Case Report: An Unexpected Complication of Intrathecal Therapy.

Traditionally, intrathecal therapy has been used for pain amelioration in cancer patients, but now has indications for nonmalignant chronic pain conditions. Due to its expanding use, it is imperative to understand the risks and management of intrathecal pump implantation. This case illustrates a series of uncommon intrathecal pump complications in a 52-year-old woman with complex regional pain syndrome. Considering the complications outlined in this case, there is a need to conduct retrospective studies and establish guidelines to address when it is optimal to remove a chronically placed catheter as well as the proper technique for removal.

A brief review of complex regional pain syndrome and current management.

Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition that, although exceedingly rare, carries a significant burden for the affected patient population. The complex and ambiguous pathophysiology of this condition further complicates clinical management and therapeutic interventions. Furthermore, being a diagnosis of exclusion requires a diligent workup to ensure an accurate diagnosis and subsequent targeted management. The development of the Budapest diagnostic criteria helped to consolidate existing definitions of CRPS but extensive work remains in identifying the underlying pathways. Currently, two distinct types are identified by the presence (CRPS type 1) or absence (CRPS type 2) of neuronal injury. Current management directed at this disease is broad and growing, ranging from non-invasive modalities such as physical and psychological therapy to more invasive techniques such as dorsal root ganglion stimulation and potentially amputation. Ideal therapeutic interventions are multimodal in nature to address the likely multifactorial pathological development of CRPS. Regardless, a significant need remains for continued studies to elucidate the pathways involved in developing CRPS as well as more robust clinical trials for various treatment modalities.

Complex regional pain syndrome (CRPS) is a debilitating and complex condition that places a significant physical, psychological and emotional burden upon afflicted patients necessitating multi-modal approaches to treatment.The development of the Budapest criteria provided a robust and well-tested set of diagnostic criteria to aid clinicians in the diagnosis of CRPS.The pathophysiology of CRPS has been challenging to elucidate with numerous proposed mechanisms, altogether suggesting a multi-factorial process is involved in the development of this condition.Non-invasive treatments for CRPS are essential in addressing the physical limitations this disease can cause as well as addressing the significant psychological burden that involves increased incidence of depression and suicidal ideation.Invasive treatments offer promising results, especially when considering dorsal root ganglion stimulation; however, the need for more robust clinical trials remains, especially when considering a small portion of patients who have refractory CRPS resort to amputation to control their pain symptoms.

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

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

Complex regional pain syndrome: advances in epidemiology, pathophysiology, diagnosis, and treatment.

Complex regional pain syndrome (CRPS) is a rare pain disorder that usually occurs in a limb after trauma. The features of this disorder include severe pain and sensory, autonomic, motor, and trophic abnormalities. Research from the past decade has offered new insights into CRPS epidemiology, pathophysiology, diagnosis, and treatment. Early identification of individuals at high risk of CRPS is improving, with several risk factors established and some others identified in prospective studies during the past 5 years. Better understanding of the pathophysiological mechanisms of CRPS has led to its classification as a chronic primary pain disorder, and subtypes of CRPS have been updated. Procedures for diagnosis have also been clarified. Although effective treatment of CRPS remains a challenge, evidence-based integrated management approaches provide new opportunities to improve patient care. Further advances in diagnosis and treatment of CRPS will require coordinated, international multicentre initiatives.

Repetitive Transcranial Magnetic Stimulation with Sensorimotor Training for the Treatment of Complex Regional Pain Syndrome Type 2 of the Upper Limb Case Report.

This case report describes the use of repetitive transcranial magnetic stimulation (rTMS) combined with sensorimotor training (SMT) to treat an individual with complex regional pain syndrome (CRPS) type 2 with allodynia of the right hand/wrist. After the 9-week intervention, there was a clinically meaningful reduction in pain intensity which continued to 3 months after intervention. Further, clinically meaningful improvements in wrist and hand function and allodynia were observed. Although the use of rTMS for CRPS has been reported, this unique report provides valuable insight into the clinical utility of rTMS plus SMT for the treatment of CRPS and related symptoms.

