Complex Regional Pain Syndrome: A Comprehensive Review

Taylor SS, Noor N, Urits I, et al. Complex Regional Pain Syndrome: A Comprehensive Review. Pain and Therapy. 2021;10(2):875-892. doi:10.1007/s40122-021-00279-4

Link to Original Article: https://pubmed.ncbi.nlm.nih.gov/34165690/

Key Points

1. Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by hyperalgesia and allodynia, often developing after extremity trauma or surgery. It is divided into CRPS-I and CRPS-II, with type II occurring after confirmed nerve injury.

2. Female gender is a significant risk factor for developing CRPS, along with fibromyalgia, rheumatoid arthritis, and psychological factors such as depression and post-traumatic stress disorder (PTSD).

3. The pathogenesis of CRPS involves inflammatory and autoimmune responses, neuropathic inflammation, and autonomic nervous system dysregulation.

4. Treatment modalities for CRPS include physical therapy, pharmacotherapy, and interventional techniques such as sympathetic blocks, spinal cord stimulation, and more novel approaches like virtual reality therapy.

5. Risk factors for CRPS include extremity injuries, surgery, and carpal tunnel syndrome, with the condition being more prevalent in women. CRPS has been associated with depression, post-traumatic stress disorder (PTSD), and fibromyalgia, suggesting a potential connection to psychological factors.

6. The Budapest Criteria are the current accepted diagnostic criteria for the diagnosis of CRPS, and early initiation of multidisciplinary therapy is crucial for improving patient prognosis and quality of life.

Introduction

The research paper explores complex regional pain syndrome (CRPS), a chronic pain condition characterized by hyperalgesia and allodynia, often linked to extremity trauma or surgery. The pathophysiology of CRPS involves central and peripheral nervous system dysfunction. The syndrome has evolved through various names and is categorized into two types: CRPS-I and CRPS-II based on nerve injury. Diagnosis relies on clinical findings due to the absence of specific diagnostic tests. CRPS presents with diverse clinical features and poor prognosis despite treatment. Early diagnosis and treatment initiation are crucial for limiting disease progression and improving quality of life.

Compliance with Ethics Guidelines

The research paper notes that this article is not based solely on previous studies and does not contain any studies with human or animal participation.

Epidemiology

The epidemiology section of the paper discusses the prevalence and factors associated with complex regional pain syndrome (CRPS) in the United States. The largest population-based study found a 0.07% discharge rate with a CRPS diagnosis, with higher prevalence in females, Caucasians, those with higher income, and comorbidities such as depression and drug abuse. Obesity, diabetes, hypothyroidism, and anemia were associated with lower rates of CRPS. Another study reported a slightly higher prevalence of 1.2%, positively correlated with female gender, long-term disability, and multiple pain diagnoses, with increased healthcare utilization and cost. The paper notes a lack of evidence on diagnosing and treating CRPS in the pediatric population but highlights a 2021 systematic review focusing on CRPS in pediatric patients. The review considers neuromodulation as a potential treatment, emphasizing pain relief and improving functioning. Treatment for pediatric CRPS includes intensive physical therapy, cognitive behavioral therapy, and possibly neuromodulation interventions such as spinal cord or dorsal root ganglion stimulation. The paper recommends careful consideration of pubertal growth spurt before device lead placement in pediatric patients.

Risk Factors

The research paper explores risk factors associated with Complex Regional Pain Syndrome (CRPS). Extremity injuries, such as fractures, sprains, surgery, and carpal tunnel syndrome, have been identified as the most common inciting events leading to CRPS. The overall prevalence of CRPS associated with these events is relatively low, with only 0.19% to 0.64% of patients diagnosed with CRPS after specific treatments or injuries. CRPS is more prevalent in women, with estimates of 2-4 times the rate in men, and male CRPS patients were found to be more likely to suffer from depression and kinesiophobia. Additionally, the presence of fibromyalgia has been shown to increase the risk of CRPS up to 2.5 times that of controls. Other musculoskeletal conditions, such as rheumatoid arthritis, may also increase the risk of CRPS. Furthermore, the paper discusses the potential correlation between CRPS and human papillomavirus (HPV) vaccination, but findings from published reports and a small case series found no statistically significant correlation.

