RARE DISEASE
Complex regional pain syndrome
Complex regional pain syndrome
Complex regional pain syndrome
Drug discovery
20
drugs
With orphan designations
Overview
Complex Regional Pain Syndrome (CRPS) is a chronic neuroinflammatory condition characterized by disproportionate limb pain, autonomic dysfunction, and sensory/motor abnormalities following trauma, surgery, or injury. Diagnosed clinically via Budapest criteria, it manifests as hyperalgesia, edema, vasomotor instability, and trophic changes. CRPS-I (no confirmed nerve injury) is more common than CRPS-II (with nerve damage). Early intervention improves outcomes, but chronic cases often lead to significant disability.
Burden
Annual healthcare costs rise 2.17-fold post-diagnosis, with median expenses exceeding $8,500 [4].
Chronic cases often lead to functional disability, psychiatric comorbidities (e.g., depression, anxiety), and reduced quality of life [9][16][18].
Up to 35% experience systemic symptom spread, complicating management [2][17].
Therapies
Multimodal approach: Physical/occupational therapy (e.g., graded motor imagery, mirror therapy) paired with medications (gabapentin, corticosteroids, ketamine infusions) [3][8][13].
Interventions: Sympathetic nerve blocks, spinal cord stimulation, and dorsal root ganglion stimulation for refractory cases [3][5][8].
Adjuvant therapies: Cognitive behavioral therapy, IV immunoglobulin (limited evidence), and plasma exchange [3][4][13].
Categories: rare neurological diseases
Research Papers
2,182 drug discovery papers about Complex regional pain syndrome, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,182 drug discovery papers about Complex regional pain syndrome, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-07 | Intravenous ketamine for complex regional pain syndrome: Pain outcomes and predictors of response. A systematic review and meta‑analysis.
Intravenous ketamine is used for complex regional pain syndrome (CRPS), but variable response and uncertain durability limit patient selection. This systematic review evaluated reported predictors of response to intravenous ketamine in CRPS and quantified the extent and duration of pain relief. The protocol is registered in PROSPERO (CRD420250655066). Databases were searched from inception through March 26, 2026. Randomized trials and observational studies reporting intravenous ketamine in CRPS were included. Pain scores were rescaled to a 0-10 scale, and the mean difference in change from baseline was pooled for the earliest post-infusion assessment within 14 days using inverse-variance random-effects meta-analysis. Random-effects meta-regression modeled outcomes at 14 days or later. Predictors of response were synthesized narratively. Twenty-one studies (3 randomized trials) included 605 ketamine-treated patients, with most studies having a moderate to high risk of bias. The pooled mean baseline pain score was 7.4. At the earliest post-infusion assessment within 14 days, the mean change in pain was -3.6 (95%CI -4.7 to -2.5). Limited longer-term data up to 90 days suggested attenuation of effect, with a gradual return toward baseline. Responder definitions varied widely, with a median responder rate of 65% (range 0-100%). Only 3 studies formally evaluated predictors, and quantitative synthesis was not feasible. Reported associations included sympathetically maintained pain (aOR 6.54, 95%CI 1.83-23.44) and obesity (aOR 8.75, 95%CI 1.45-52.73). Other exploratory predictors included bone scintigraphy phase ratios and baseline microRNAs. Intravenous ketamine may reduce pain, but limited predictor evidence precludes firm conclusions for individualized treatment selection. PERSPECTIVE: This systematic review supports intravenous ketamine as a potential interventional option for complex regional pain syndrome, while emphasizing that standardized outcome reporting and validated predictors are needed before treatment can be reliably individualized.
2026-08-05 | Why do bisphosphonates work in the treatment of CRPS? A translational pharmacological perspective to solve a conundrum.
Bisphosphonates (BPs) have consistently yielded positive results in the treatment of Complex Regional Pain Syndrome (CRPS). However, biochemical and histopathological evidence suggests that osteoclasts, the primary pharmacological target of BPs, is not a key driver in the early pathogenetic steps of CRPS. To critically review and integrate current evidence on pharmacological mechanisms of action of BPs in CRPS and to propose unifying hypotheses explaining their clinical efficacy beyond antiosteoclastic activity. Literature from in vitro studies, animal models, and randomized clinical trials was integrated. Approximately 80 primary and review articles were critically reviewed. BPs efficacy in CRPS is best explained by a bone-driven pharmacological model by which local drug accumulation is achieved in the site of disease. This enables modulation of inflammatory and nociceptive processes on adjacent non-bone cells, including macrophages, neutrophils, keratinocytes, and nociceptive fibers. Inhibition of the mevalonate pathway in these cells may reduce inflammatory cytokines, nerve growth factor (NGF), and reactive oxygen species (ROS), while modulating nociceptive signaling pathways. Additional mechanisms, including modulation of vascular tone and neuropeptide signaling, may further contribute to therapeutic effects. This hypothesis may inform optimal treatment strategies and together improve understanding of CRPS pathophysiology.
2026-07-14 | Advances in evidence-based management of complex regional pain syndrome
Use of the best available evidence is fundamental to management of complex regional pain syndrome (CRPS), a rare and debilitating chronic pain disorder. While understanding of CRPS has evolved in recent decades, important clinical and research challenges remain. This thesis aimed to provided new evidence to advance CRPS management. Chapter Two showed that while the evidence supporting most CRPS interventions is of poor methodological quality, bisphosphonates, N-methyl D-aspartate receptor antagonists, and sensorimotor rehabilitation are promising treatments. Chapter Three found moderate certainty evidence that bisphosphonates may be effective for CRPS and identified important treatment effect modifiers that warrant further investigation before clinical implementation. Chapter Four found no clear evidence for the efficacy of ketamine and other N-methyl D-aspartate receptor antagonists for chronic pain. Chapter Five developed a guideline-informed, evidence-based treatment algorithm to inform international management of CRPS. Chapter Six outlined the design and analysis plan of MEMOIR, a 2x2 factorial randomised trial of memantine and graded motor imagery for CRPS. Chapter Seven provided data on the progress, participant characteristics, treatment adherence and safety of MEMOIR, showing rapid participant accrual and high follow-up rates. This program of work provides new evidence to improve the evidence-based management of CRPS by addressing important evidence gaps and proposing potential solutions to advance treatment identification and evaluation.
2026-07-14 | Inhibition of Janus kinase/signal transducer and activator of transcription reduces nociceptive sensitization in a murine model of complex regional pain syndrome.
Complex regional pain syndrome (CRPS) is a disabling condition relying in part on the production of pain-supporting autoantibodies. The Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling system regulates the adaptive system of immunity and is targeted to control autoimmune diseases. To evaluate the hypothesis that JAK-STAT inhibition could reduce the behavioral, cellular, and biochemical correlates of CRPS in a well-characterized murine tibia fracture model. Tofacitinib was used to inhibit JAK-STAT activity. Mechanical sensitization and hindlimb unweighting were used to follow nociceptive changes. Assays of regional lymph node hypertrophy, germinal center formation, and autoantibody production probed activation of adaptive immunity while single cell mass cytometry (CyTOF) identified specific cell sets sensitive to tofacitinib in this model. Tofacitinib reduced hindlimb allodynia and unweighting in male and female mice after tibial fracture. Subsequent experiments focused on male mice showed reduced autoantibody binding to keratin 16, histone 3.2, GFAP, and NMDAR2B in fracture animals treated with tofacitinib. The enhanced deposition of IgM in the skin of fracture limb hind paws was also eliminated by tofacitinib. Correspondingly, tofacitinib reduced lymph node hypertrophy and germinal center formation. Mass cytometry demonstrated that CD4+ and CD8+ T lymphocytes in regional lymph nodes show tofacitinib-sensitive changes in the activation of key immune signaling systems after fracture including BCL6, IkB, pCREB, and pS6. Conversely, enhanced production of the innate immune mediators IL-1β and IL-6 were not suppressed by tofacitinib. We conclude that tofacitinib reduces the regional nociceptive changes found in a murine model of CRPS possibly through inhibition of autoantibody production.
2026-07-09 | Mesotherapy With Lidocaine and Ketamine in Complex Regional Pain Syndrome Type 1: A Randomized Double-Blind Trial.
Complex regional pain syndrome type 1 (CRPS1) is a disabling pain syndrome whose treatment remains challenging. Mesotherapy is a therapeutic method involving the injection of low doses of active substances through the skin. No studies assessed mesotherapy in CRPS1 patients. The aim of this study was to evaluate the efficacy on pain relief of ketamine and lidocaine mixtures versus lidocaine alone administered by mesotherapy. This three-arm, randomized, double-blind trial compared mesotherapy with lidocaine 20 mg alone or mixed with ketamine at a dose of 20 mg or 40 mg, in addition to standard treatment. The primary outcome was the difference in pain between inclusion and D56 after four mesotherapy sessions, assessed by a visual analog scale (VAS). Thirty-one patients were randomized to receive lidocaine 20 mg (n = 10), lidocaine 20 mg + ketamine 20 mg (n = 11), or lidocaine 20 mg + ketamine 40 mg (n = 10). The mean difference in VAS score between inclusion and D56 was -25.60 (95% CI: -42.81, -8.39) in the lidocaine 20 mg group, -10.13 (95% CI: -26.24, 5.99) in the lidocaine 20 mg + ketamine 20 mg group, and -19.06 (95% CI: -36.11, -2.02) in the lidocaine 20 mg + ketamine 40 mg group. There was no statistically significant difference in change of VAS score between the 3 groups (p = 0.36). No infectious or severe adverse events occurred. This study did not demonstrate the superiority of mesotherapy with ketamine and lidocaine mixtures compared to lidocaine alone in relieving pain for CRPS1 patients. Lidocaine alone or mixed with ketamine can be administered safely with a rigorous mesotherapy procedure. The study was registered with ClinicalTrials.gov, number NCT04650074, and EudraCT, number 2020-005557-24.
antibodies
2026-03-01 | (105) Recognizing Complex Regional Pain Syndrome of the Vulvar Vestibule: Are We Missing the Mark?
