Complex regional pain syndrome: diagnostic challenges and favorable response to prednisolone.

Complex regional pain syndrome (CRPS), characterized by severe and disproportionate pain, is a rare and debilitating condition. Due to its rarity, evidence-based treatment guidelines remain limited, creating a challenge for clinicians. We present the case of a 20-year-old female with CRPS type 1 of the right hand. Her pain, initially triggered by a minor trauma, had persisted for three months. The patient demonstrated severe pain, swelling, hyperesthesia, and restricted range of motion. Despite multiple hospital visits, her symptoms did not improve until she was diagnosed with CRPS and treated with oral prednisolone. A dosage of 40 mg daily led to a dramatic response within 10 days. Our report emphasizes the importance of recognizing CRPS and highlights the potential of prednisolone as a treatment option, particularly in resource-limited settings, where more specialized interventions may be unavailable. Further research is essential to establish a stronger evidence base for the use of steroids in CRPS management.

Teriparatide and clodronate combination as a potential treatment for complex regional pain syndrome type I in delayed consolidation after foot surgery: a case report and review of the literature.

BACKGROUND: Complex regional pain syndrome type I is a pathological condition characterized by an exaggerated response of tissues to low or moderate pain stimuli. The exact pathogenesis and optimal medical treatment for complex regional pain syndrome type I are still not fully understood, although bisphosphonates have shown positive effects in reducing pain. Foot surgery can be complicated by the development of complex regional pain syndrome type I, leading to functional decline and difficulties in weight-bearing. CASE PRESENTATION: The authors present a clinical case involving complex regional pain syndrome type I that developed after surgical foot arthrodesis. The patient, a 42-year-old Caucasian male, did not respond to clodronate treatment but experienced successful outcomes upon the addition of teriparatide, which effectively stimulated the healing of arthrodesis. CONCLUSION: Teriparatide cannot be considered the primary treatment for complex regional pain syndrome due to insufficient solid clinical data. However, when complex regional pain syndrome is associated with or caused by delayed union, teriparatide can be used to address the underlying cause of complex regional pain syndrome.

An update on the pharmacotherapeutic options for complex regional pain syndrome.

INTRODUCTION: Complex regional pain syndrome (CRPS) is a rare and painful condition that has a wide range of triggering factors, often traumatic, and can present various clinical manifestations. The lack of knowledge about the underlying mechanisms has led to numerous treatment approaches, both conservative and surgical, which work through different mechanisms of action. AREAS COVERED: In this review, the authors explore the key aspects of CRPS, including definition, diagnostic criteria, pitfalls, pathogenic hypotheses, and treatment strategies with a focus on pharmacotherapy. The review was based on a comprehensive search of the literature using PubMed, while also considering international guidelines for managing CRPS. EXPERT OPINION: Based on the available evidence, pharmacological interventions appear to be effective in treating CRPS, especially when they target peripheral mechanisms, specifically nociceptive inflammatory pain, and when administered early in the course of the disease. However, there is still a lack of reliable evidence regarding the effects of drugs on central mechanisms of chronic pain in CRPS. In our expert opinion, drug therapy should be initiated as soon as possible, particularly in warm CRPS patient clusters, to prevent significant functional limitations, psychological distress, and negative impacts on individuals' social and economic well-being.

Remission of hypersensitivity by simple weight load stimuli in a complex regional pain syndrome mouse model.

Painful sensitivity of the hand or foot are the most common and debilitating symptoms of complex regional pain syndrome (CRPS). Physical therapy is standard treatment for CRPS, but evidence supporting its efficacy is minimal and it can be essentially impossible for CRPS patients to actively exercise the painful limb. Using the well-characterized distal tibial fracture CRPS mouse model, we compared the therapeutic effects of several weeks of daily hindlimb loading versus rotarod walking exercise. The effects of loading and exercise were evaluated by weekly testing of hind-paw withdrawal thresholds to von Frey fibers and radiant heat, as well as measurements of paw and ankle edema. At 6 weeks after fracture, the mice were killed and the ipsilateral femur, spinal cord and L4/5 dorsal root ganglia, and hind-paw skin collected for PCR assays and paw skin Immunohistochemistry evaluation. Hindlimb loading reduced hind-paw von Frey allodynia and heat hyperalgesia and edema within a week and these effects persisted for at least a week after discontinuing treatment. These therapeutic effects of loading exceeded the beneficial effects observed with rotarod walking exercise in fracture mice. Levels of nerve growth factor and transient receptor potential vanilloid 1 (TRPV1) immunostaining in the hind-paw skin were increased at 6 weeks after fracture, and both loading and exercise treatment reduced increases. Collectively, these results suggest that loading may be an effective and possibly curative treatment in CRPS patients with sensitivity in the affected limb.