Sensibilidad de la respuesta simpática cutánea y de la gammagrafía en el diagnóstico del síndrome dolor regional complejo / Sensitivity of the sympathetic skin response and scintigraphy in the diagnosis of complex regional pain syndrome

Objetivo: Evaluar la sensibilidad de la respuesta simpática cutánea (RSC) y compararla con la gammagrafía en pacientes con síndrome de dolor regional complejo diagnosticados según criterios de Budapest. Material y métodos: Se evaluó prospectivamente a 22 pacientes con síndrome de dolor regional complejo que acudieron al Servicio de Rehabilitación y Medicina Física entre enero-2018 y mayo-2022. La gammagrafía se consideró positiva si en la 1.a-2.a fase se apreció leve captación asimétrica y difusa, o cuando en la 3.a fase se apreció marcada captación periarticular del radioisótopo. La RSC era anormal si se observaba: a) ausencia de respuesta tras 20 estímulos; b) falta de habituación con permanencia de los estímulos mayor al 67,2%. Resultados: Edad 55,4±8,57 años. Síndrome de dolor regional complejo más frecuente en mujeres (90,9%), más común en miembros superiores (68,2%) que en inferiores (31,8%). En la RSC hemos observado respuesta normal (<67,2%) en 2 pacientes (11,1%), falta de RSC en 2 pacientes (11,1%) y falta de habituación (>67,2%) en 14 pacientes (77,8%). En total, 16 pacientes presentaron respuestas anormales o ausentes (88,8%). La sensibilidad diagnóstica de la gammagrafía es similar a la de la RSC (89,5 vs. 88,8%), sin diferencia estadística (p=0,6721). Conclusión: La Gammagrafía ha demostrado una sensibilidad similar a la RSC, aunque la simpleza, el bajo coste y la no invasividad de esta última técnica sugieren que podría ser más coste/efectiva y segura (no ionizante). La falta de habituación y la ausencia de respuesta podrían identificar patrones de respuesta y localizar la afectación en las vías aferente, central, eferente o post ganglionar.(AU)

Objective: To evaluate the sensitivity of sympathetic skin response (SSR) and compare it with scintigraphy in patients with complex regional pain syndrome diagnosed according to the Budapest criteria. Material and methods: Twenty-two patients with complex regional pain syndrome who attended the Rehabilitation and Physical Medicine Department between January-2018 and May-2022 have been prospectively evaluated. The scintigraphy was considered positive if in the 1st-2nd phase slight asymmetric and diffuse uptake was observed, or when in the 3rd phase marked periarticular radioisotope uptake was observed. SSR was abnormal if: a) no response after 20 stimuli; b) lack of habituation with permanence of the stimuli greater than 67.2%. Results: Age 55.4±8.57 years. Complex regional pain syndrome was more frequent in women (90.9%), more common in upper limbs (68.2%) than lower limbs (31.8%). In SSR, we have observed normal response (<67.2%) in 2 patients (11.1%), lack of SSR in 2 patients (11.1%) and lack of habituation (>67.2%) in 14 patients (77.8%). In total, 16 patients presented abnormal or absent responses (88.8%). The diagnostic sensitivity of scintigraphy is similar to that of SSR (89.5% vs 88.8%), with no statistical difference (P=.6721). Conclusion: Scintigraphy has shown similar sensitivity to SSR, although the simplicity, security, low cost, non-ionizing and non-invasiveness of the latter technique suggest that it could be more cost-effective. The lack of habituation and the absence of response could identify response patterns and localize the involvement in the afferent, central, efferent or post-ganglionic pathways.(AU)

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

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

Mirror visual feedback as therapeutic modality in unilateral upper extremity complex regional pain syndrome type I: randomized controlled trial.