Abstract Introduction Complex regional pain syndrome (CRPS) is a chronic pain condition diagnosed by the Budapest criteria (Harden et al. 2007) that has classically been described as affecting the extremities. Although it is historically described in orthopedics as occurring in the extremities, the same pathophysiology may also occur in the pelvis where the presentation may be overlooked by clinicians outside of orthopedic specialties who are unfamiliar with the pattern outlined by the Budapest criteria. Recognition of CRPS pathophysiology may be further complicated due to the affected pelvic anatomy containing mucosa and visceral tissue in addition to bone and connective tissue found in joints where it is classically described. Given its rich somatic and autonomically innervation, the vulvar vestibule may be an under-recognized locus for CRPS-type mechanisms-yet this has not previously been characterized in gynecology literature. Building on the neuroanatomical and pathophysiologic insights previously outlined in the interventional pain literature (Hunter et al. 2018), we describe CRPS localized to the vestibule to highlight its clinical presentation and implications for management in otherwise intractable pelvic pain. Objective To describe the clinical and pathophysiologic framework of CRPS of the vulvar vestibule and to call for standardized terminology that bridges gynecology, sexual medicine, pain medicine, orthopedics, neurology and neurosurgery. Recognition of CRPS pathophysiology will provide a roadmap for treatment of a subset of intractable pelvic pain. Methods We retrospectively reviewed cases from a multidisciplinary sexual medicine clinic (2021–2025). Inclusion criteria were pain confined to the vestibule and were fulfillment of Budapest diagnostic criteria for CRPS, with absence of infection, dermatosis, or other explanatory pathology, and documented sensory, sudomotor, vasomotor, and motor/trophic changes. Data collected included symptom profiles, diagnostic testing, and treatment outcomes. Results We propose that a subset of patients currently diagnosed with “refractory vestibulodynia” exhibit hallmarks of CRPS: disproportionate burning pain, dynamic allodynia, temperature or color change, and responsiveness to sympathetic nerve blocks. These features suggest an underlying process of neurogenic inflammation and maladaptive sympathetic–sensory coupling and possible central sensitization rather than a purely mucocutaneous pain disorder. Recognizing vulvar vestibular CRPS reframes these cases within an established pain taxonomy, enabling precise communication across specialties and guiding the use of targeted interventions such as sympathetic blockade, neuromodulation, and graded desensitization. Conclusions We describe the first conceptualization of vulvar vestibular CRPS-a distinct, localized expression of complex regional pain syndrome within the female genital tract. Awareness of vestibular CRPS allows for appropriate targeted therapy-including multimodal and interventional pain management. Adoption of this terminology across gynecology, sexual medicine, and interventional pain disciplines will provide a unifying diagnosis for what are can be seen as co-existing but discrete diagnoses in gynecology (high pelvic floor tone disorder, vulvodynia/vestibulodynia, pelvic congestion), facilitate collaborative research, and potentially increase access to care through insurance coverage to improve therapeutic outcomes for women with this disabling but underrecognized condition. Disclosure No.
2026-01-01 | Autophagy and Barrier Disruption in Patients with Complex Regional Pain Syndrome
The Complex Regional Pain Syndrome (CRPS) significantly impairs the quality of life of patients. It is characterized by a complex of symptoms indicating disturbances of the trophic, vascular, and somatosensory systems. In our previous study, a deficiency of miRNA-223 in blood exosomes was detected. It has been described that such a deficiency impairs autophagy. Additionally, individuals with edema, indicating barrier dysfunction, showed particularly low miRNA-223 levels. In this dissertation project, CRPS patients with low miRNA-223 were examined for autophagy disorders. Additionally, the barrier integrity formed by tight junction proteins and changes in trophicity, vascular supply, and the somatosensory system were analyzed. For this purpose, we investigated a series of autophagy proteins in the blood plasma of individuals with miRNA-223 deficiency. Skin samples were also taken from participants in the “ResolveCRPS” study. These samples were used for the analysis of mRNA and immunofluorescence of selected tight junction proteins, as well as for the examination of skin morphology, mechanoreceptors, and blood vessels. Our screening tests showed no general autophagy deficiency. However, elevated ATG16L1 levels were observed in “non-resolving” CRPS patients, correlating with exosomal miRNA-223. Furthermore, we observed a deficiency in claudin-19 mRNA gene expression in ipsilateral skin biopsies. Despite the use of new semi-automated analysis methods for tight junction proteins, no impairment of claudin-19 protein expression was observed. Morphological analysis revealed a bilateral reduction in Meissner corpuscles and blood vessels in CRPS skin biopsies. Overall, our results indicate impaired myelin barrier integrity as well as bilateral deficiency in Meissner corpuscles and papillary blood vessels. These findings are consistent with previous preclinical studies and morphological observations from biopsies of amputated limbs. The bilateral changes in skin morphology could represent a predisposition for CRPS. Future studies should validate our findings, evaluate the potential of Claudin-19 as a new therapeutic target, and investigate the effectiveness of skin biopsies in identifying at-risk patients.
2025-11-07 | Immunological Therapy in Persistent Complex Regional Pain Syndrome: A Systematic Review and Narrative Synthesis.
Immunological pathophysiological mechanisms have been postulated in Complex Regional Pain Syndrome (CRPS).Clinical features suggest abnormal immune activation, supported in laboratory studies. The purpose of this review is to systematically review the effects of therapies that can modulate the immune system in persistent CRPS. Articles were screened from PubMed, Embase, Scopus, clinicaltrials.gov, ISRCTN databases and Web of Science for articles, studies and conference abstracts in CRPS and immune therapies from inception up to April 2024. Titles and abstracts were screened, followed by reading the full text and reference lists to determine the final articles for analysis. Studies were restricted to adults and a duration of disease greater than 1 year. Randomised controlled trials were appraised using the Cochrane Risk of Bias (RoB2). A total of 1404 studies were yielded, and 23 articles were retrieved for full-text analysis after reviewing the titles, texts and abstracts. A narrative synthesis was used due to the heterogeneity of studies. The immune therapies used were glucocorticoids, thalidomide/lenalidomide, immunoglobulin, plasmapheresis, mycophenolate, anti-TNF-alpha inhibitors and epidermal growth factor receptor inhibitors. There were 16 reports of beneficial effects from non-randomised trials, case series and case reports of treatment with immunomodulating drugs or interventions. Small randomised trials of low-dose immunoglobulin, epidermal growth factor receptor inhibitors and mycophenolate suggest possible treatment benefit, but larger randomised trials of immunoglobulin and lenalidomide demonstrated no effect. The emergence of novel immune therapies for persistent CRPS shows promise, but evidence based on high-quality randomised trials remains limited and does not show a positive effect. This work summarises the current use of immune-modulating therapies in managing patients with persistent Complex Regional Pain Syndrome (CRPS). It complements the current interest in immunological approaches to pain management with the increasing role of immune mechanisms in both pain and CRPS. While promise has been shown in small case reports and cohort studies, the need for high-quality clinical trials is highlighted by the few large randomised controlled trials.
2025-08-11 | Do nerve resection, amputation, and immunotherapy relieve causalgia in the long term?
Reported here is the unpublished long follow-up (22 years and 14 years) of 2 patients with longstanding causalgia initially successfully treated by nerve resection and reported in detail previously in this journal. There are very little such long-term data for causalgia of this nature available. This is a rare opportunity to reevaluate these 2 patients who began their stories not too differently but went on to follow very different paths. One of these patients (CH) had causalgia after a traumatic right infraorbital nerve injury. This pain was relieved by nerve resection with no recurrence of facial pain for over 22 years. The other patient (HG) had many years of intractable complex regional pain syndrome type 2 of the common peroneal and sural nerves after a left leg injury in childhood. HG had 4 years and 4 months of good relief by nerve resection. At this time, severe pain recurrence and incipient gangrene of the left leg required amputation, which saved the leg but did not affect the pain, a worsening severe skin rash, and frequent respiratory infections. The amputated limb pathology suggested an autoimmune response and further tests provided evidence of autoimmune antibodies and immunoglobulin deficiency. Only after immunotherapy did these problems resolve and this improvement has persisted for 4 years and 9 months. There are few long-term assessments of causalgia treated by nerve resection, amputation, and/or immunotherapy. Short-term failures of these treatments may be due to treatable conditions such as immunological abnormalities.
2025-05-01 | COMPLEX REGIONAL PAIN SYNDROME: A MULTIDIMENSIONAL REVIEW OF PATHOPHYSIOLOGY, DIAGNOSIS, AND MANAGEMENT
Complex Regional Pain Syndrome (CRPS) is a debilitating condition characterized by disproportionate pain, autonomic dysfunction, and trophic changes that typically develops after limb trauma. Emerging research highlights neurogenic inflammation, central sensitization, and autoimmune mechanisms as key contributors [1]. Despite advances in understanding, CRPS remains frequently misdiagnosed due to its complex presentation and overlap with other pain disorders [2]. Early multidisciplinary intervention has been shown to improve functional outcomes, yet significant treatment gaps persist [3]. This comprehensive review synthesizes current evidence on CRPS pathophysiology, diagnostic challenges, and evidence-based management strategies, with particular emphasis on recent advances in immunomodulatory therapies and neuromodulation techniques.
proteins
2026-07-13 | Early Recognition and Management of Complex Regional Pain Syndrome Following Distal Radius Fracture: A Structured Narrative Review.
Complex regional pain syndrome (CRPS) is a chronic pain disorder that may develop following a distal radius fracture and can result in significant functional impairment and prolonged disability. Early diagnosis remains challenging because symptoms frequently overlap with normal post-fracture recovery. This structured narrative review evaluated current evidence regarding the timing of diagnosis, early predictors, and early management strategies influencing outcomes of CRPS following distal radius fracture. A structured literature search of PubMed/MEDLINE and Embase was performed for English-language studies published between 2000 and 2026 using combinations of keywords related to CRPS, distal radius fracture, diagnosis, risk factors, prevention, and management. Studies involving adult patients with CRPS following distal radius or wrist fracture and addressing diagnosis, predictors, or early management strategies were included. Owing to heterogeneity in study designs and outcome measures, findings were synthesized using thematic narrative analysis. Twenty-six studies met the inclusion criteria. Evidence suggests that clinical and physiological abnormalities associated with CRPS may emerge during the early post-injury period, although formal diagnosis is often established weeks to months after fracture treatment. Higher early pain intensity, enhanced pain sensitization, fibromyalgia, female sex, older age, lower vitamin D levels, and certain genetic polymorphisms were associated with an increased risk of CRPS. Early mobilization and structured rehabilitation strategies were associated with improved functional outcomes and lower reported CRPS incidence in several studies. Evidence regarding vitamin C prophylaxis was heterogeneous, with meta-analyses suggesting potential benefit while individual randomized controlled trials reported inconsistent findings. Imaging modalities demonstrated limited sensitivity for early diagnosis, reinforcing the importance of longitudinal clinical assessment. CRPS remains an uncommon but clinically important complication following a distal radius fracture. Current evidence supports the concept that altered recovery trajectories and early pain amplification may precede formal diagnosis. Careful monitoring of recovery, recognition of disproportionate symptoms, and promotion of early functional rehabilitation may facilitate earlier identification and management. Further prospective studies using standardized diagnostic criteria are required to better define early predictors and optimize preventive strategies.