Experience from a single-center study on multimodal medication therapy for patients with complex regional pain syndrome.

BACKGROUND: Despite the application of various therapeutic methods, pain caused by complex regional pain syndrome (CRPS) is not sufficiently managed and often progresses to a chronic stage. For the systematic and effective treatment of CRPS, we developed an algorithm for multimodal medication therapy based on the established pathophysiology of CRPS to control CRPS-related pain. OBJECTIVE: In this study, we present the outcomes of our novel algorithm for multimodal medication therapy for patients with CRPS, consisting of three major components: multimodal oral medication, intravenous ketamine, and intravenous lidocaine therapy. METHODS: We retrospectively investigated patients with CRPS who received multimodal therapy. Pain severity scores were evaluated using a numerical rating scale at four time points (P1, pain at initial consultation; P2, pain after oral medication; P3, pain after ketamine treatment; and P4, pain after lidocaine treatment). The effect of the multimodal medication therapy algorithm on pain management was evaluated at each time point. RESULTS: In patients with CRPS, multimodal oral medication, intravenous ketamine, and intravenous lidocaine therapies led to significantly improved pain control (p< 0.05). Additionally, the combination of these three therapies (through the multimodal medication therapy algorithm) resulted in significant pain relief in patients with CRPS (p< 0.05). CONCLUSIONS: Our multimodal medication therapy algorithm effectively controlled pain in patients with CRPS. However, further prospective studies with large sample sizes and randomized controlled trials are needed for more accurate generalization.

Microbiota-Accessible Boron-Containing Compounds in Complex Regional Pain Syndrome.

The microbiota-gut-brain axis has garnered increasing attention in recent years for its role in various health conditions, including neuroinflammatory disorders like complex regional pain syndrome (CRPS). CRPS is a debilitating condition characterized by chronic neuropathic pain, and its etiology and pathophysiology remain elusive. Emerging research suggests that alterations in the gut microbiota composition and function could play a significant role in CRPS development and progression. Our paper explores the implications of microbiota in CRPS and the potential therapeutic role of boron (B). Studies have demonstrated that individuals with CRPS often exhibit dysbiosis, with imbalances in beneficial and pathogenic gut bacteria. Dysbiosis can lead to increased gut permeability and systemic inflammation, contributing to the chronic pain experienced in CRPS. B, an essential trace element, has shown promise in modulating the gut microbiome positively and exerting anti-inflammatory effects. Recent preclinical and clinical studies suggest that B supplementation may alleviate neuropathic pain and improve CRPS symptoms by restoring microbiota balance and reducing inflammation. Our review highlights the complex interplay between microbiota, inflammation, and neuropathic pain in CRPS and underscores the potential of B as a novel therapeutic approach to target the microbiota-gut-brain axis, offering hope for improved management of this challenging condition.

Complex Regional Pain Syndrome (CRPS) and the Value of Early Detection.

PURPOSE OF REVIEW: The goal of this narrative review is to describe the current understanding of the pathology of Complex Regional Pain Syndrome (CRPS), as well as diagnostic standards and therapeutic options. We will then make the case for early recognition and management. RECENT FINDINGS: CRPS remains an enigmatic pain syndrome, comprising several subtypes. Recent recommendations clarify diagnostic ambiguities and emphasize the importance of standardized assessment and therapy. Awareness of CRPS should be raised to promote prevention, early detection, and rapid escalation of therapy in refractory cases. Comorbidities and health costs (i.e., the socioeconomic impact) must also be addressed early to prevent negative consequences for patients.

