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How to choose the right RSD treatment

Complex regional pain syndrome (CRPS) is a painful condition that usually affects a single limb, often as a result of an injury. The basic pathophysiology seems to be complex and varies from one patient to another. Although rodent models provide valuable information on different aspects of the pathophysiology of acute post-traumatic pain and inflammation, these models do not reproduce all the symptoms that patients experience, especially in cases of CRPS lasting months or years, which is why CRPS is thought to be a strictly human disease. Although considerable progress has been made in understanding CRPS, the disease is still clinically defined and diagnosed with clinical criteria. 

The criteria currently approved and validated against different neuropathic pain conditions, include the symptoms reported and the presence of signs in four different clinical categories, in the absence of any other explanation for the disorders. These clinical categories are as follows: sensory symptoms; vasomotor differences between affected and unaffected limbs; sudomotor differences or the presence of edema of the limbs; and a traumatized motor disorder that includes weakness, tremor or dystonia and/or characteristic trophic changes in skin, hair and nail growth. In order for CRPS to be diagnosed, at least three of the four categories of symptoms mentioned and their simultaneous presence at the time of consultation with the referring physician must be present. 

CRPS has traditionally been differentiated into two clinical subtypes. CRPS that develops after severe nerve damage is labeled CRPS type 2, while the remaining cases are called CRPS type 1. The second subtype is much more common than the first. A recent study suggested two further subtypes: “hot” CRPS and “cold” CRPS. The hot subtype is characterized by a warm, red, edematous and sweaty end, while the cold type is typically indicated by a cold, blue, less edematous end. Although the pathophysiology of CRPS is still controversial, the latest research suggests a scenario in which solemnly the triggering event is a trauma to the peripheral limb followed by post-traumatic inflammation and subsequent release of neuropeptides. At the same time, growth factors, catecholamines and autoantibodies contribute to trophic changes and sensitize peripheral nociceptors, inducing phenomena such as motion-related pain and thermal hyperalgesia. Some of these mediators make second-rate neurons in the spinal cord more sensitive, whose unresolved, long-term inflammation can cause damage to peripheral nerves, loss of function, and brain changes in sensitive patients. Related symptoms include non dermal sensory deficits, body perception disorders, motor symptoms. These may also have a spinal pathophysiology, such as the regulation of aberrant force returning from the organs of the Golgi tendon involving inhibitory interneurons. 

Development and training of CRPS. What are the factors that determine the choice of RSD treatment?

As CRPS may evolve over time, there are cases where acute CRPS becomes chronic, or where hot CRPS becomes cold, for which the presence of a single biomarker exclusive to this condition is unlikely. It is therefore preferable to look for the conditioning elements that can predict the development of CRPS and trace the best and most appropriate RSD treatment to the patient’s disorders. 

In order to establish the most appropriate RSD treatment, it is important to observe the patient’s subjective response, as well as the characteristics that differentiate the painful limbs from the non-painful ones, also based on adequate pain control groups. In a recent survey, magnetic resonance imaging was used to compare the size of the blood oxygen-dependent response in the primary somatosensory cortex after vibration stimuli on the affected hand with the non-infected response in patients with CRPS. The area of cortical representation was larger on the unaffected side, probably demonstrating the compensatory use of the healthy and painless hand. An increasing number of evidence suggests that disturbances in body representation and perception are key characteristics of the CRPS type. Neglect phenomena, distorted body image, dysmorphic body characteristics, spatial deficits and and impairment of the executive function have all been reported in CRPS. Impaired spatial perception has been shown to modulate limb temperature, tactile processing, spontaneous pain and sense of hand ownership in patients with this condition. Experiments in which perceived hand movements were altered by the use of prismatic glasses showed that in patients with CRPS, the temperature of the affected hand was modulated by the perceived position of the hands relative to their actual position or anatomical alignment. Based on clinical trials, these features were linked to parietal dysfunction. However, another investigation showed that these disorders of body perception occurred regularly after the fracture, regardless of CRPS. All these factors make it difficult to choose the right RSD treatment, as the responses of the subject affected by CRPS vary from case to case even during the period of hospitalization. This is evident in the value differences found between patients with CRPS and limb pain maps that are not sufficient to formally identify the CRPS biomarker and establish the appropriate RSD treatment. These differences increase the specificity of the CRPS report and may demonstrate phenotypic characteristics. Think of the cases of some patients with CRPS for whose diagnosis and subsequent formulation of RSD treatment were considered several factors. In this study, cases were revealed where right patients with CRPS had a wider subjective midline of view to the left than right patients with limb pain and healthy controls, regardless of the hand involved. Interestingly, neglect phenomena have another incidence factor in CRPS, not necessarily related to the patient’s pain threshold and response to RSD treatment, but related to anxiety, depression, somatization and depersonalization. In implementing RSD treatment, it was also found that in some cases the vision of bistable images exacerbated pain and sensory disturbances in CRPS, including changes in the perception of temperature and weight of the affected limb. To verify this normally for proper treatment planning RSD a quantitative sensory test that revealed significant sensory disturbances in patients with CRPS and a significantly reduced pain threshold. In fact, this minimal pain threshold particularly emerges as a response to RSD treatment in patients with central sensory processing disorders, in whom impaired bilateral suppression of the impulse of somatosensory evoked potentials has been exerted. 