2026-07-08 | Workers' compensation status is associated with increased complications following distal radius fracture open reduction and internal fixation.
BackgroundWhile workers' compensation (WC) patients often experience worse orthopedic outcomes, complication patterns following distal radius fracture (DRF) open reduction and internal fixation (ORIF) remain poorly defined. Prior DRF-specific studies include only small, regional cohorts. This study leverages Epic Cosmos to conduct the first nationwide analysis comparing complications between WC and non-WC populations.MethodsThis retrospective study queried the Epic Cosmos database for DRF ORIF procedures (2017-2024). WC patients (N = 4,101) were matched 1:5 with non-WC patients (N = 20,505) based on demographic and comorbidity characteristics. Patients required ≥6-month follow-up (mean 48.2 ± 28.6 and 48.9 ± 27.3 months for WC and non-WC patients, respectively). A subgroup analysis excluding patients with prior tendon injuries evaluated if WC status independently contributed to complication risk.ResultsWC patients had higher odds of complex regional pain syndrome (CRPS) (1.6% vs. 0.8%; OR 2.17, 95% CI [1.60, 2.91], p < 0.001), subsequent hardware removal (14.7% vs. 10.4%; OR 1.48, 95% CI [1.34, 1.63], p < 0.001), and postoperative stiffness (21.1% vs. 19.0%; OR 1.14, 95% CI [1.04, 1.23], p = 0.003), and lower odds of skin infection (2.9% vs. 4.0%; OR 0.73, 95% CI [0.59, 0.88], p = 0.001); all four associations remained significant after Bonferroni correction. No differences existed for venous thromboembolism, myocardial infarction, pulmonary embolism, or mechanical complication. Excluding prior tendon injury, CRPS remained significantly elevated in WC patients (OR 2.62, 95% CI [1.92, 3.57], p < 0.001).ConclusionsWC status is associated with higher risks of CRPS, subsequent hardware removal, and stiffness. Notably, CRPS risk remains elevated even after controlling for prior tendon injuries. As the largest WC-specific complication analysis for DRF ORIF to date, this exploratory study suggests that payer status may be a clinically meaningful correlate of postoperative morbidity. Future prospective studies are needed to confirm these associations.
2026-06-04 | Thoracic sympathetic block with botulinum toxin A for complex regional pain syndrome: a retrospective case series.
Sympathetic interventions are frequently used in complex regional pain syndrome (CRPS). However, the evidence is inconclusive, and the response may depend on phenotype, anatomical target, and treatment durability. For upper-extremity CRPS, clinical data on thoracic sympathetic block (TSB) with botulinum toxin type A (BoNT-A) are lacking. To describe patient characteristics, procedural details, and clinical and thermographic outcomes after computed tomography (CT)-guided TSB with BoNT-A in upper-extremity CRPS. We performed a retrospective single-center case series of consecutive adults with upper-extremity CRPS who underwent CT-guided TSB with BoNT-A between January 2023 and March 2026. For each procedure, medical records were reviewed to descriptively assess pain change, duration of effect, repeat procedures, thermographic change, and adverse events. Six patients underwent 7 procedures. Most suffered from persistent, treatment-refractory CRPS. Responses varied: 3 patients experienced a clinically meaningful analgesic benefit, 1 had thermographic improvement without clear analgesic benefit, and 2 had no meaningful response. No serious procedure-related complications were observed. CT-guided TSB with BoNT-A was feasible in this small retrospective series of refractory upper-extremity CRPS. Responses were heterogeneous, and thermographic improvement was not always accompanied by pain relief. The findings may prompt hypotheses regarding phenotype-based patient selection and the role of thermography.
2026-06-03 | How does iontophoresis enhance the transdermal delivery of calcitonin for managing complex regional pain syndrome?
Iontophoresis enhances the transdermal delivery of calcitonin by using electrical currents to improve skin permeability, offering potential benefits in managing complex regional pain syndrome. However, further research is needed to establish standardized protocols and verify its effectiveness specifically for CRPS.
2026-04-27 | Botulinum Toxin as Targeted Neuromodulation in Complex Regional Pain Syndrome: An Anatomy-Informed Mechanistic Review.
Complex regional pain syndrome (CRPS) is a heterogeneous and disabling chronic pain condition characterized by maladaptive neuroplasticity involving persistent peripheral nociceptive input, autonomic dysregulation, and central sensitization. Despite increasing clinical use, the role of botulinum toxin in CRPS remains controversial, with inconsistent outcomes reported across studies. This review synthesizes mechanistic, translational, and clinical evidence suggesting that these apparent inconsistencies may be partly explained by heterogeneity in anatomical targeting and route of administration rather than absence of biological efficacy. Available evidence suggests that botulinum toxin may exhibit its most consistent therapeutic signal when delivered to neural structures directly implicated in dominant CRPS pathophysiology, particularly the sympathetic nervous system and proximal somatic afferents, whereas superficial or non-specific delivery strategies appear to yield more variable responses. Importantly, differences across anatomical targets should not be interpreted as evidence of comparative effectiveness, as observed variation may reflect phenotype selection, procedural heterogeneity, confounding, and differences in outcome reporting. By integrating experimental data, randomized trials, and case-based clinical evidence, an anatomy-informed, route-specific neuromodulation framework is proposed to reconcile existing findings and inform future research. This mechanism-informed perspective is intended to guide rational trial design and phenotype-aligned clinical application of botulinum toxin in CRPS, rather than to provide a definitive evidence-closing synthesis.
cell therapies
2026-07-17 | Transradial Amputation With Nerve Management: Case Presentation and Surgical Technique.
Transradial amputation of appropriate length preserves forearm rotation and facilitates prosthetic use; however, high rates of phantom limb pain and neuropathic medication use persist. This case describes a multidisciplinary approach to transradial amputation that integrates targeted muscle reinnervation, regenerative peripheral nerve interfaces, and bone and soft tissue management to optimize pain control and prosthetic success. A 29-year-old man with a severe ballistic injury and complex regional pain syndrome underwent transradial amputation with targeted muscle reinnervation and regenerative peripheral nerve interface. Limb length was preserved in accordance with prosthetic guidelines, and myodesis was performed to improve residual limb stability and myoelectric signal quality. This case highlights how nerve management and prosthetic-informed surgical planning optimizes functional outcomes and quality of life after traumatic transradial amputation.
2026-06-26 | Pectoralis Minor Tenotomy with Occasional Secondary Neurolysis Significantly Reduces Self-Reported Pain and Headaches Across Heterogenous Chronic Pain Disorders of the Upper Limb.
Background and Objectives: Many patients suffer from chronic pain of the shoulder, neck, upper back, and/or arm. They may be diagnosed with fibromyalgia, complex regional pain syndrome, myofascial pain, thoracic outlet, subacromial pain, cervical radiculopathy, cervicogenic headaches, post-mastectomy pain, and/or occupational shoulder disorder. The pectoralis minor (PM) is the only muscle of the scapula controlled by the lower trunk of the brachial plexus. In the Human Disharmony Loop (HDL), this neurologic asymmetry produces persistent protraction of the scapula. Protraction deforms the scapula's connections, generating headaches and neck stiffness, upper back tightness, shoulder weakness, and hand numbness. We hypothesize patients with the above who meet HDL diagnostic criteria will benefit from PM tenotomy with brachial plexus neurolysis (PM+ICN). Materials and Methods: Patients diagnosed with the above disorders who also met HDL criteria of medial coracoid tenderness and scapula protraction on exam underwent PM+ICN, with secondary neurolysis after 3 months if needed. Clinical neuropathy was diagnosed via the scratch-collapse test. Outcomes included self-reported Visual Analogue Score pain scores, active shoulder abduction range of motion (ROM), prevalence of occipital headaches. Results: N = 318 patients were included. Average age was 51; 68.0% were female. Following treatment, average pain decreased from 7.3/10 to 2.1/10 (p < 0.001), average shoulder ROM increased from 96 to 170 degrees (p < 0.001), and occipital headaches decreased from 76.7% to 1.6% (p < 0.001). Scapular protraction normalized from 98.8% static to 92.5% none (p < 0.001). Overall, 17% required subsequent neurolysis, chiefly of the axillary, radial, and ulnar nerves. The pain reductions were statistically indistinguishable across all diagnoses (p = 0.709, I2 = 0.02%). Average follow-up was 22 months. Conclusions: PM+ICN significantly reduced self-reported pain and headaches in select intractable patients. The PM pathologizing the scapula may constitute a shared anatomic mechanism that contributes to chronic pain across heterogenous disorders of the upper limb.