CRPS Pathophysiology

The pathophysiology of complex regional pain syndrome (CRPS) remains incompletely understood despite several decades of study. CRPS is characterized by an abnormal tissue response to injury, increased sensitization of the peripheral and central nervous systems, inflammatory changes, and autonomic dysregulation. Genetic and psychological factors are also believed to contribute to the progression of CRPS. The clinical course of CRPS is thought to involve two phases: the acute/warm phase, marked by the release of pro-inflammatory modulators, and the chronic/cold phase, characterized by the activation of keratinocytes, fibroblasts, and osteocytes.

Inflammation

The research paper discusses the role of inflammation in complex regional pain syndrome (CRPS). CRPS is associated with a heightened and persistent activation of the innate immune system, leading to the release of pro-inflammatory cytokines such as interleukin-6 (IL-6), IL-1b, and tumor necrosis factor-a (TNF-a). This immune cascade results in histamine-induced vasodilation, causing the characteristic symptoms of redness, swelling, pain, and warmth in the acute phase of CRPS. Additionally, pro-inflammatory cytokines activate osteoblasts and osteoclasts, leading to rapid bone turnover and osteoporotic changes in the chronic phase of CRPS. The paper also highlights the presence of expanded populations of CD4+ and CD8+ lymphocytes in CRPS patients, indicating an antigen-mediated T lymphocyte response.

Furthermore, the study identifies IL-37 and GM-CSF as novel biomarkers in the immune response of CRPS patients. Decreased serum levels of IL-37 suggest suppression of the immune response, while increased levels of GM-CSF highlight a predominantly pro-inflammatory state. Neuropathic inflammation is also considered pivotal in CRPS development, involving the activation of peripheral nociceptors and the production of proinflammatory neuropeptides such as Substance P and calcitonin gene-related peptide (CGRP). Skin biopsies from CRPS patients confirmed the binding of Substance P and CGRP to their receptors on keratinocytes, resulting in neurogenic inflammatory changes and subsequent hyperalgesia and allodynia. Finally, a case study noted degeneration of A-a nerve fibers but spared A-d nerve fibers in a CRPS patient, hypothesizing that increased A-d nociceptive activity may explain the observed allodynia and hyperalgesia in CRPS patients.

Autonomic Nervous System

The autonomic nervous system plays a critical role in complex regional pain syndrome (CRPS) by influencing clinical symptoms such as skin color changes, heart rate fluctuations, and sweating. The imbalance in CRPS patients is explained by increased expression of a-1 adrenergic receptors on skin cells and pain receptors. Contrary to normal sympathetic activation which causes vasoconstriction, CRPS patients have decreased norepinephrine levels in the affected limb but increased systemic catecholamine expression. In the acute phase, sympathetic activity decreases, leading to upregulation and sensitization of peripheral a-1 adrenergic receptors resulting in vasodilation and warmth. In the chronic cold phase, excessive release of proinflammatory cytokines leads to heightened sympathetic activity and reduced a-1 adrenergic receptor expression, causing vasoconstriction and a cold, blue limb.

Furthermore, increased a-1 adrenergic receptor expression is associated with pain, evidenced by hyperalgesia after phenylephrine (a-1 analog) injections in CRPS patients. Additionally, studies showed that the sympathetic nervous system is implicated in local pain pathways in CRPS, with evidence indicating that the knockdown of sympathetic pathways led to reduced pain behaviors and decreased sympathetic nerve fiber sprouting.