BACKGROUND: There is growing evidence for the effectiveness of mirror therapy (MT) on pain reduction in patients with type I complex regional pain syndrome (CRPS I). AIM: To evaluate the efficacy of MT on pain reduction and hand function in subjects with unilateral upper extremity CRPS I. DESIGN: Randomized controlled trial with control group cross-over (half cross-over design). SETTING: Subjects with CRPS I were outpatients of a university hospital and cooperating centers. All patients carried out the daily exercise at home. POPULATION: Subjects with unilateral upper extremity CRPS I meeting the Budapest diagnostic criteria. METHODS: Subjects were randomly divided into two groups. Group A (N.=13) carried out a ten-minute MT exercise daily, for a total duration of six weeks. Group B (N.=14) acted as a control group for six weeks followed by six weeks of MT with the same characteristics as Group A. Upper extremity active range of motion, strength, dexterity, limb volume, affected-to-unaffected hand temperature difference, and health-related quality of life were evaluated before and after each period. Daily records on the visual analogue scale were used for pain evaluation. Effectiveness was calculated using mixed-effects modelling for between-group comparisons and within-group variability, and identification of significant predictors. RESULTS: Twenty-three females and four males with an average age of 56.1±9.6 years completed the study. Except for the affected-to-unaffected hand temperature difference, both groups consistently demonstrated significant or near-significant improvements in measured parameters after MT period. The improvements were evident upon an intergroup comparison of Group A and the control period of Group B as well as longitudinally within Group B. No significant improvement was found during the control period. CONCLUSIONS: Principles focused on mirror visual feedback to the central nervous system can sustain promising therapeutic potential as part of the treatment for pain reduction and hand function in CRPS I patients. CLINICAL REHABILITATION IMPACT: MT can be considered as part of the therapeutic regimen employed for the treatment of CRPS I.

Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed. METHODS: We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells. RESULTS: Intraepidermal Schwann cells were detected in human skin of the finger-but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other-but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin. CONCLUSIONS: Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.

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

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

Successful therapy of complex regional pain syndrome after hip arthroscopy for femoroacetabular impingement syndrome: a case report.

BACKGROUND: Complex regional pain syndrome is a neuropathic pain disorder associated with ongoing pain that persists beyond the usual expected tissue healing time and that is disproportionate to the degree of tissue injury present. Complex regional pain syndrome after hip arthroscopy has not been reported before. Hip arthroscopy is a fast-growing domain that could lead to an increasing number of complex regional pain syndrome cases, probably owing to the high traction forces that are necessary. CASE PRESENTATION: We report the case of a 30-year-old German female semiprofessional tennis player who presented with complex regional pain syndrome type I in the lower leg 3 weeks after hip arthroscopy for femoroacetabular impingement syndrome with suture anchor labral repair and femoroplasty. After 2 months of immediate multimodal conservative therapy including administration of gabapentin, prompt full weight-bearing, and intensified physiotherapy, complete recovery was achieved. CONCLUSION: Complex regional pain syndrome does occur after elective hip arthroscopy. Disproportionate postoperative pain or other symptoms raising suspicion of complex regional pain syndrome should be promptly evaluated and treated through a multimodal approach. Postless hip arthroscopy may be advantageous.

Long-term efficacy of spinal cord stimulation for chronic primary neuropathic pain in the contemporary era: a systematic review and meta-analysis.