2026-05-07 | A Pilot Study Of Pain And Functional Outcomes Following Elective Osseointegration As A Novel Surgical Solution For Refractory Complex Regional Pain Syndrome
PURPOSE: Complex Regional Pain Syndrome (CRPS) is a debilitating neuropathic pain condition that often resists medical management, nerve blocks, and spinal interventions. Historically, amputation has been discouraged because of poor prosthetic outcomes, high rates of residual limb pain, and the risk of worsening neuropathic symptoms. The advent of osseointegration (OI) has altered this paradigm by enabling direct skeletal fixation and enhanced prosthetic control, eliminating the discomfort associated with a socket. When combined with contemporary nerve reconstruction techniques such as targeted muscle reinnervation (TMR), regenerative peripheral nerve interfaces (RPNI), or hybrid TMRpni, patients may achieve both durable pain relief and enhanced function. This study presents a pilot series of patients with refractory CRPS who elected for amputation and OI as definitive management for otherwise untreatable pain. METHODS: A retrospective review was conducted of ten CRPS patients who underwent elective amputation followed by OI implantation. The mean age at surgery was 41.1 ± 14.2 years, and the mean BMI was 31.5 ± 7.6 kg/m². ². Reconstruction techniques included TMR in four patients, RPNI performed with orthopedics in three, and TMRpni in three. Pain scores were recorded preoperatively and at 30 days using a 0-10 numeric rating scale. Neuroma recurrence was documented. Statistical analyses included paired t-tests to compare pain improvement, ANOVA for differences between reconstruction types, and Fisher's exact test for infection rates. RESULTS: Mean preoperative pain scores were 7.7 ± 2.3, which decreased to 2.9 ± 2.5 postoperatively (p = 0.009; 95% CI 1.97-7.14). Although the differences between groups were not statistically significant (p = 0.314), all patients demonstrated clinically meaningful improvement. Neuroma recurrence was observed in one TMR and one TMRpni patient, while none occurred in the RPNI cohort. CONCLUSION: This pilot series highlights osseointegration as a promising surgical solution for CRPS patients with refractory pain who previously had no viable reconstructive options. When combined with modern nerve reconstruction, elective amputation with OI can provide substantial pain relief and restore functional independence. While there is a mild increase in pain scores at one year compared to 30 days postoperatively, levels remain well below preoperative baselines, indicating sustained improvement. These early results suggest a paradigm shift in the multidisciplinary management of severe CRPS and warrant larger prospective studies to refine technique and optimize outcomes Pain Scores Over Time Based on Nerve Reconstruction Group Group N Preop Pain Score 30 day Postoperative Pain Score 1-year Postoperative Pain Score Change in Pain Scores Preop to Most Recent RPNI 3 9±1.7 4.5±0.71 NA NA TMR 4 8±2.45 1.75±2.06 3.75±3.5 −4.25 ± 4.35 TMRpni 3 6±2 3.33±3.51 5.33±2.1 −0.67 ± 2.52
2026-02-02 | Mechanisms and clinical progress of spinal cord stimulation in refractory chronic pain: an overview.
Chronic pain is a major global health issue, affecting approximately 25% of the population. Managing this condition remains challenging due to the limited efficacy of current therapeutic options. Spinal cord stimulation (SCS), a form of neuromodulation, has been utilized to treat intractable visceral pain. This review summarizes recent advancements in understanding the effects and mechanisms of SCS in refractory chronic pain. Key mechanisms include neurotransmitter modulation, descending inhibition, and cortical changes. SCS operates through various modes, such as high-frequency, burst, closed-loop, dorsal horn inhibition, and descending control. Clinical indications for SCS encompass Failed Back Surgery Syndrome (FBSS), Complex Regional Pain Syndrome (CRPS), Painful Diabetic Peripheral Neuropathy (PDPN), ischemic pain, and cancer pain. This article aims to explore the clinical potential of SCS and the mechanisms underlying its therapeutic efficacy.
2025-11-25 | Bone marrow mesenchymal stem cells attenuate pain and modulate peripheral sodium channel activity in a rat model of complex regional pain syndrome type I.
Complex Regional Pain Syndrome Type I (CRPS-I) is a chronic neuropathic pain disorder characterized by peripheral nerve hyperexcitability and altered nociceptive signaling. Voltage-gated sodium channels (Nav1.7, Nav1.8, Nav1.9) in dorsal root ganglia (DRG) are key contributors to pain hypersensitivity. This study investigated the analgesic effects and underlying mechanisms of bone marrow mesenchymal stem cell (BMSC) transplantation in a CRPS-I rat model. The model was induced by hind limb ischemia-reperfusion, followed by intrathecal administration of BMSCs. Pain behaviors were assessed using thermal withdrawal latency (TWL), mechanical withdrawal latency (MWL), spontaneous pain scoring, and acetone-evoked cold allodynia. RT-PCR and Western blot analysis were used to evaluate Nav channel expression in DRG tissue, while electrophysiological properties were examined using whole-cell patch clamp to generate current-voltage (I-V) curves. CRPS-I rats exhibited decreased TWL and MWL, elevated expression of Nav1.7, Nav1.8, and Nav1.9, and enhanced sodium current density with delayed inactivation. BMSC transplantation significantly alleviated pain behaviors, downregulated sodium channel expression, and normalized I-V characteristics-marked by increased activation thresholds, reduced peak currents, and faster inactivation kinetics. These findings suggest that BMSCs mitigate neuronal hyperexcitability by modulating peripheral Nav channel activity. This study provides mechanistic evidence supporting the therapeutic potential of BMSC-based interventions for CRPS-I and related neuropathic pain conditions.
other
2026-05-06 | Genetic modulation of pain pathways: toward a new era in pain therapy- a systematic review.
Gene therapy represents a new strategy in pain management targeting the causes of pain rather than its symptoms. This review summarizes recent advances across RNA interference (RNAi), viral vector delivery systems, CRISPR/Cas9, gene replacement therapy, and endogenous opioid gene delivery, emphasizing efficacy, safety, and mechanisms of action in pain conditions. RNAi and gene replacement techniques remain powerful tools for reducing pain and improving the quality of life by modulating pain-associated genes. Long-term relief may also be achieved with CRISPR/Cas9 and site-directed delivery using nanoparticle systems. Safety profiles especially with CRISPR/Cas9 remains a concern. A systematic search of Web of Science, Medline, Scopus, and Google Scholar identified 512 records (January 2010-March 2023). Following PRISMA screening, 18 studies met inclusion criteria. These studies evaluated strategies of gene therapy in neuropathy, arthritis, fibromyalgia, and complex regional pain syndrome. The review outlines available options and highlights preclinical findings.
2024-10-09 | Sex-specific role of RNA-binding protein, pAUF1, on prolonged hypersensitivity after repetitive ischemia with reperfusion injury.
Repetitive ischemia with reperfusion (I/R) injury is a common cause of myalgia. Ischemia with reperfusion injuries occur in many conditions that differentially affect males and females including complex regional pain syndrome and fibromyalgia. Our preclinical studies have indicated that primary afferent sensitization and behavioral hypersensitivity caused by I/R injury may be due to sex-specific gene expression in the dorsal root ganglia (DRG) and distinct upregulation of growth factors and cytokines in the affected muscles. To determine how these unique gene expression programs may be established in a sex-dependent manner in a model that more closely mimics clinical scenarios, we used a developed prolonged ischemic myalgia model in mice whereby animals experience repeated I/R injuries and compared behavioral results with unbiased and targeted screening strategies in male and female DRG. Several distinct proteins were found to be differentially expressed in male and female DRG, including phosphorylated AU-rich element RNA-binding protein (pAUF1), which is known to regulate gene expression. Nerve-specific siRNA-mediated knockdown of AUF1 inhibited prolonged hypersensitivity in females only, whereas overexpression of AUF1 in male DRG neurons increased pain-like responses. AUF1 knockdown was able to specifically inhibit repeated I/R-induced gene expression in females potentially downstream of prolactin receptor signaling. Data suggest RNA-binding proteins such as pAUF1 may underlie the sex-specific effects on DRG gene expression that modulates behavioral hypersensitivity after repeated I/R injury through prolactin signaling. This study may aid in finding distinct receptor differences related to the evolution of acute to chronic ischemic muscle pain development between sexes.
2022-06-21 | Microvascular Barrier Protection by microRNA-183 via FoxO1 Repression: A Pathway Disturbed in Neuropathy and Complex Regional Pain Syndrome.
Blood nerve barrier disruption and edema are common in neuropathic pain as well as in complex regional pain syndrome (CRPS). MicroRNAs (miRNA) are epigenetic multitarget switches controlling neuronal and non-neuronal cells in pain. The miR-183 complex attenuates hyperexcitability in nociceptors, but additional non-neuronal effects via transcription factors could contribute as well. This study explored exosomal miR-183 in CRPS and murine neuropathy, its effect on the microvascular barrier via transcription factor FoxO1 and tight junction protein claudin-5, and its antihyperalgesic potential. Sciatic miR-183 decreased after CCI. Substitution with perineural miR-183 mimic attenuated mechanical hypersensitivity and restored blood nerve barrier function. In vitro, serum from CCI mice und CRPS patients weakened the microvascular barrier of murine cerebellar endothelial cells, increased active FoxO1 and reduced claudin-5, concomitant with a lack of exosomal miR-183 in CRPS patients. Cellular stress also compromised the microvascular barrier which was rescued either by miR-183 mimic via FoxO1 repression or by prior silencing of Foxo1. PERSPECTIVE: Low miR-183 leading to barrier impairment via FoxO1 and subsequent claudin-5 suppression is a new aspect in the pathophysiology of CRPS and neuropathic pain. This pathway might help untangle the wide symptomatic range of CRPS and nurture further research into miRNA mimics or FoxO1 inhibitors.
2022-06-18 | MicroRNA‐21‐5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury
Abstract Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA‐21‐5p (miR‐21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR‐21 in neuropathic pain and its impact on the BNB in a human‐murine back translational approach. MiR‐21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin‐1 in both injured and spared nerves. Moreover, the putative miR‐21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb . In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR‐21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB . Perineurial miR‐21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR‐21 after nerve injury reversed it. In summary, the data support a novel role for miR‐21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.
2022-03-07 | Acute worsening of clinical presentation in CRPS after SARS-CoV-2 (COVID-19) vaccination: a case series.
We present the acute worsening of clinical presentation in complex regional pain syndrome (CRPS), following mRNA-based COVID-19 vaccination. We report the case series of three patients diagnosed with CRPS type I who presented with acute worsening of symptoms after mRNA-based COVID-19 vaccination and their medical management. The acute clinical worsening after mRNA-based COVID-19 vaccination was transient and effectively managed with adjustment of individualized therapy in all three patients. The mortality and morbidity of COVID-19 infection are serious, and vaccination is recommended in the general population, including patients with a diagnosis of CRPS. However, clinicians should be aware of the possibility that there may be a clinical worsening CRPS after mRNA-based COVID-19 vaccination. This case series presents the worsening of symptoms in complex regional pain syndrome (CRPS), following mRNA-based COVID-19 vaccination. We report on three patients diagnosed with CRPS who presented with worsening of symptoms after mRNA-based COVID-19 vaccination and their medical management. The worsening of symptoms was temporary and managed with adjustment of individualized therapy in all three patients. The dangers of COVID-19 infection are serious, and vaccination is highly recommended in the general population, including patients with a diagnosis of CRPS. However, healthcare providers should be aware of the possibility of clinical worsening of CRPS after mRNA-based COVID-19 vaccination.
small molecules
2026-08-07 | Intravenous ketamine for complex regional pain syndrome: Pain outcomes and predictors of response. A systematic review and meta‑analysis.