Autoimmunity

The research paper discusses the evidence for autoimmunity in Complex Regional Pain Syndrome (CRPS). Previous studies have shown elevated levels of autoantibodies in the serum, skin, and tissues of CRPS patients, as well as in animal models. It is believed that these autoantibodies cause pain in CRPS by sensitizing nociceptors. Experiments with mice showed that transferring serum IgG from CRPS patients increased hypersensitivity to painful mechanical stimuli like cold and heat but not to painful tactile stimulation. Furthermore, CRPS patients with higher pain levels had higher IgG antibody titers. In experimental fracture models, increased levels of IgM antibodies were found in the skin and spinal tissue of rats, which were believed to cause increased nociceptive sensitization. Studies also found that patients with longstanding CRPS had elevated serum levels of functionally active autoantibodies with a-1 adrenergic, b-2 adrenergic, and M2 muscarinic agonist activity. These antibodies were commonly present in the serum of CRPS patients but not found in patients with other chronic pain conditions.

Genetic/Epigenetic Factors

Genetic Factors

The relationship between genetic and epigenetic factors in Complex Regional Pain Syndrome (CRPS) has been extensively studied, though no concrete genetic link has been found. However, familial aggregation and similar findings among CRPS patients suggest a suspected link. Studies have focused on the human leukocyte antigen system (HLA), with the genes HLA-DRB1 and HLA-DQB1 showing abnormal regulation. This suggests that the immune system, particularly the adaptive immune response, may play a pivotal role in CRPS development. Specifically, the increased expression of HLA-DQB1 among CRPS patients and its association with immune cells indicates its potential significance. The relationship between HLA-DQB1 and CRPS resembles the association between HLA-DQ8 and celiac disease, where the HLA gene binds gluten-peptides on antigen-presenting cells, leading to a downstream inflammatory effect. Additionally, a study explored the correlation between CRPS and exosomes enriched in miR-939, revealing changes in gene expression in human cells. However, gaps remain in understanding exosomes and their relation to pain, specifically CRPS.

Epigenetic Factors

The study explores the influence of epigenetics, specifically DNA methylation, on pain and Complex Regional Pain Syndrome (CRPS). The research, conducted on post-war amputee victims, focused on CpG sites, which are known to be affected by genetic and environmental factors such as trauma, smoking, and diet and suppress transcriptional activity. The study found 48 statistically significant CpG sites that were methylated, with the majority being hypomethylated in CRPS patients compared to non-CRPS patients. Many of these sites were associated with immune function. Additionally, over one-third of CRPS patients exhibited higher levels of antineuronal antibodies. The study suggests commonalities in genetic and epigenetic factors within the immune system characteristics. Based on these findings, the study proposes a focus on the immune system and its relationship to CRPS for further understanding.

Psychological Factors

The research paper states there is an inconclusive association between the role of psychological factors and CRPS despite the fact that recent studies suggest a connection between psychological factors and pain outcome. The findings suggest more studies are needed to understand the relationship between the psychological factors and CRPS.

Depression

The research paper discusses the potential link between psychological disorders, specifically depression, and the development of Complex Regional Pain Syndrome (CRPS). A study comparing CRPS patients, major depressive disorder (MDD) patients, and a control group found that psychological profiles do not predispose individuals to the development of CRPS. The study suggested that the psychological profile might be secondary to pain or contribute to its chronicity. While MDD patients experienced anxiety and depression involving emotional dysregulation, CRPS patients showed differences in the mechanism of depression. This may indicate that CRPS patients have intact emotional regulation, and their depression differs from the mental disorder depression. The causal relationship between depression and CRPS remains unclear, although it is known that depression is common among CRPS patients.

PTSD

A study explored the potential link between Post-Traumatic Stress Disorder (PTSD) and Complex Regional Pain Syndrome (CRPS). It involved 152 CRPS patients, 55 individuals with chronic pain, and 55 healthy controls. The findings indicated that 38% of CRPS patients, 10% of non-CRPS pain patients, and 4% of healthy individuals met the criteria for PTSD. Notably, 86% of CRPS patients with PTSD symptoms had them prior to the CRPS diagnosis, while 14% developed PTSD during the course of CRPS. The study suggests a higher prevalence of PTSD in CRPS patients. However, the authors note the limited scope of the study and emphasize the need for further research to establish a more definitive conclusion.