Perineural treatment with anti-TNF-α antibody ameliorates persistent allodynia and edema in novel mouse models with complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is an intractable chronic pain syndrome with various signs and symptoms including allodynia/hyperalgesia, edema, swelling, and skin abnormalities. However, a definitive therapeutic treatment for CRPS has not been established. In CRPS patients, inflammatory cytokines such as TNF-α and IL-1ß have been shown to increase in affected areas, suggesting that these molecules may be potential therapeutic targets for CRPS. Here, we first created a novel CRPS mouse model (CRPS-II-like) via sciatic nerve injury and cast immobilization, which was characterized by mechanical allodynia, local edema, and skin abnormalities, to evaluate the pathophysiology and pharmacotherapy of CRPS. When an anti-TNF-α antibody was consecutively administered near the injured sciatic nerve of CRPS model mice, persistent allodynia and CRPS-related signs in the ipsilateral hindpaw were markedly attenuated to control levels. Perineural administration of anti-TNF-α antibody also suppressed the upregulation of inflammatory cytokines as well as the activation of macrophages and Schwann cells in the injured sciatic nerve. These findings indicate that persistent allodynia and CRPS-related signs in CRPS models are primarily associated with TNF-α-mediated immune responses in injured peripheral nerves, suggesting that perineural treatment with anti-TNF-α antibody might be therapeutically useful.

Animal models of complex regional pain syndrome: A scoping review.

BACKGROUND: complex regional pain syndrome (CRPS) leads to a debilitating chronic pain condition. The lack of cause, etiology, and treatment for CRPS has been widely explored in animal models. OBJECTIVE: Provide a comprehensive framework of the animal models used for investigating CRPS. ELIGIBILITY CRITERIA: Preclinical studies to induce the characteristics of CRPS, with a control group, in any language or publication date. SOURCES OF EVIDENCE: The search was performed in the Medline (PubMed) and ScienceDirect databases. RESULTS: 93 studies are included. The main objective of the included studies was to understand the CRPS model. Rats, males and adults, exposed to ischemia/reperfusion of the paw or fracture of the tibia were the most common characteristics. Nociceptive evaluation using von Frey monofilaments was the most widely adopted in the studies. CONCLUSIONS: For the best translational science between the animal models and individuals with CRPS, future studies should include more heterogeneous animals, and multiple assessment tools, in addition to improving the description and performance of measures that reduce the risk of bias.

Perspectives on the pharmacological management of complex regional pain syndrome.

INTRODUCTION: Complex regional pain syndrome (CRPS) is a chronic pain condition that is notoriously difficult to treat. Therapies for CRPS include cognitive behavioral, physical, and occupational therapy, single or multidrug pharmacotherapy, and a variety of interventional techniques. Unfortunately, randomized clinical trials of these therapies are limited. The large number of potential pharmacologic options can be overwhelming for providers in their attempts to develop a treatment plan. AREAS COVERED: This article will review the literature on the pharmacologic management of CRPS. It is based on a systematic search of PubMed using keywords, followed by evaluation of the bibliographies for relevant articles. EXPERT OPINION: No single drug has amassed enough evidence to suggest clear efficacy, but a handful of agents with at least modest evidence are commonly used, including gabapentinoids, bisphosphonates, ketamine, and pulsed dose steroids. Meanwhile, other agents that lack significant evidence specifically in CRPS but have evidence in other neuropathic conditions are commonly prescribed, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SNRIs). In our opinion, careful selection and prompt initiation of appropriate pharmacotherapy may optimize pain relief and improve functionality in patients burdened with this debilitating condition.

Ketamine for Complex Regional Pain Syndrome: A Narrative Review Highlighting Dosing Practices and Treatment Response.

This is a narrative review of intravenous ketamine infusions for the treatment of complex regional pain syndrome (CRPS). It briefly covers the definition of CRPS, its epidemiology, and other treatments before introducing ketamine as the article's focus. A summary of ketamine's evidence base and its mechanisms of action is provided. The authors then review ketamine dosages reported in peer-reviewed literature for the treatment of CRPS, and their associated duration of pain relief. The observed response rates to ketamine and predictors of treatment response are also discussed.

Prednisolone 20 mg vs 40 mg in complex regional pain syndrome type I: A randomized controlled trial.

