief; however, transdermal application of colistin, which inhibits norepinephrine release by activating α2 receptors in peripheral sympathetic nerve endings, reduced nociceptive hypersensitivity in patients with SMP. Nevertheless, only four patients were included in this open study, and the results should be interpreted with caution.
There is growing evidence that only a subset of patients develop SMP symptoms, with significant individual differences; this means that the design of clinical trials using sympathetic blockers should be reevaluated. In addition, controlled studies that can assess the short- and long-term efficacy of sympathetic blockers and IVRS in pain and other CRPS symptoms are now the most urgent need.
Inflammatory response
As mentioned above, CRPS can occur after tissue injury and in some cases may also be induced by injury involving peripheral nerves. In response to tissue injury, different inflammatory cells, such as lymphocytes, monocytes, mast cells and neutrophils, migrate to the site of injury and release inflammatory mediators and pro-inflammatory cytokines and interleukin 1β, which can induce pain hypersensitivity.
Following nerve destruction, these mediators can also be released from primary sensory endings or damaged axons that wrap around Schwann cells. In CRPS
patients, elevated levels of proinflammatory cytokines are seen in blister fluid, skin, blood and cerebrospinal fluid along with decreased levels of anti-inflammatory cytokines.
Neurogenic inflammation
The nonspecific inflammatory response described above extends to neurogenic inflammation: in addition to the cis-conduction of nerve impulses toward the dorsal root ganglion, activation and sensitization of pain receptors lead to retrograde excitation; this excitation allows the release of vasoactive peptides from peripheral nerve endings.
These peptides induce vasodilation and fluid leakage around the peripheral nerve terminals, resulting in local edema, warmth, and redness. This peptide release has been observed during CRPS and patients with CRPS may present with increased serum concentrations of CGRP and substance P.
Corticosteroids and immunomodulatory drugs
It is well established that corticosteroids and free radical scavengers can target the inflammatory process in CRPS; however, there are conflicting results from clinical trials regarding the effectiveness of corticosteroids. Oral prednisone is effective in improving the clinical symptoms of acute CRPS, but subdural injection of methylprednisone alone does not improve the symptoms of chronic CRPS. Treatment with 40 mg methylprednisone and 2% lidocaine topical closure was not superior to placebo.
In conclusion, oral cortisol may be effective in patients with CRPS whose inflammatory response is clinically evident; however, the evidence is weak regarding the ability to relieve pain, and there are no recommendations at this stage regarding the dose or duration of use of the drug. Prolonged application of cortisol should be avoided because of its adverse effects.
A clinical trial using the anti-TNF monoclonal antibody, infliximab, was discontinued because it was not superior to placebo in relieving pain. At this time, there are no clinical studies evaluating the effects of other immunomodulatory treatments (e.g., immunosuppressants).
Free radical scavengers
One study comparing topical administration of the free radical scavenger dimethyl sulfoxide with oral administration of N-acetylcysteine showed that both were effective for CRPS.
DMSO may be more effective in “hot” CRPS, where there is increased skin temperature, redness, and other signs of inflammation in the involved extremity, and NAC may be more effective in “cold” CRPS, where there is decreased temperature and tissue necrosis. As the disease progresses, the effect of both drugs tends to diminish. Other studies on the effectiveness of DMSO in the treatment of CRPS have yielded contradictory results. Thus the evidence on pain management in CRPS is generally of low rank.
Autoimmunity in CRPS
Some CRPS may be associated with autoantibody-mediated autoimmune processes. There is some empirical evidence supporting this hypothesis: intravenous application of immunoglobulins relieves pain symptoms in CRPS; serum levels of IgM and IgG antibodies against different bacterial and viral surface antigen epitopes are more likely to be elevated in patients with CRPS compared to normal controls, suggesting that abnormal autoimmune activity may lead to the production of crossed autoantibodies. In addition, the sera of patients with CRPS may contain autoantibodies against autonomic nervous system structures.
The hypothesis that after the onset of CRPS, pre-existing circulating autoantibodies become further pathogenic and maintain hypersensitization, leading to chronic CRPS, is noteworthy, but its relevance to CRPS is unclear; additional studies are necessary to confirm this hypothesis due to the high cost of intravenous immunoglobulin therapy.
The role of deep somatic tissues in CRPS
The pathophysiological processes associated with CRPS are not limited to the skin, but deep somatic tissues may also play an important role. Injection of low pH fluids into muscle tissue can lead to pain, which is similar to the characteristics of CRPS-related pain. In addition, CRPS often follows deep tissue injury, and patients with CRPS also commonly experience pressure hyperalgesia, bone atrophy, and increased periarticular uptake on delayed phase of triphasic bone scintigraphy.