Intravenous ketamine is used for complex regional pain syndrome (CRPS), but variable response and uncertain durability limit patient selection. This systematic review evaluated reported predictors of response to intravenous ketamine in CRPS and quantified the extent and duration of pain relief. The protocol is registered in PROSPERO (CRD420250655066). Databases were searched from inception through March 26, 2026. Randomized trials and observational studies reporting intravenous ketamine in CRPS were included. Pain scores were rescaled to a 0-10 scale, and the mean difference in change from baseline was pooled for the earliest post-infusion assessment within 14 days using inverse-variance random-effects meta-analysis. Random-effects meta-regression modeled outcomes at 14 days or later. Predictors of response were synthesized narratively. Twenty-one studies (3 randomized trials) included 605 ketamine-treated patients, with most studies having a moderate to high risk of bias. The pooled mean baseline pain score was 7.4. At the earliest post-infusion assessment within 14 days, the mean change in pain was -3.6 (95%CI -4.7 to -2.5). Limited longer-term data up to 90 days suggested attenuation of effect, with a gradual return toward baseline. Responder definitions varied widely, with a median responder rate of 65% (range 0-100%). Only 3 studies formally evaluated predictors, and quantitative synthesis was not feasible. Reported associations included sympathetically maintained pain (aOR 6.54, 95%CI 1.83-23.44) and obesity (aOR 8.75, 95%CI 1.45-52.73). Other exploratory predictors included bone scintigraphy phase ratios and baseline microRNAs. Intravenous ketamine may reduce pain, but limited predictor evidence precludes firm conclusions for individualized treatment selection. PERSPECTIVE: This systematic review supports intravenous ketamine as a potential interventional option for complex regional pain syndrome, while emphasizing that standardized outcome reporting and validated predictors are needed before treatment can be reliably individualized.
2026-08-05 | Why do bisphosphonates work in the treatment of CRPS? A translational pharmacological perspective to solve a conundrum.
Bisphosphonates (BPs) have consistently yielded positive results in the treatment of Complex Regional Pain Syndrome (CRPS). However, biochemical and histopathological evidence suggests that osteoclasts, the primary pharmacological target of BPs, is not a key driver in the early pathogenetic steps of CRPS. To critically review and integrate current evidence on pharmacological mechanisms of action of BPs in CRPS and to propose unifying hypotheses explaining their clinical efficacy beyond antiosteoclastic activity. Literature from in vitro studies, animal models, and randomized clinical trials was integrated. Approximately 80 primary and review articles were critically reviewed. BPs efficacy in CRPS is best explained by a bone-driven pharmacological model by which local drug accumulation is achieved in the site of disease. This enables modulation of inflammatory and nociceptive processes on adjacent non-bone cells, including macrophages, neutrophils, keratinocytes, and nociceptive fibers. Inhibition of the mevalonate pathway in these cells may reduce inflammatory cytokines, nerve growth factor (NGF), and reactive oxygen species (ROS), while modulating nociceptive signaling pathways. Additional mechanisms, including modulation of vascular tone and neuropeptide signaling, may further contribute to therapeutic effects. This hypothesis may inform optimal treatment strategies and together improve understanding of CRPS pathophysiology.
2026-07-14 | Advances in evidence-based management of complex regional pain syndrome
Use of the best available evidence is fundamental to management of complex regional pain syndrome (CRPS), a rare and debilitating chronic pain disorder. While understanding of CRPS has evolved in recent decades, important clinical and research challenges remain. This thesis aimed to provided new evidence to advance CRPS management. Chapter Two showed that while the evidence supporting most CRPS interventions is of poor methodological quality, bisphosphonates, N-methyl D-aspartate receptor antagonists, and sensorimotor rehabilitation are promising treatments. Chapter Three found moderate certainty evidence that bisphosphonates may be effective for CRPS and identified important treatment effect modifiers that warrant further investigation before clinical implementation. Chapter Four found no clear evidence for the efficacy of ketamine and other N-methyl D-aspartate receptor antagonists for chronic pain. Chapter Five developed a guideline-informed, evidence-based treatment algorithm to inform international management of CRPS. Chapter Six outlined the design and analysis plan of MEMOIR, a 2x2 factorial randomised trial of memantine and graded motor imagery for CRPS. Chapter Seven provided data on the progress, participant characteristics, treatment adherence and safety of MEMOIR, showing rapid participant accrual and high follow-up rates. This program of work provides new evidence to improve the evidence-based management of CRPS by addressing important evidence gaps and proposing potential solutions to advance treatment identification and evaluation.
2026-07-14 | Inhibition of Janus kinase/signal transducer and activator of transcription reduces nociceptive sensitization in a murine model of complex regional pain syndrome.
Complex regional pain syndrome (CRPS) is a disabling condition relying in part on the production of pain-supporting autoantibodies. The Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling system regulates the adaptive system of immunity and is targeted to control autoimmune diseases. To evaluate the hypothesis that JAK-STAT inhibition could reduce the behavioral, cellular, and biochemical correlates of CRPS in a well-characterized murine tibia fracture model. Tofacitinib was used to inhibit JAK-STAT activity. Mechanical sensitization and hindlimb unweighting were used to follow nociceptive changes. Assays of regional lymph node hypertrophy, germinal center formation, and autoantibody production probed activation of adaptive immunity while single cell mass cytometry (CyTOF) identified specific cell sets sensitive to tofacitinib in this model. Tofacitinib reduced hindlimb allodynia and unweighting in male and female mice after tibial fracture. Subsequent experiments focused on male mice showed reduced autoantibody binding to keratin 16, histone 3.2, GFAP, and NMDAR2B in fracture animals treated with tofacitinib. The enhanced deposition of IgM in the skin of fracture limb hind paws was also eliminated by tofacitinib. Correspondingly, tofacitinib reduced lymph node hypertrophy and germinal center formation. Mass cytometry demonstrated that CD4+ and CD8+ T lymphocytes in regional lymph nodes show tofacitinib-sensitive changes in the activation of key immune signaling systems after fracture including BCL6, IkB, pCREB, and pS6. Conversely, enhanced production of the innate immune mediators IL-1β and IL-6 were not suppressed by tofacitinib. We conclude that tofacitinib reduces the regional nociceptive changes found in a murine model of CRPS possibly through inhibition of autoantibody production.
2026-07-09 | Mesotherapy With Lidocaine and Ketamine in Complex Regional Pain Syndrome Type 1: A Randomized Double-Blind Trial.
Complex regional pain syndrome type 1 (CRPS1) is a disabling pain syndrome whose treatment remains challenging. Mesotherapy is a therapeutic method involving the injection of low doses of active substances through the skin. No studies assessed mesotherapy in CRPS1 patients. The aim of this study was to evaluate the efficacy on pain relief of ketamine and lidocaine mixtures versus lidocaine alone administered by mesotherapy. This three-arm, randomized, double-blind trial compared mesotherapy with lidocaine 20 mg alone or mixed with ketamine at a dose of 20 mg or 40 mg, in addition to standard treatment. The primary outcome was the difference in pain between inclusion and D56 after four mesotherapy sessions, assessed by a visual analog scale (VAS). Thirty-one patients were randomized to receive lidocaine 20 mg (n = 10), lidocaine 20 mg + ketamine 20 mg (n = 11), or lidocaine 20 mg + ketamine 40 mg (n = 10). The mean difference in VAS score between inclusion and D56 was -25.60 (95% CI: -42.81, -8.39) in the lidocaine 20 mg group, -10.13 (95% CI: -26.24, 5.99) in the lidocaine 20 mg + ketamine 20 mg group, and -19.06 (95% CI: -36.11, -2.02) in the lidocaine 20 mg + ketamine 40 mg group. There was no statistically significant difference in change of VAS score between the 3 groups (p = 0.36). No infectious or severe adverse events occurred. This study did not demonstrate the superiority of mesotherapy with ketamine and lidocaine mixtures compared to lidocaine alone in relieving pain for CRPS1 patients. Lidocaine alone or mixed with ketamine can be administered safely with a rigorous mesotherapy procedure. The study was registered with ClinicalTrials.gov, number NCT04650074, and EudraCT, number 2020-005557-24.
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2026-03-01 | (105) Recognizing Complex Regional Pain Syndrome of the Vulvar Vestibule: Are We Missing the Mark?
Abstract Introduction Complex regional pain syndrome (CRPS) is a chronic pain condition diagnosed by the Budapest criteria (Harden et al. 2007) that has classically been described as affecting the extremities. Although it is historically described in orthopedics as occurring in the extremities, the same pathophysiology may also occur in the pelvis where the presentation may be overlooked by clinicians outside of orthopedic specialties who are unfamiliar with the pattern outlined by the Budapest criteria. Recognition of CRPS pathophysiology may be further complicated due to the affected pelvic anatomy containing mucosa and visceral tissue in addition to bone and connective tissue found in joints where it is classically described. Given its rich somatic and autonomically innervation, the vulvar vestibule may be an under-recognized locus for CRPS-type mechanisms-yet this has not previously been characterized in gynecology literature. Building on the neuroanatomical and pathophysiologic insights previously outlined in the interventional pain literature (Hunter et al. 2018), we describe CRPS localized to the vestibule to highlight its clinical presentation and implications for management in otherwise intractable pelvic pain. Objective To describe the clinical and pathophysiologic framework of CRPS of the vulvar vestibule and to call for standardized terminology that bridges gynecology, sexual medicine, pain medicine, orthopedics, neurology and neurosurgery. Recognition of CRPS pathophysiology will provide a roadmap for treatment of a subset of intractable pelvic pain. Methods We retrospectively reviewed cases from a multidisciplinary sexual medicine clinic (2021–2025). Inclusion criteria were pain confined to the vestibule and were fulfillment of Budapest diagnostic criteria for CRPS, with absence of infection, dermatosis, or other explanatory pathology, and documented sensory, sudomotor, vasomotor, and motor/trophic changes. Data collected included symptom profiles, diagnostic testing, and treatment outcomes. Results We propose that a subset of patients currently diagnosed with “refractory vestibulodynia” exhibit hallmarks of CRPS: disproportionate burning pain, dynamic allodynia, temperature or color change, and responsiveness to sympathetic nerve blocks. These features suggest an underlying process of neurogenic inflammation and maladaptive sympathetic–sensory coupling and possible central sensitization rather than a purely mucocutaneous pain disorder. Recognizing vulvar vestibular CRPS reframes these cases within an established pain taxonomy, enabling precise communication across specialties and guiding the use of targeted interventions such as sympathetic blockade, neuromodulation, and graded desensitization. Conclusions We describe the first conceptualization of vulvar vestibular CRPS-a distinct, localized expression of complex regional pain syndrome within the female genital tract. Awareness of vestibular CRPS allows for appropriate targeted therapy-including multimodal and interventional pain management. Adoption of this terminology across gynecology, sexual medicine, and interventional pain disciplines will provide a unifying diagnosis for what are can be seen as co-existing but discrete diagnoses in gynecology (high pelvic floor tone disorder, vulvodynia/vestibulodynia, pelvic congestion), facilitate collaborative research, and potentially increase access to care through insurance coverage to improve therapeutic outcomes for women with this disabling but underrecognized condition. Disclosure No.