The RSD treatment: characteristics and development 

Given that each case of CRPS is different from the other, we need to ask ourselves what is the best RSD treatment and how to implement it. There are different forms of treatment for the treatment of CRPS, and a combination of them is good use. In order to achieve a fast and definitive recovery, it is advisable to start the treatment with a pharmacological RSD treatment. There are currently several medical currents that prefer one drug over another, but there is unanimous thinking when referring to the effectiveness of the use of neridronic acid (Neridronate) intravenously or intramuscularly. 

Therapeutic strategies for RSD treatment 

Several therapeutic strategies have also been used in the management of the chronic stage of CRPS. It has been reported that blocking calcium channels with nifedipine is effective in managing the vasoconstriction that occurs at this stage of CRPS. In addition, the use of gamma-aminobutyric acid agonist (GABA), such as baclofen, has also been effective in reducing dystonia and pain, improving function and quality of life in patients with chronic CRPS. In fact, a recent study on neuromodulation combined with baclofen in addition to spinal cord stimulation therapy (SCS) has shown its effectiveness in reducing pain intensity and dystonia, suggesting the need for further large-scale studies. 


Ketamine is a well-established treatment for CRPS in some countries, but the response to this RSD treatment has not always been positive. A proof of concept study investigated whether the expression of miRNA circulating in the whole blood of patients with treatment-resistant CRPS was altered in response to ketamine therapy 69. This analysis identified 14 miRNAs that were expressed differently before and after treatment, both in patients who responded well or badly to ketamine. Comparison of miRNAs in transponders compared to the results of the to poor respondents prior to treatment showed a differential expression of 33 miRNAs. In the post-treatment samples, 43 miRNAs differed between respondents and poor respondents. These results indicate the potential feasibility of using miRNA signatures in circulation as biomarkers to predict treatment response. 

Bisphosphonates: what they are and what role they play in RSD treatment 

Bisphosphonate compounds are potent inhibitors of osteoclastic activity and are clinically used to treat bone-related conditions such as osteoporosis and Paget’s disease; and cancer-related conditions, including multiple myeloma, and bone metastases from solid tumors. They generally have low oral bioavailability. 

Patchy osteoporosis and bone marrow oedema may result from osteoclastic hyperactivity. Zoledronic acid is a potent inhibitor of bone resorption and osteoclast activity. Nitrogen containing bisphosphonates, such as zoledronic acid, also inhibits the mevalonate pathway in osteoclast, thus interrupting normal osteoclast function. 

There are several fields of application for bisphosphonates, the efficacy of which has been found in several diseases. 

For example, neridronic acid or another bisphosphonate may be administered orally to alleviate musculoskeletal pain, including lower back pain and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid) arthropathies, non-joint rheumatism, periarticular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget’s disease, fibrous dysplasia, transient hip osteoarthritis, vertebral crush fractures, osteoporosis, etc. In some forms of realization, a greater bioavailability of zoledronic acid can be obtained in the treatment of one of these conditions by administering a dosage form including zoledronic acid in the form of disodium salt. This may allow the use of a reduced molar amount of disodium salt compared to that which would be used with the diacidia form. As an osteoclast inhibitor, neridronic acid can also be used to treat bone fractures or to improve bone fracture healing. In some cases neridronic acid may also be administered orally to relieve neuropathic pain, such as mono radiculopathies, phantom limb pain, central pain and other causes of neuropathic pain. Over the last few years, several therapies have been proposed, which have seen too small randomised studies that have not allowed us to draw the necessary conclusions and make certain statements. However, what has emerged is significant in how to date one of the most effective treatments for pain CRPS is the administration of bisphosphonates in the form of neridronic acid, via infusions. In fact, the results of the studies have revealed substantial benefits and excellent results have been found in patients in the early stages of the disease, often with persistent remission or complete recovery. Since the only accredited mechanism of action of bisphosphonates is the suppression of osteoclastic bone resorption, it is likely that dramatic initial bone loss will play a role in the maintenance and evolution of CRPS 1. Short courses of high doses of bisphosphonates should be considered the treatment of choice for patients with CRPS 1. 

That is why the use of neridronic acid in RSD treatment is recommended. The effectiveness of this drug in treating bone related disorders is incomparable to other treatments for success. 


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