BACKGROUND: High dose of corticosteroid has been found beneficial in complex regional pain syndrome type I (CRPS-I). We report the efficacy and safety of prednisolone 20 mg versus 40 mg in CRPS-I in an open label randomized controlled trial. METHODS: The patients with CRPS-I of the shoulder joint with a CRPS score of ≥8 were included. Their demographic details, comorbidities, and underlying etiology were noted. The severity of CRPS was assessed using a 0-14 CRPS scale, the pain using a 0-10 Visual Analogue Scale (VAS), and sleep quality using a 0-10. Daily Sleep Interference Scale (DSIS). Patients were randomized to prednisolone 40 mg/day (group I) or 20 mg/day (group II) for 14 days, then tapered to 10 mg in group I and to 5 mg in group II by 1 month. Thereafter both groups received prednisolone 5 mg/day for 2 months. The primary outcome was a >50% reduction in VAS score, and secondary outcomes were a reduction in CRPS score, DSIS score, and adverse events. RESULTS: Fifty patients were included, and their baseline characteristics were comparable. At one month, all the patients had >50% reduction in the VAS score. The effect size was 0.38 (95% CI 0.93-0.20; p = 0.20). On the Kaplan-Mayer analysis, the improvement in the VAS score (Hazard ratio-1.43, 95 % CI-0.80-2.56, p = 0.22) and the CRPS score (HR-0.79,95 % CI-0.45-1.39; p = 0.41) was insignificant between the two groups. The DSIS score improved in group II (HR-1.85,95 % Cl-1.04-3.31,p = 0.04). Group I patients needed frequent adjustment of antidiabetic drugs (14 vs 6; p = 0.04). CONCLUSION: The efficacy of prednisolone 20 mg is not inferior to 40 mg in CRPS-I, and is safe in diabetic patients. LIMITATIONS: This is an open label randomized controlled trial with small sample size without a placebo arm.

Intermittent versus continuous esketamine infusions for long-term pain modulation in complex regional pain syndrome: protocol of a randomized controlled non-inferiority study (KetCRPS-2).

BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic pain condition of an extremity. While achieving pain relief in CRPS is challenging, esketamine infusions can accomplish pain relief for several weeks post-infusion in a subgroup of CRPS patients. Unfortunately, CRPS esketamine protocols are very heterogeneous in advice on dosage, administration and treatment setting. Currently, no trials are available that study differences between intermittent and continuous esketamine infusions for CRPS. With the current situation of bed shortages, it is difficult to admit patients for several consecutive days for inpatient esketamine treatments. In this study, we investigate whether 6 intermittent outpatient esketamine treatments are not inferior to a continuous 6-day inpatient esketamine treatment in establishing pain relief. In addition, several secondary study parameters will be assessed in order to investigate mechanisms responsible for pain relief by esketamine infusions. Furthermore, the cost-effectiveness will be analyzed. METHODS: In this RCT, the primary objective is to demonstrate that an intermittent esketamine dosing regimen is non-inferior to a continuous esketamine dosing regimen at 3 months follow-up. We will include 60 adult CRPS patients. The inpatient treatment group receives a continuous intravenous esketamine infusion for 6 consecutive days. The outpatient treatment group receives a 6-hour intravenous esketamine infusion every 2 weeks for 3 months. Esketamine dose will be individually tailored and is started at 0.05 mg/kg/h and can be increased to a maximum of 0.2 mg/kg/h. Each patient will be followed for 6 months. The primary study parameter is perceived pain intensity, measured by an 11-point Numerical Rating Scale. Secondary study parameters are conditioned pain modulation, quantitative sensory testing, adverse events, thermography, blood inflammatory parameter, questionnaires about functionality, quality of life and mood and costs per patient. DISCUSSION: If our study reveals non-inferiority between intermittent and continuous esketamine infusions, these findings can be beneficial to increase the availability and flexibility of esketamine infusions through outpatient treatments. Furthermore, the costs of outpatient esketamine infusions could be lower than inpatient esketamine infusions. In addition, secondary parameters may predict response to esketamine treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT05212571 , date of registration 01-28-2022. PROTOCOL VERSION: Version 3, February 2022.