In CRPS patients with combined SMP, sympathetic blockade was more effective than selective sympathetic transcutaneous modulation in reducing spontaneous pain symptoms, which also demonstrates the association of deep somatic tissues with the disease. These findings suggest that pain in CRPS is, at least in part, of deep tissue origin. Despite the importance of the relevance of deep somatic tissues in CRPS, their function has been widely neglected in clinical studies.
Although diphosphonates are drugs that regulate bone metabolism, they also have analgesic effects, probably because of their role in modulating bone resorption function. Early treatment of CRPS with oral or intravenous diphosphonates has been documented to reduce pain and improve function, but a recently published systematic review concluded that the evidence for the use of diphosphonates in the treatment of painful symptoms in CRPS is of poor quality and that the reported effects may be specifically associated with a combination of bone loss or osteoporosis in CRPS. Further evaluation of the effect of this drug is therefore needed.
With regard to calcitonin, the available evidence prefers that the drug is ineffective.
Central mechanisms
Peripheral sensitization of afferent C fibers can induce central sensitization – a prolonged increase in excitability and synaptic efficacy in the spinal cord, brainstem, and brain neurons – but this process is reversible. Central sensitization is thought to contribute to the chronicity of CRPS pain symptoms. An important potential mechanism for central sensitization and subsequent nociceptive hypersensitivity is the release of excitatory neurotransmitters in the spinal cord.
Neuronal activation and transmitter release in the spinal cord regulated by calcium channels and opioid receptors, and neurotransmitter release can lead to activation of neurokinin and N-methyl -D-aspartate, stimulating nociceptive processes.CPRS often has clinical manifestations of central sensitization: including fluctuating tactile hyperalgesia, secondary dotted nociceptive hyperalgesia, and/or enhanced temporal sum effect.
Endogenous nociceptive modulation
Endogenous nociceptive modulation allows for modulation of nociceptive-related signals within the spinal cord. The brainstem is essential for endogenous nociceptive modulation because both the downstream inhibitory and downstream excitatory systems originate in the brainstem, and CRPS-involved hands may show both reduced adaptation to nociceptive stimuli and increased areas of nociceptive sensitivity, suggesting a shift from inhibition to facilitation of injury sensory input signals, which may result from differences in activation levels of subcomponents of the endogenous nociceptive modulation system. The
Drugs targeting central sensitization
There are still no randomized controlled studies on the use of tramadol and oral potent opioids in the treatment of CRPS. Although some high-quality randomized controlled studies have demonstrated the effectiveness of opioids for different types of neuropathic pain, the adverse effects of this class of drugs and concerns about the safety of long-term application have limited their use.
Adverse effects of opioids include constipation, nausea, and drowsiness; safety risks for long-term application include hypogonadism, altered immune function, misuse or abuse, and opioid-induced nociceptive hypersensitivity. Therefore, the International Consortium for the Study of Pain typically recommends opioids as second-line therapeutic agents only.
This recommendation also applies to CRPS The recently published CRPS treatment guidelines recommend that strong opioids should not be used in such patients due to lack of evidence of their effectiveness. However, in certain circumstances, opioids may be used as first-line therapy.
However, it should be noted that there are no prospective controlled long-term studies on the use of oral opioids in chronic neuropathic pain. Potent opioids should be administered in mild doses and discontinued when an initial dose increase or adverse effects are documented in patients.
Gabapentin and pregabalin reduce the release of excitatory amino acids and neuropeptides by modulating calcium channels on spinal cord neurons. A machine-based, double-blind, placebo-controlled crossover trial found that gabapentin improved symptoms of sensory deficits, but had no significant advantage in pain relief. Although evidence for the use of gabapentin in the treatment of CRPS is sparse and no studies are available to assess the effectiveness of pregabalin, because of the neuropathic nature of CRPS pain symptoms, calcium channel modulators should be used to treat CRPS with consideration of adverse effects.
Ketamine, dextromethorphan and memantine, which block NMDA receptors and are now in clinical use, are strong candidates for the treatment of CRPS. Two randomized controlled studies have demonstrated the effectiveness of intravenous ketamine for painful symptoms in CRPS, but both studies had small sample sizes and the pain-relieving effect lasted only a short time after treatment was stopped.