2026-01-01 | Autophagy and Barrier Disruption in Patients with Complex Regional Pain Syndrome
The Complex Regional Pain Syndrome (CRPS) significantly impairs the quality of life of patients. It is characterized by a complex of symptoms indicating disturbances of the trophic, vascular, and somatosensory systems. In our previous study, a deficiency of miRNA-223 in blood exosomes was detected. It has been described that such a deficiency impairs autophagy. Additionally, individuals with edema, indicating barrier dysfunction, showed particularly low miRNA-223 levels. In this dissertation project, CRPS patients with low miRNA-223 were examined for autophagy disorders. Additionally, the barrier integrity formed by tight junction proteins and changes in trophicity, vascular supply, and the somatosensory system were analyzed. For this purpose, we investigated a series of autophagy proteins in the blood plasma of individuals with miRNA-223 deficiency. Skin samples were also taken from participants in the “ResolveCRPS” study. These samples were used for the analysis of mRNA and immunofluorescence of selected tight junction proteins, as well as for the examination of skin morphology, mechanoreceptors, and blood vessels. Our screening tests showed no general autophagy deficiency. However, elevated ATG16L1 levels were observed in “non-resolving” CRPS patients, correlating with exosomal miRNA-223. Furthermore, we observed a deficiency in claudin-19 mRNA gene expression in ipsilateral skin biopsies. Despite the use of new semi-automated analysis methods for tight junction proteins, no impairment of claudin-19 protein expression was observed. Morphological analysis revealed a bilateral reduction in Meissner corpuscles and blood vessels in CRPS skin biopsies. Overall, our results indicate impaired myelin barrier integrity as well as bilateral deficiency in Meissner corpuscles and papillary blood vessels. These findings are consistent with previous preclinical studies and morphological observations from biopsies of amputated limbs. The bilateral changes in skin morphology could represent a predisposition for CRPS. Future studies should validate our findings, evaluate the potential of Claudin-19 as a new therapeutic target, and investigate the effectiveness of skin biopsies in identifying at-risk patients.
2025-11-07 | Immunological Therapy in Persistent Complex Regional Pain Syndrome: A Systematic Review and Narrative Synthesis.
Immunological pathophysiological mechanisms have been postulated in Complex Regional Pain Syndrome (CRPS).Clinical features suggest abnormal immune activation, supported in laboratory studies. The purpose of this review is to systematically review the effects of therapies that can modulate the immune system in persistent CRPS. Articles were screened from PubMed, Embase, Scopus, clinicaltrials.gov, ISRCTN databases and Web of Science for articles, studies and conference abstracts in CRPS and immune therapies from inception up to April 2024. Titles and abstracts were screened, followed by reading the full text and reference lists to determine the final articles for analysis. Studies were restricted to adults and a duration of disease greater than 1 year. Randomised controlled trials were appraised using the Cochrane Risk of Bias (RoB2). A total of 1404 studies were yielded, and 23 articles were retrieved for full-text analysis after reviewing the titles, texts and abstracts. A narrative synthesis was used due to the heterogeneity of studies. The immune therapies used were glucocorticoids, thalidomide/lenalidomide, immunoglobulin, plasmapheresis, mycophenolate, anti-TNF-alpha inhibitors and epidermal growth factor receptor inhibitors. There were 16 reports of beneficial effects from non-randomised trials, case series and case reports of treatment with immunomodulating drugs or interventions. Small randomised trials of low-dose immunoglobulin, epidermal growth factor receptor inhibitors and mycophenolate suggest possible treatment benefit, but larger randomised trials of immunoglobulin and lenalidomide demonstrated no effect. The emergence of novel immune therapies for persistent CRPS shows promise, but evidence based on high-quality randomised trials remains limited and does not show a positive effect. This work summarises the current use of immune-modulating therapies in managing patients with persistent Complex Regional Pain Syndrome (CRPS). It complements the current interest in immunological approaches to pain management with the increasing role of immune mechanisms in both pain and CRPS. While promise has been shown in small case reports and cohort studies, the need for high-quality clinical trials is highlighted by the few large randomised controlled trials.
2025-08-11 | Do nerve resection, amputation, and immunotherapy relieve causalgia in the long term?
Reported here is the unpublished long follow-up (22 years and 14 years) of 2 patients with longstanding causalgia initially successfully treated by nerve resection and reported in detail previously in this journal. There are very little such long-term data for causalgia of this nature available. This is a rare opportunity to reevaluate these 2 patients who began their stories not too differently but went on to follow very different paths. One of these patients (CH) had causalgia after a traumatic right infraorbital nerve injury. This pain was relieved by nerve resection with no recurrence of facial pain for over 22 years. The other patient (HG) had many years of intractable complex regional pain syndrome type 2 of the common peroneal and sural nerves after a left leg injury in childhood. HG had 4 years and 4 months of good relief by nerve resection. At this time, severe pain recurrence and incipient gangrene of the left leg required amputation, which saved the leg but did not affect the pain, a worsening severe skin rash, and frequent respiratory infections. The amputated limb pathology suggested an autoimmune response and further tests provided evidence of autoimmune antibodies and immunoglobulin deficiency. Only after immunotherapy did these problems resolve and this improvement has persisted for 4 years and 9 months. There are few long-term assessments of causalgia treated by nerve resection, amputation, and/or immunotherapy. Short-term failures of these treatments may be due to treatable conditions such as immunological abnormalities.
2025-05-01 | COMPLEX REGIONAL PAIN SYNDROME: A MULTIDIMENSIONAL REVIEW OF PATHOPHYSIOLOGY, DIAGNOSIS, AND MANAGEMENT
Complex Regional Pain Syndrome (CRPS) is a debilitating condition characterized by disproportionate pain, autonomic dysfunction, and trophic changes that typically develops after limb trauma. Emerging research highlights neurogenic inflammation, central sensitization, and autoimmune mechanisms as key contributors [1]. Despite advances in understanding, CRPS remains frequently misdiagnosed due to its complex presentation and overlap with other pain disorders [2]. Early multidisciplinary intervention has been shown to improve functional outcomes, yet significant treatment gaps persist [3]. This comprehensive review synthesizes current evidence on CRPS pathophysiology, diagnostic challenges, and evidence-based management strategies, with particular emphasis on recent advances in immunomodulatory therapies and neuromodulation techniques.
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2026-07-13 | Early Recognition and Management of Complex Regional Pain Syndrome Following Distal Radius Fracture: A Structured Narrative Review.
Complex regional pain syndrome (CRPS) is a chronic pain disorder that may develop following a distal radius fracture and can result in significant functional impairment and prolonged disability. Early diagnosis remains challenging because symptoms frequently overlap with normal post-fracture recovery. This structured narrative review evaluated current evidence regarding the timing of diagnosis, early predictors, and early management strategies influencing outcomes of CRPS following distal radius fracture. A structured literature search of PubMed/MEDLINE and Embase was performed for English-language studies published between 2000 and 2026 using combinations of keywords related to CRPS, distal radius fracture, diagnosis, risk factors, prevention, and management. Studies involving adult patients with CRPS following distal radius or wrist fracture and addressing diagnosis, predictors, or early management strategies were included. Owing to heterogeneity in study designs and outcome measures, findings were synthesized using thematic narrative analysis. Twenty-six studies met the inclusion criteria. Evidence suggests that clinical and physiological abnormalities associated with CRPS may emerge during the early post-injury period, although formal diagnosis is often established weeks to months after fracture treatment. Higher early pain intensity, enhanced pain sensitization, fibromyalgia, female sex, older age, lower vitamin D levels, and certain genetic polymorphisms were associated with an increased risk of CRPS. Early mobilization and structured rehabilitation strategies were associated with improved functional outcomes and lower reported CRPS incidence in several studies. Evidence regarding vitamin C prophylaxis was heterogeneous, with meta-analyses suggesting potential benefit while individual randomized controlled trials reported inconsistent findings. Imaging modalities demonstrated limited sensitivity for early diagnosis, reinforcing the importance of longitudinal clinical assessment. CRPS remains an uncommon but clinically important complication following a distal radius fracture. Current evidence supports the concept that altered recovery trajectories and early pain amplification may precede formal diagnosis. Careful monitoring of recovery, recognition of disproportionate symptoms, and promotion of early functional rehabilitation may facilitate earlier identification and management. Further prospective studies using standardized diagnostic criteria are required to better define early predictors and optimize preventive strategies.
2026-07-08 | Workers' compensation status is associated with increased complications following distal radius fracture open reduction and internal fixation.
BackgroundWhile workers' compensation (WC) patients often experience worse orthopedic outcomes, complication patterns following distal radius fracture (DRF) open reduction and internal fixation (ORIF) remain poorly defined. Prior DRF-specific studies include only small, regional cohorts. This study leverages Epic Cosmos to conduct the first nationwide analysis comparing complications between WC and non-WC populations.MethodsThis retrospective study queried the Epic Cosmos database for DRF ORIF procedures (2017-2024). WC patients (N = 4,101) were matched 1:5 with non-WC patients (N = 20,505) based on demographic and comorbidity characteristics. Patients required ≥6-month follow-up (mean 48.2 ± 28.6 and 48.9 ± 27.3 months for WC and non-WC patients, respectively). A subgroup analysis excluding patients with prior tendon injuries evaluated if WC status independently contributed to complication risk.ResultsWC patients had higher odds of complex regional pain syndrome (CRPS) (1.6% vs. 0.8%; OR 2.17, 95% CI [1.60, 2.91], p < 0.001), subsequent hardware removal (14.7% vs. 10.4%; OR 1.48, 95% CI [1.34, 1.63], p < 0.001), and postoperative stiffness (21.1% vs. 19.0%; OR 1.14, 95% CI [1.04, 1.23], p = 0.003), and lower odds of skin infection (2.9% vs. 4.0%; OR 0.73, 95% CI [0.59, 0.88], p = 0.001); all four associations remained significant after Bonferroni correction. No differences existed for venous thromboembolism, myocardial infarction, pulmonary embolism, or mechanical complication. Excluding prior tendon injury, CRPS remained significantly elevated in WC patients (OR 2.62, 95% CI [1.92, 3.57], p < 0.001).ConclusionsWC status is associated with higher risks of CRPS, subsequent hardware removal, and stiffness. Notably, CRPS risk remains elevated even after controlling for prior tendon injuries. As the largest WC-specific complication analysis for DRF ORIF to date, this exploratory study suggests that payer status may be a clinically meaningful correlate of postoperative morbidity. Future prospective studies are needed to confirm these associations.