Neuropsychological

The research paper states that CRPS causes complex neurological changes in the brain in a similar manner to how a brain lesion can impact a person's life. These changes include a sense of ownership over the affected body part, distortion of its size, negative emotions towards the affected body part, and deficits in both lateralized spatial and non-spatial-lateralized cognitive functions.

Diagnosis Criteria

The International Association for the Study of Pain (IASP) developed diagnostic criteria for Complex Regional Pain Syndrome (CRPS) in 1993 in an effort to enhance its clinical recognition. However, studies revealed that the IASP criteria lacked specificity, leading to overdiagnosis and inappropriate treatments. One notable shortcoming was the failure to incorporate motor and trophic features commonly associated with CRPS. Subsequently, the Budapest Criteria was established in 2003 to address these issues and is currently the accepted diagnostic criteria for CRPS.

According to the Budapest Criteria, the diagnosis of CRPS requires continuing pain disproportionate to any inciting event, the presence of specific symptoms from four sensory, vasomotor, sudomotor/edema, and motor/trophic categories, signs in at least two of these categories, and the absence of a better explanation for the patient's signs and symptoms. The sensory symptoms include hyperesthesia and allodynia, while vasomotor symptoms involve temperature and skin color changes, sudomotor/edema symptoms encompass edema and sweating changes, and motor/trophic symptoms entail decreased range of motion and motor dysfunction.

An analysis of diagnostic subgroups found that CRPS predominantly affected the lower extremities (47.7%) and was more prevalent on the right side (50.5%). This indicates a distinct pattern of involvement for CRPS compared to non-CRPS cases. These findings underline the importance of the Budapest Criteria in diagnosing CRPS, and its potential to provide more accurate and specific identification of this condition.

Current Treatment

The research paper suggests that early initiation of therapy is associated with a positive prognosis for the patient. The goals of therapy include restoring limb functionality, reducing pain, and improving quality of life. A multidisciplinary approach to therapy is necessary, which includes patient education, physical and occupational therapy, psychiatry, and pain medicine specialists who can provide pharmacological and surgical interventions.

Physical and Occupational Therapy

The research paper emphasizes the importance of physical and occupational therapies in the initial treatment of Complex Regional Pain Syndrome (CRPS) patients to help them overcome their fear of pain and kinesophobia. A variety of therapeutic modalities such as massage, electrotherapy, acupuncture, contrast baths, biofeedback, isometric strengthening exercise, counter strain, and gentle range of motion have been studied. According to a Cochrane review of 18 Randomized Controlled Trials (RCTs), graded motor imagery and mirror therapy were found to provide the greatest rehabilitation benefit, significantly improving pain and quality of life, although the quality of evidence was assessed as very low. A recent randomized comparative effectiveness trial focused on a modified graded motor imagery program in women at risk for developing CRPS after distal radius fracture treated with cast immobilization.

Pharmacotherapy

The paper discusses various pharmacotherapies for treating Complex Regional Pain Syndrome (CRPS). Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids have been traditionally used but have shown limited evidence of effectiveness. Bisphosphonates have shown positive effects in modulating inflammatory mediators and reducing pain. Gabapentin has demonstrated efficacy in reducing pain, while ketamine targets NMDA pain pathways and has shown effectiveness in providing pain relief. Vitamin C has been shown to decrease the risk of CRPS after wrist fracture. Naltrexone and Botulinum toxin A (BTX-A) are new areas of research, with limited data on their effectiveness in CRPS. Plasma exchange therapy has shown promising results in reducing pain. The paper also discusses the use of medical cannabis-based treatments with conflicting results in efficacy and dosing. A recent study demonstrated a reduction in pain after using a metered-dose cannabis inhaler, showing promise for individualized treatment.