Usefulness of the perfusion index for monitoring the response to intravenous ketamine infusion therapy in patients with complex regional pain syndrome.

BACKGROUND: This study was performed to compare the perfusion index (PI) between affected and unaffected limbs in patients with complex regional pain syndrome (CRPS); it also evaluated the usefulness of the PI for monitoring the response to intravenous ketamine infusion therapy in such patients. METHODS: In total, 46 patients with CRPS in one arm or leg were enrolled in this study. The PIs of the unaffected (PIControl ) and affected (PICRPS ) limbs were simultaneously evaluated before and after treatment. RESULTS: PICRPS was significantly lower than PIControl at all time points. The change in PI from immediately before to 30 min after intravenous ketamine infusion therapy (TBefore and T30 min , respectively) in the affected limb was significantly correlated with the change in visual analog pain scale (VAS) between the two time points (r = 0.646, p < 0.001). The area under the curve for the changes in VAS and PICRPS between TBefore and T30 min was 0.928. The optimal threshold value for the change in PICRPS between TBefore and T30 min , to distinguish responders with a ≥ 50-point reduction in VAS score from nonresponders, was 22.60% with a sensitivity of 0.811 (95% CI: 0.774-0.848) and a specificity of 0.889 (95% CI: 0.848-0.930). Thirty-one patients showed a ≥ 50-point reduction in VAS score [67% (95% CI: 54%-80%)] and 15 patients showed a < 50-point reduction in VAS score [33% (95% CI: 20%-46%)]. Thirty patients showed an increased PI ≥ 22.60% [65% (95% CI: 50%-78%)] and 16 patients showed an increased PI < 22.60% [35% (95% CI: 22%-50%)]. Twenty-seven patients had a ≥ 50-point reduction in VAS score and an increased PI ≥ 22.60% [59% (95% CI: 44%-74%)]. Eleven patients had shown a < 50-point pain reduction in VAS score and increased PI < 22.60% [24% (95% CI: 13%-37%)]. CONCLUSION: The PI significantly differed between affected and unaffected limbs in patients with CRPS. The PI may be useful for monitoring the response to intravenous ketamine therapy in patients with CRPS.

Modulation of mTORC1 and IL-6 following mirror therapy and pregabalin in complex regional pain syndrome type 1.

Aim: The study was designed to evaluate the modulation of mTOR complex 1 (mTORC1) and IL-6 genes following the use of mirror therapy (MT) and pregabalin in complex regional pain syndrome type-1 patients. Materials & methods: Two groups of 20 patients: MT group received MT and pregabalin, control therapy group received pregabalin. Neuropathic pain symptom inventory (NPSI), numeric rating scale - pain, modified motor activity log, SF-12 questionnaire for quality of life and IL-6 and mTORC1 expression were evaluated. Results: Group MT demonstrated a statistically significant improvement in NPSI burning, NPSI allodynia and numeric rating scale pain scores, modified motor activity log and SF-12 scores. Significant downregulation of mTORC1 and IL-6 observed in both. Conclusion: MT is a significant adjunct to pregabalin in improving motor function, quality of life and alleviating pain in complex regional pain syndrome type 1. Clinical Trial Registration: CTRI/2019/01/017272 (ClinicalTrials.gov).

Complex regional pain syndrome is a form of long-term pain that involves an arm or a leg. It can develop after an injury, a surgery or a stroke. Although many drugs have been used for its treatment, the limited relief that these drugs produce along with their side effects have shifted focus to other physical and psychological modes of therapy. Mirror therapy is one such modality where the image of normal functioning limb seen in a mirror placed over the affected limb leads to pain relief in the affected limb. We have provided evidence that mirror therapy can reduce the pain of this syndrome and also decrease the levels of pain related genes in the body. This will help us to devise better treatment strategies for complex regional pain syndrome.

Harmful or safe? Exposure and pain provocation during physiotherapy of complex regional pain syndrome I: a narrative review.