2026-06-04 | Thoracic sympathetic block with botulinum toxin A for complex regional pain syndrome: a retrospective case series.
Sympathetic interventions are frequently used in complex regional pain syndrome (CRPS). However, the evidence is inconclusive, and the response may depend on phenotype, anatomical target, and treatment durability. For upper-extremity CRPS, clinical data on thoracic sympathetic block (TSB) with botulinum toxin type A (BoNT-A) are lacking. To describe patient characteristics, procedural details, and clinical and thermographic outcomes after computed tomography (CT)-guided TSB with BoNT-A in upper-extremity CRPS. We performed a retrospective single-center case series of consecutive adults with upper-extremity CRPS who underwent CT-guided TSB with BoNT-A between January 2023 and March 2026. For each procedure, medical records were reviewed to descriptively assess pain change, duration of effect, repeat procedures, thermographic change, and adverse events. Six patients underwent 7 procedures. Most suffered from persistent, treatment-refractory CRPS. Responses varied: 3 patients experienced a clinically meaningful analgesic benefit, 1 had thermographic improvement without clear analgesic benefit, and 2 had no meaningful response. No serious procedure-related complications were observed. CT-guided TSB with BoNT-A was feasible in this small retrospective series of refractory upper-extremity CRPS. Responses were heterogeneous, and thermographic improvement was not always accompanied by pain relief. The findings may prompt hypotheses regarding phenotype-based patient selection and the role of thermography.
2026-06-03 | How does iontophoresis enhance the transdermal delivery of calcitonin for managing complex regional pain syndrome?
Iontophoresis enhances the transdermal delivery of calcitonin by using electrical currents to improve skin permeability, offering potential benefits in managing complex regional pain syndrome. However, further research is needed to establish standardized protocols and verify its effectiveness specifically for CRPS.
2026-04-27 | Botulinum Toxin as Targeted Neuromodulation in Complex Regional Pain Syndrome: An Anatomy-Informed Mechanistic Review.
Complex regional pain syndrome (CRPS) is a heterogeneous and disabling chronic pain condition characterized by maladaptive neuroplasticity involving persistent peripheral nociceptive input, autonomic dysregulation, and central sensitization. Despite increasing clinical use, the role of botulinum toxin in CRPS remains controversial, with inconsistent outcomes reported across studies. This review synthesizes mechanistic, translational, and clinical evidence suggesting that these apparent inconsistencies may be partly explained by heterogeneity in anatomical targeting and route of administration rather than absence of biological efficacy. Available evidence suggests that botulinum toxin may exhibit its most consistent therapeutic signal when delivered to neural structures directly implicated in dominant CRPS pathophysiology, particularly the sympathetic nervous system and proximal somatic afferents, whereas superficial or non-specific delivery strategies appear to yield more variable responses. Importantly, differences across anatomical targets should not be interpreted as evidence of comparative effectiveness, as observed variation may reflect phenotype selection, procedural heterogeneity, confounding, and differences in outcome reporting. By integrating experimental data, randomized trials, and case-based clinical evidence, an anatomy-informed, route-specific neuromodulation framework is proposed to reconcile existing findings and inform future research. This mechanism-informed perspective is intended to guide rational trial design and phenotype-aligned clinical application of botulinum toxin in CRPS, rather than to provide a definitive evidence-closing synthesis.
cell therapies
2026-07-17 | Transradial Amputation With Nerve Management: Case Presentation and Surgical Technique.
Transradial amputation of appropriate length preserves forearm rotation and facilitates prosthetic use; however, high rates of phantom limb pain and neuropathic medication use persist. This case describes a multidisciplinary approach to transradial amputation that integrates targeted muscle reinnervation, regenerative peripheral nerve interfaces, and bone and soft tissue management to optimize pain control and prosthetic success. A 29-year-old man with a severe ballistic injury and complex regional pain syndrome underwent transradial amputation with targeted muscle reinnervation and regenerative peripheral nerve interface. Limb length was preserved in accordance with prosthetic guidelines, and myodesis was performed to improve residual limb stability and myoelectric signal quality. This case highlights how nerve management and prosthetic-informed surgical planning optimizes functional outcomes and quality of life after traumatic transradial amputation.
2026-06-26 | Pectoralis Minor Tenotomy with Occasional Secondary Neurolysis Significantly Reduces Self-Reported Pain and Headaches Across Heterogenous Chronic Pain Disorders of the Upper Limb.
Background and Objectives: Many patients suffer from chronic pain of the shoulder, neck, upper back, and/or arm. They may be diagnosed with fibromyalgia, complex regional pain syndrome, myofascial pain, thoracic outlet, subacromial pain, cervical radiculopathy, cervicogenic headaches, post-mastectomy pain, and/or occupational shoulder disorder. The pectoralis minor (PM) is the only muscle of the scapula controlled by the lower trunk of the brachial plexus. In the Human Disharmony Loop (HDL), this neurologic asymmetry produces persistent protraction of the scapula. Protraction deforms the scapula's connections, generating headaches and neck stiffness, upper back tightness, shoulder weakness, and hand numbness. We hypothesize patients with the above who meet HDL diagnostic criteria will benefit from PM tenotomy with brachial plexus neurolysis (PM+ICN). Materials and Methods: Patients diagnosed with the above disorders who also met HDL criteria of medial coracoid tenderness and scapula protraction on exam underwent PM+ICN, with secondary neurolysis after 3 months if needed. Clinical neuropathy was diagnosed via the scratch-collapse test. Outcomes included self-reported Visual Analogue Score pain scores, active shoulder abduction range of motion (ROM), prevalence of occipital headaches. Results: N = 318 patients were included. Average age was 51; 68.0% were female. Following treatment, average pain decreased from 7.3/10 to 2.1/10 (p < 0.001), average shoulder ROM increased from 96 to 170 degrees (p < 0.001), and occipital headaches decreased from 76.7% to 1.6% (p < 0.001). Scapular protraction normalized from 98.8% static to 92.5% none (p < 0.001). Overall, 17% required subsequent neurolysis, chiefly of the axillary, radial, and ulnar nerves. The pain reductions were statistically indistinguishable across all diagnoses (p = 0.709, I2 = 0.02%). Average follow-up was 22 months. Conclusions: PM+ICN significantly reduced self-reported pain and headaches in select intractable patients. The PM pathologizing the scapula may constitute a shared anatomic mechanism that contributes to chronic pain across heterogenous disorders of the upper limb.
2026-05-07 | A Pilot Study Of Pain And Functional Outcomes Following Elective Osseointegration As A Novel Surgical Solution For Refractory Complex Regional Pain Syndrome
PURPOSE: Complex Regional Pain Syndrome (CRPS) is a debilitating neuropathic pain condition that often resists medical management, nerve blocks, and spinal interventions. Historically, amputation has been discouraged because of poor prosthetic outcomes, high rates of residual limb pain, and the risk of worsening neuropathic symptoms. The advent of osseointegration (OI) has altered this paradigm by enabling direct skeletal fixation and enhanced prosthetic control, eliminating the discomfort associated with a socket. When combined with contemporary nerve reconstruction techniques such as targeted muscle reinnervation (TMR), regenerative peripheral nerve interfaces (RPNI), or hybrid TMRpni, patients may achieve both durable pain relief and enhanced function. This study presents a pilot series of patients with refractory CRPS who elected for amputation and OI as definitive management for otherwise untreatable pain. METHODS: A retrospective review was conducted of ten CRPS patients who underwent elective amputation followed by OI implantation. The mean age at surgery was 41.1 ± 14.2 years, and the mean BMI was 31.5 ± 7.6 kg/m². ². Reconstruction techniques included TMR in four patients, RPNI performed with orthopedics in three, and TMRpni in three. Pain scores were recorded preoperatively and at 30 days using a 0-10 numeric rating scale. Neuroma recurrence was documented. Statistical analyses included paired t-tests to compare pain improvement, ANOVA for differences between reconstruction types, and Fisher's exact test for infection rates. RESULTS: Mean preoperative pain scores were 7.7 ± 2.3, which decreased to 2.9 ± 2.5 postoperatively (p = 0.009; 95% CI 1.97-7.14). Although the differences between groups were not statistically significant (p = 0.314), all patients demonstrated clinically meaningful improvement. Neuroma recurrence was observed in one TMR and one TMRpni patient, while none occurred in the RPNI cohort. CONCLUSION: This pilot series highlights osseointegration as a promising surgical solution for CRPS patients with refractory pain who previously had no viable reconstructive options. When combined with modern nerve reconstruction, elective amputation with OI can provide substantial pain relief and restore functional independence. While there is a mild increase in pain scores at one year compared to 30 days postoperatively, levels remain well below preoperative baselines, indicating sustained improvement. These early results suggest a paradigm shift in the multidisciplinary management of severe CRPS and warrant larger prospective studies to refine technique and optimize outcomes Pain Scores Over Time Based on Nerve Reconstruction Group Group N Preop Pain Score 30 day Postoperative Pain Score 1-year Postoperative Pain Score Change in Pain Scores Preop to Most Recent RPNI 3 9±1.7 4.5±0.71 NA NA TMR 4 8±2.45 1.75±2.06 3.75±3.5 −4.25 ± 4.35 TMRpni 3 6±2 3.33±3.51 5.33±2.1 −0.67 ± 2.52
2026-02-02 | Mechanisms and clinical progress of spinal cord stimulation in refractory chronic pain: an overview.
Chronic pain is a major global health issue, affecting approximately 25% of the population. Managing this condition remains challenging due to the limited efficacy of current therapeutic options. Spinal cord stimulation (SCS), a form of neuromodulation, has been utilized to treat intractable visceral pain. This review summarizes recent advancements in understanding the effects and mechanisms of SCS in refractory chronic pain. Key mechanisms include neurotransmitter modulation, descending inhibition, and cortical changes. SCS operates through various modes, such as high-frequency, burst, closed-loop, dorsal horn inhibition, and descending control. Clinical indications for SCS encompass Failed Back Surgery Syndrome (FBSS), Complex Regional Pain Syndrome (CRPS), Painful Diabetic Peripheral Neuropathy (PDPN), ischemic pain, and cancer pain. This article aims to explore the clinical potential of SCS and the mechanisms underlying its therapeutic efficacy.