Percutaneous application of ketamine to the affected extremity has been shown in one study to suppress tactile evoked pain and nociceptive sensitization due to light brushing, but this study was limited in that overall pain levels were not assessed as a clinical outcome. A treatment using a ketamine-morphine mixture was found to be superior to placebo in reducing pain and normalizing nociceptive processing in the brain, and was confirmed by functional MRI.
However, the overall quality of evidence on the intravenous or percutaneous application of ketamine, dextromethorphan, or memantine in the treatment of CRPS-related pain remains limited; the adverse effects of these drugs also limit their use. More in-depth studies are needed to assess the effectiveness and risk-benefit values of these drugs.
Epidural spinal cord stimulation has been found to reduce central sensitization. A study on the efficacy of SCS combined with physiotherapy in patients with refractory CRPS showed that patients in the SCS group had better pain relief than the physiotherapy alone group at 2 years after implantation; however, there was no significant difference between the two groups at 5 years after implantation, and complications increased in the SCS group. When complication rates and treatment costs are taken into account, it becomes clear that SCS may be useful only for a small number of patients selected after a rigorous diagnostic evaluation.
Management of downstream inhibitory pathways
Antidepressants (tricyclic antidepressants, selective 5hydroxytryptamine and norepinephrine reuptake inhibitors) are thought to enhance downstream inhibitory pathway activity and have been shown to be effective in different types of neuropathic pain; however, there is no direct evidence from randomized clinical studies to support the use of antidepressants for the treatment of CRPS.
Colistin is an α2-adrenergic agonist that modulates the downward inhibitory pathway. In selected patients with severe refractory CRPS, subdural application of colistin reduced pain until 6 hours after the end of treatment; however, there were important adverse effects, such as sedation and hypotension.
Because of limitations in study design, small sample size, and short follow-up, the above studies provide a low quality grade of evidence; and because of potential adverse effects and invasive methods, this treatment should be limited to cases that are ineffective to other methods. Nevertheless, oral antidepressants should also be considered as an option to manage the neuropathic component of pain in CRPS.
Interference with afferent-transmitter feedback
Interference with body perception
The processing of painful stimuli is not limited to nociceptive afferent pathways, but also to a wide range of cortical grid structures: somatosensory areas, insula and cingulate areas, frontal and parietal areas necessary for conscious perception, attentional modulation, and vegetative response modulation. There is proprioceptive afferent feedback from affected tissues to subcortical and cortical somatosensory centers and somatic and visceral motor centers, and it has been hypothesized that dysfunction of this feedback plays an important role in the mechanisms leading to
It has been hypothesized that disruption of this feedback plays an important role in the mechanisms leading to the development of CRPS.
Some patients with CRPS exhibit symptoms that resemble neuropathic neglect, although unlike classical neglect symptoms, patients understand that they have a dysfunction. This finding has led to the idea that such neglect-like symptoms are limb-specific, positively correlate with pain intensity, reduce tactile sensitivity, and may be better described as a “somatosensory disorder”.
In some patients with CRPS, the primary somatosensory cortices reflect a reduction in the somatosensory map of the affected limb, and nociceptive intensity and mechanical nociceptive hypersensitivity are associated with this reduction, and clinical improvement is associated with recovery of the somatosensory map. Changes in cortical representation areas due to afferent nerve block or enhanced pain input signals are likely to result in observable somatosensory deficits and may lead to impairment of afferent and efferent feedback mechanisms.
The importance of visual control
Nociceptive processes are known to be influenced by visual input signals. When subjects look into their own soma, their neural response to nociceptive stimuli is attenuated and the intensity of the reported nociception is reduced. This phenomenon is known as visually evoked nociceptive deficits. Visual distortion of somatic size modulates nociceptive perception.
For example, providing a reduced phantom limb shape to be seen may reduce phantom limb pain; in patients with chronic hand pain, similar visual reduction of the affected limb may reduce motion-induced pain and swelling symptoms. This phenomenon can be explained by the fact that patients’ perceptual areas for stimuli are not aligned in anatomical areas versus visuospatial areas.
Compared to healthy controls, patients with CRPS experienced localization difficulties in both the affected and healthy limbs; precise localization of the affected limb was significantly improved by visual control. Visual and somatosensory perceptual deficits and nociception are known to be closely associated with CRPS. Conflicting visual information may alleviate pain and/or sensory deficits, asymmetric peripheral vasodilatory sympathetic responses, and peripheral vascular dystonia in some patients with CRPS.