BACKGROUND: Complex regional pain syndrome (CRPS) is a clinical diagnosis and an umbrella term for a heterogeneous group of states associated with pain disproportionate to any inciting event, together with a number of signs and symptoms that are manifested mainly in the limbs. There are often concerns among clinicians and patients about the potential harms caused by pain provocation during physiotherapy of CRPS, even though clinical guidelines de-emphasize pain-contingency. OBJECTIVE: The objective of this narrative review is to summarize current evidence regarding potential harms due to pain provocation during so-called exposure-based therapies in individuals with CRPS. METHODS: Six studies evaluating exposure-based approach were included (n= 6). RESULTS: Although only one included study focused primarily on safety and in the rest of the included studies the reporting of harms was insufficient and therefore our certainty in evidence is very low, taken together with outcome measures, available data does not point to any long-term deterioration in symptoms or function, or any major harms associated with pain provocation during physiotherapy of CRPS. CONCLUSION: There is a great need for higher-quality studies to determine which therapeutic approach is the most appropriate for whom and to evaluate the risks and benefits of different approaches in more detail.

Randomized controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in adults with complex regional pain syndrome.

OBJECTIVE: The objective was to investigate the efficacy and safety of soticlestat as adjunctive therapy in participants with complex regional pain syndrome (CRPS). DESIGN: A proof-of-concept phase 2a study, comprising a 15-week randomized, double-blind, placebo-controlled, parallel-group study (part A), and an optional 14-week open-label extension (part B). METHODS: Twenty-four participants (median age 44.5 years [range, 18-62 years]; 70.8% female) with chronic CRPS were randomized (2:1) to receive oral soticlestat or placebo. Soticlestat dosing started at 100 mg twice daily and was titrated up to 300 mg twice daily. In part B, soticlestat dosing started at 200 mg twice daily and was titrated up or down at the investigator's discretion. Pain intensity scores using the 11-point Numeric Pain Scale (NPS) were collected daily. The Patient-Reported Outcomes Measurement Information System (PROMIS)-29, Patients' Global Impression of Change (PGI-C), and CRPS Severity Score (CSS) were completed at screening and weeks 15 and 29. RESULTS: From baseline to week 15, soticlestat treatment was associated with a mean change in 24-hour pain intensity NPS score (95% confidence interval) of -0.75 (-1.55, 0.05) vs -0.41 (-1.41, 0.59) in the placebo group, resulting in a non-significant placebo-adjusted difference of -0.34 (-1.55, 0.88; P = .570). Statistically non-significant numerical changes were observed for the PROMIS-29, PGI-C, and CSS at weeks 15 and 29. CONCLUSIONS: Adjunctive soticlestat treatment did not significantly reduce pain intensity in participants with chronic CRPS.

Sympathetic Blocks as a Predictor for Response to Ketamine Infusion in Patients with Complex Regional Pain Syndrome: A Multicenter Study.

BACKGROUND: Ketamine infusions are frequently employed for refractory complex regional pain syndrome (CRPS), but there are limited data on factors associated with treatment response. Sympathetic blocks are also commonly employed in CRPS for diagnostic and therapeutic purposes and generally precede ketamine infusions. OBJECTIVES: We sought to determine whether demographic and clinical factors, and technical and psychophysical characteristics of sympathetic blocks are associated with response to ketamine infusion. METHODS: In this multi-center retrospective study, 71 patients who underwent sympathetic blocks followed by ketamine infusions at 4 hospitals were evaluated. Sympathetically maintained pain (SMP) was defined as ≥ 50% immediate pain relief after sympathetic block and a positive response to ketamine was defined as ≥ 30% pain relief lasting over 3 weeks. RESULTS: Factors associated with a positive response to ketamine in univariable analysis were the presence of SMP (61.0% success rate vs 26.7% in those with sympathetically independent pain; P = .009) and post-block temperature increase (5.66 ± 4.20 in ketamine responders vs 3.68 ± 3.85 in non-responders; P = .043). No psychiatric factor was associated with ketamine response. In multivariable analysis, SMP (OR 6.54 [95% CI 1.83, 23.44]) and obesity (OR 8.75 [95% 1.45, 52.73]) were associated with a positive ketamine infusion outcome. CONCLUSIONS: The response to sympathetic blocks may predict response to ketamine infusion in CRPS patients, with alleviation of the affective component of pain and predilection to a positive placebo effect being possible explanations.