2025-11-25 | Bone marrow mesenchymal stem cells attenuate pain and modulate peripheral sodium channel activity in a rat model of complex regional pain syndrome type I.
Complex Regional Pain Syndrome Type I (CRPS-I) is a chronic neuropathic pain disorder characterized by peripheral nerve hyperexcitability and altered nociceptive signaling. Voltage-gated sodium channels (Nav1.7, Nav1.8, Nav1.9) in dorsal root ganglia (DRG) are key contributors to pain hypersensitivity. This study investigated the analgesic effects and underlying mechanisms of bone marrow mesenchymal stem cell (BMSC) transplantation in a CRPS-I rat model. The model was induced by hind limb ischemia-reperfusion, followed by intrathecal administration of BMSCs. Pain behaviors were assessed using thermal withdrawal latency (TWL), mechanical withdrawal latency (MWL), spontaneous pain scoring, and acetone-evoked cold allodynia. RT-PCR and Western blot analysis were used to evaluate Nav channel expression in DRG tissue, while electrophysiological properties were examined using whole-cell patch clamp to generate current-voltage (I-V) curves. CRPS-I rats exhibited decreased TWL and MWL, elevated expression of Nav1.7, Nav1.8, and Nav1.9, and enhanced sodium current density with delayed inactivation. BMSC transplantation significantly alleviated pain behaviors, downregulated sodium channel expression, and normalized I-V characteristics-marked by increased activation thresholds, reduced peak currents, and faster inactivation kinetics. These findings suggest that BMSCs mitigate neuronal hyperexcitability by modulating peripheral Nav channel activity. This study provides mechanistic evidence supporting the therapeutic potential of BMSC-based interventions for CRPS-I and related neuropathic pain conditions.
other
2026-05-06 | Genetic modulation of pain pathways: toward a new era in pain therapy- a systematic review.
Gene therapy represents a new strategy in pain management targeting the causes of pain rather than its symptoms. This review summarizes recent advances across RNA interference (RNAi), viral vector delivery systems, CRISPR/Cas9, gene replacement therapy, and endogenous opioid gene delivery, emphasizing efficacy, safety, and mechanisms of action in pain conditions. RNAi and gene replacement techniques remain powerful tools for reducing pain and improving the quality of life by modulating pain-associated genes. Long-term relief may also be achieved with CRISPR/Cas9 and site-directed delivery using nanoparticle systems. Safety profiles especially with CRISPR/Cas9 remains a concern. A systematic search of Web of Science, Medline, Scopus, and Google Scholar identified 512 records (January 2010-March 2023). Following PRISMA screening, 18 studies met inclusion criteria. These studies evaluated strategies of gene therapy in neuropathy, arthritis, fibromyalgia, and complex regional pain syndrome. The review outlines available options and highlights preclinical findings.
2024-10-09 | Sex-specific role of RNA-binding protein, pAUF1, on prolonged hypersensitivity after repetitive ischemia with reperfusion injury.
Repetitive ischemia with reperfusion (I/R) injury is a common cause of myalgia. Ischemia with reperfusion injuries occur in many conditions that differentially affect males and females including complex regional pain syndrome and fibromyalgia. Our preclinical studies have indicated that primary afferent sensitization and behavioral hypersensitivity caused by I/R injury may be due to sex-specific gene expression in the dorsal root ganglia (DRG) and distinct upregulation of growth factors and cytokines in the affected muscles. To determine how these unique gene expression programs may be established in a sex-dependent manner in a model that more closely mimics clinical scenarios, we used a developed prolonged ischemic myalgia model in mice whereby animals experience repeated I/R injuries and compared behavioral results with unbiased and targeted screening strategies in male and female DRG. Several distinct proteins were found to be differentially expressed in male and female DRG, including phosphorylated AU-rich element RNA-binding protein (pAUF1), which is known to regulate gene expression. Nerve-specific siRNA-mediated knockdown of AUF1 inhibited prolonged hypersensitivity in females only, whereas overexpression of AUF1 in male DRG neurons increased pain-like responses. AUF1 knockdown was able to specifically inhibit repeated I/R-induced gene expression in females potentially downstream of prolactin receptor signaling. Data suggest RNA-binding proteins such as pAUF1 may underlie the sex-specific effects on DRG gene expression that modulates behavioral hypersensitivity after repeated I/R injury through prolactin signaling. This study may aid in finding distinct receptor differences related to the evolution of acute to chronic ischemic muscle pain development between sexes.
2022-06-21 | Microvascular Barrier Protection by microRNA-183 via FoxO1 Repression: A Pathway Disturbed in Neuropathy and Complex Regional Pain Syndrome.
Blood nerve barrier disruption and edema are common in neuropathic pain as well as in complex regional pain syndrome (CRPS). MicroRNAs (miRNA) are epigenetic multitarget switches controlling neuronal and non-neuronal cells in pain. The miR-183 complex attenuates hyperexcitability in nociceptors, but additional non-neuronal effects via transcription factors could contribute as well. This study explored exosomal miR-183 in CRPS and murine neuropathy, its effect on the microvascular barrier via transcription factor FoxO1 and tight junction protein claudin-5, and its antihyperalgesic potential. Sciatic miR-183 decreased after CCI. Substitution with perineural miR-183 mimic attenuated mechanical hypersensitivity and restored blood nerve barrier function. In vitro, serum from CCI mice und CRPS patients weakened the microvascular barrier of murine cerebellar endothelial cells, increased active FoxO1 and reduced claudin-5, concomitant with a lack of exosomal miR-183 in CRPS patients. Cellular stress also compromised the microvascular barrier which was rescued either by miR-183 mimic via FoxO1 repression or by prior silencing of Foxo1. PERSPECTIVE: Low miR-183 leading to barrier impairment via FoxO1 and subsequent claudin-5 suppression is a new aspect in the pathophysiology of CRPS and neuropathic pain. This pathway might help untangle the wide symptomatic range of CRPS and nurture further research into miRNA mimics or FoxO1 inhibitors.
2022-06-18 | MicroRNA‐21‐5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury
Abstract Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA‐21‐5p (miR‐21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR‐21 in neuropathic pain and its impact on the BNB in a human‐murine back translational approach. MiR‐21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin‐1 in both injured and spared nerves. Moreover, the putative miR‐21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb . In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR‐21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB . Perineurial miR‐21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR‐21 after nerve injury reversed it. In summary, the data support a novel role for miR‐21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.
2022-03-07 | Acute worsening of clinical presentation in CRPS after SARS-CoV-2 (COVID-19) vaccination: a case series.
We present the acute worsening of clinical presentation in complex regional pain syndrome (CRPS), following mRNA-based COVID-19 vaccination. We report the case series of three patients diagnosed with CRPS type I who presented with acute worsening of symptoms after mRNA-based COVID-19 vaccination and their medical management. The acute clinical worsening after mRNA-based COVID-19 vaccination was transient and effectively managed with adjustment of individualized therapy in all three patients. The mortality and morbidity of COVID-19 infection are serious, and vaccination is recommended in the general population, including patients with a diagnosis of CRPS. However, clinicians should be aware of the possibility that there may be a clinical worsening CRPS after mRNA-based COVID-19 vaccination. This case series presents the worsening of symptoms in complex regional pain syndrome (CRPS), following mRNA-based COVID-19 vaccination. We report on three patients diagnosed with CRPS who presented with worsening of symptoms after mRNA-based COVID-19 vaccination and their medical management. The worsening of symptoms was temporary and managed with adjustment of individualized therapy in all three patients. The dangers of COVID-19 infection are serious, and vaccination is highly recommended in the general population, including patients with a diagnosis of CRPS. However, healthcare providers should be aware of the possibility of clinical worsening of CRPS after mRNA-based COVID-19 vaccination.
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Drug Discovery Landscape
20 orphan drug designations for Complex regional pain syndrome.
20 orphan drug designations for Complex regional pain syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
psilocybin | small molecules | FDA | 2026-01-23 | — | Cy Biopharma AG |
afatinib | small molecules | FDA | 2024-11-20 | — | AKIGAI AS |
high cannabidiol botanical extract | small molecules | FDA | 2024-11-20 | — | Biopharmaceutical Research Company, LLC |
Interleukin 4 - interleukin 10 fusion protein | proteins | EMA | 2024-08-21 | — | Synerkine Pharma B.V. |
Afatinib | small molecules | EMA | 2024-06-28 | — | Akigai AS |
Ketamine | small molecules | FDA | 2022-06-06 | — | Vitalis Analgesics, LLC |
Cannabidiol, dronabinol | small molecules | EMA | 2021-11-12 | — | Tetra Bio-Pharma Europe Limited |
Ketamine | small molecules | FDA | 2021-10-12 | — | PharmaTher Inc. |
Naltrexone | small molecules | FDA | 2021-06-14 | — | Soin Theraputics |
ketamine | small molecules | FDA | 2021-05-10 | — | iX Biopharma Ltd. |
ketamine | small molecules | FDA | 2019-02-01 | — | Bexson Biomedical, Inc. |
delta-9-tetrahydrocannabinol and cannabidiol | small molecules | FDA | 2018-03-07 | — | PhytoPain Pharma Inc. |
hydromorphone hydrochloride (intrathecal infusion) | small molecules | FDA | 2016-06-16 | — | Piramal Critical Care, Inc. |
baclofen | small molecules | FDA | 2015-10-28 | — | Piramal Critical Care, Inc. |
zoledronate D,L-lysine monohydrate (ZLM) | small molecules | FDA | 2015-04-15 | — | Thar Pharma, LLC |
Zoledronic acid | small molecules | EMA | 2013-10-07 | — | Axsome Therapeutics Limited |
zoledronic acid | small molecules | FDA | 2013-05-06 | — | Axsome Therapeutics, Inc. |
neridronate | small molecules | FDA | 2013-03-25 | — | Ambros Therapeutics, Inc. |
Ziconotide [Prialt] | peptides | EMA | 2001-07-09 | — | Eisai Limited |
Guanethidine monosulfate | small molecules | FDA | 1986-01-06 | — | Novartis Pharmaceuticals Corporation |
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