Conflicting sensory and motor information
In the presence of altered somatosensory and cortical remodeling, patients’ cortical motor and sensory maps no longer accurately reflect somatic sites, which may lead to motor-sensory dysfunction and ultimately to pain. A study in healthy volunteers confirmed that when looking at a limb in the mirror and performing uncoordinated movements in the corresponding limb, contradictory motor-sensory information can induce the production of pain and sensory disturbances. Touching a healthy limb when a CRPS patient looks in the mirror can induce pain or sensory abnormalities in the corresponding area of the affected limb that is hidden from view.
Reconstructing mismatched afferent – efferent feedback
Physical therapy and occupational therapy can be considered the most important therapeutic approaches in the treatment of CRPS. Clinical experience and randomized controlled studies clearly show that physical therapy is extremely important in reducing pain and reestablishing function in the affected limb. Occupational therapy can further promote recovery. The application of standard physical therapy in pediatric CRPS patients has been shown to achieve long-term pain relief and functional improvement.
It has been hypothesized that inconsistencies between motor intent, proprioception, and vision can lead to affective perceptual pain; therefore (these) treatments may be the best way to re-establish the integrity of cortical information pathways. Patients wearing a specially designed prism that visually displaces the healthy side for target pointing once a day for 2 weeks did reduce pain and other related symptoms in patients with CRPS.
In addition, although the effectiveness of mirror visual feedback is based primarily on the evaluation of post-stroke CRPS patients, the method is a common therapy in the treatment of CRPS. Graded motor training methods that include combining a number of lateralized cognitive tasks in a fixed order, imagining hand activities, and mirror therapy have been shown to reduce pain symptoms and improve function in patients with CRPS, but this evidence should be interpreted with caution because of its small sample size and methodological limitations.
Central motor dysfunction
Intrathecal baclofen has been shown to be effective in the treatment of CRPS dystonia symptoms, but these studies have also reported many complications and adverse effects associated with baclofen and intrathecal injections, including drowsiness, psychiatric symptoms, urinary retention, post-puncture headache, cerebrospinal fluid leakage, infection, and wandering or displacement of the catheter device. The small volume sample and limitations of these studies mean that they are only Level 3 evidence.
Psychological symptoms
Many different psychological symptoms, such as anxiety, depression, and personality abnormalities, often occur during the course of CRPS, but it is controversial whether these symptoms precede or are secondary to CRPS. According to most studies, the psychological profile of patients with CRPS does not differ from that of other chronic pain patients.
In addition, most prospective studies have not found more psychological symptoms or specific psychological features in patients with CRPS than in those who have fully recovered from the initial trauma. A recent review concluded that there is indeed no evidence for specific personality or psychological predictors in CRPS.
Despite these findings, it is also clear that CRPS is associated with adverse mental health outcomes, such as increased depression and anxiety due to pain and physical disability, and that psychological and behavioral factors can alternatively contribute to the pathophysiological progression of CRPS.
One possible mechanism by which psychological symptoms can affect CRPS is because chronic stress such as depression, anxiety, pain, or other life stressors lead to systemic catecholamine release, which increases nociceptive capacity and worsens the manifestation of abnormal vasodilatory function due to upregulation of adrenergic receptors and upregulation of sympathetic afferent coupling.
The idea that psychological co-morbidity can worsen CRPS is confirmed by the results of a randomized single-blind prospective trial. The trial, which administered physical therapy and cognitive-behavioral therapy to pediatric and adult CRPS patients, was shown to produce prolonged pain relief and improvement in motor function. This is the only randomized controlled trial to date of the efficacy of psychological interventions in CRPS. There are several non-controlled studies that suggest that some other psychological interventions may be effective, including relaxation training, biofeedback, and cognitive and behavioral focus interventions.
Conclusion
CRPS has complex pathophysiological mechanisms. Although multiple approaches to understanding and interpreting the pathophysiological mechanisms of CRPS can lead to different treatment measures, only a few studies have evaluated treatment approaches based on pathogenic mechanisms. An important reason for the lack of such studies is the low prevalence of CRPS and the highly individualized nature of CRPS in terms of clinical signs and symptoms suggesting the heterogeneity of the underlying mechanisms. Multicenter studies completed by hospital networks could provide large sample sizes and improve stratification factors, thereby assisting in the evaluation of potential treatments.
CRPS is a serious disease, and successful treatment may require a combination of modalities, including pharmacotherapy, invasive treatment, physical therapy, occupational therapy, and psychological counseling or therapy, making it difficult to conduct single-mechanism-based treatment outcome studies for a particular treatment modality. Research on CRPS treatment based on causative mechanisms will need to find a balance between ethics and the urgency of improving access to treatment.