Minimally Invasive/Interventional Therapy Treatments

Sympathetic Block

The paper discusses minimally invasive/interventional therapy treatments for Complex Regional Pain Syndrome (CRPS), focusing on the use of sympathetic blocks. It highlights the limited evidence on the short- and long-term analgesic effects of sympathetic blocks in CRPS. Weissman et al. described the role of sympathetic blocks and epidural catheters, while Zernikow et al. concluded that there is weak evidence for the use of invasive treatments for CRPS in pediatric patients. A study involving 318 patients, 255 of whom were diagnosed with CRPS, found that 155 patients experienced a pain reduction of over 50% after receiving sympathetic blocks. The majority of these patients (71%) reported relief from pain lasting 1-4 weeks, with a smaller percentage (14%) experiencing relief for more than a month. This data demonstrates the clinical significance of sympathetic blocks and supports their use as a treatment for CRPS, providing evidence where there was previously a lack of it. The findings suggest that sympathetic blocks can be an effective option for managing CRPS, particularly considering the significant pain reduction experienced by the majority of patients following this minimally invasive treatment.

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) has emerged as a potential treatment for pain management due to its safety and non-invasiveness. This technique involves delivering a brief magnetic pulse to the brain, which can induce cortical excitability. High-frequency TMS has been shown to have a rapid effect on reducing pain, with noticeable results as early as 30 seconds after treatment. The pain reduction effects also extend beyond 1 week post-treatment. However, the long-term efficacy of TMS in providing pain relief requires further investigation to draw conclusive statements about its effectiveness. Therefore, while TMS shows promise in clinical applications for pain management, more research is needed to fully understand its long-term therapeutic potential.

Surgical Management

The surgical management of Complex Regional Pain Syndrome (CRPS) involves several options aimed at reducing the reliance on opioids and improving quality of life. Spinal cord stimulation (SCS), a traditional approach involving electrical stimulation of the dorsal columns, has shown effectiveness in modulating neuronal hyperexcitability and neurotransmitter concentration. High-frequency SCS at 10 kHz (HF10-SCS) has been found to significantly improve symptoms, even in patients who had not responded to traditional SCS. Implantable peripheral nerve stimulation (PNS) targets specific problem nerves and has shown significant improvements in pain rating, opioid therapy reduction, and functional outcomes. Dorsal root ganglion (DRG) stimulation has been found to be more effective than SCS with higher rates of treatment success, longer persistence of effects, and improved quality of life. Amputation, although controversial, has shown improvement in symptoms in some studies, and targeted muscle reinnervation has been applied with conflicting results. Pre-, peri-, and postoperative care, accurate diagnosis, procedure selection, and appropriate follow-up care are critical for successful outcomes irrespective of the surgical intervention chosen.

Future Therapy

The future of therapy for neuropathic pain holds promise with the potential use of mycophenolate, which, despite historical use as an immunosuppressant, has shown anecdotal evidence of improving neuropathic pain. However, its unknown mechanism and inconsistent results pose considerations. Similarly, the application of polydeoxyribonucleotide (PDRN) has demonstrated anti-inflammatory and regenerative effects along with some reduction in allodynia in animal models, warranting further investigation. Additionally, immersive virtual reality has been explored as a novel approach to reduce neuropathic pain in complex regional pain syndrome (CRPS), with a study showing potential improvement in participants who completed at least ten sessions. This approach may stimulate mirror neurons and neuroplasticity, akin to mirror therapy. While these innovative therapies show promise, they necessitate further examination to establish their effectiveness and long-term impact.

Conclusions

The research paper concludes that Complex Regional Pain Syndrome (CRPS) is a complex and multifactorial condition and its understanding has advanced considerably but is not yet complete. It emphasizes the need for larger, high-quality clinical studies to further understand the underlying mechanisms of CRPS, which in turn could lead to the development of more targeted therapies. Despite the expansion of therapy options through novel treatments, the paper notes that there is currently no successful therapeutic intervention for CRPS. As a result, the authors stress the importance of continued research efforts to explore combinations of medical and surgical therapies in order to pave the way for future CRPS treatment advancements.