INTRODUCTION: Spinal cord stimulation (SCS) is a modern neuromodulation technique extensively proven to be an effective modality for treatment of chronic neuropathic pain. It has been mainly studied for complex regional pain syndrome (CRPS) and failed back surgery syndrome (FBSS) and recent data almost uniformly establishes its statistically significant positive therapeutic results. It has also been compared with other available treatment modalities across various studies. However, long term data on maintenance of its efficacious potential remains less explored. Few studies have reported data on long follow-up times (>= 12 months) and have compared its efficacy with other treatment options for chronic pain, respectively. Our study pools and analyzes the available data and compares SCS with other treatment options. It also analyzes the efficacy of SCS in long term management of patients with chronic pain. EVIDENCE ACQUISITION: We reviewed all the data available on MEDLINE, Embase and Cochrane CENTRAL using a search strategy designed to fit our pre-set inclusion and exclusion criteria. Both single-arm and double-arm studies were included. The primary outcome was defined as decrease of visual analogue scale (VAS) by >50% at 6, 12 and/or 24 months after SCS. EVIDENCE SYNTHESIS: According to the pooled data of double-arm studies, SCS has unanimously proven its superiority over other treatment options at 6 months follow-up; however it fails to prove statistically significant difference in results at longer treatment intervals. Dorsal root ganglion stimulation, a relatively recent technique with the same underlying physiologic mechanisms as SCS, showed far more promising results than SCS. Single-arm studies show around 70% patients experiencing greater than 50% reduction in their VAS scores at 6 and 12 months. CONCLUSIONS: SCS is a viable option for management of chronic neuropathic pain secondary to FBSS and CRPS. However, data available for its long term efficacy remains scarce and show no further statistically significant results.

Early versus persistent Complex Regional Pain Syndrome: Is there a difference in patient reported outcomes following rehabilitation?

BACKGROUND: Expert consensus asserts that early treatment of Complex Regional Pain Syndrome (CRPS) leads to better outcomes. Yet no evidence supports this assumption regarding the recognized gold standard of multidisciplinary functional rehabilitation. To address this, we aimed to establish if there is a difference in outcomes between early CRPS (<1 year symptom duration) and persistent CRPS (= >1 year symptom duration) following rehabilitation and whether any gains are maintained at three months. METHOD: Secondary analysis was conducted on previously collected clinical Patient Reported Outcome Measures (PROMS) data from 218 patients attending a residential multidisciplinary rehabilitation programme. Datasets were categorized into early CRPS (n = 40) or persistent CRPS (n = 178) dependent on symptom duration. Function, pain, self-efficacy, kinesiophobia and psychological health domains were compared using repeated measures analysis of covariance for a two group design for group difference post rehabilitation and at three month follow-up. RESULTS: Post-rehabilitation, both groups improved in pain, function, kinesiophobia, psychological health and self-efficacy. At three months, the persistent CRPS group maintained improvements in pain and function. This was not achieved in early CRPS. CONCLUSION: This exploratory study is the first to empirically test the assumption that those with early CRPS have better outcomes following rehabilitation. Our clinical data challenges this, as both early and persistent CRPS groups improved following rehabilitation. Findings indicate that rehabilitation benefits those with CRPS, regardless of symptom duration. However, unlike early CRPS, those with persistent CRPS sustain gains at follow-up. Further prospective exploration is warranted. SIGNIFICANCE: Expert consensus recommends early treatment for Complex Regional Pain Syndrome, yet there is little empirical evidence to support this. Our findings are the first to challenge this assumption by revealing no difference in outcomes between early and persistent CRPS post-rehabilitation. However, those with persistent CRPS maintain gains after three months, unlike people with early CRPS (symptoms < one year). These findings are relevant to clinical practice as they challenge established assumptions, suggesting a focus on improving early CRPS follow-up outcomes.

[Sensitivity of the sympathetic skin response and scintigraphy in the diagnosis of complex regional pain syndrome]. / Sensibilidad de la respuesta simpática cutánea y de la gammagrafía en el diagnóstico del síndrome dolor regional complejo.

OBJECTIVE: To evaluate the sensitivity of sympathetic skin response (SSR) and compare it with scintigraphy in patients with complex regional pain syndrome diagnosed according to the Budapest criteria. MATERIAL AND METHODS: Twenty-two patients with complex regional pain syndrome who attended the Rehabilitation and Physical Medicine Department between January-2018 and May-2022 have been prospectively evaluated. The scintigraphy was considered positive if in the 1st-2nd phase slight asymmetric and diffuse uptake was observed, or when in the 3rd phase marked periarticular radioisotope uptake was observed. SSR was abnormal if: a) no response after 20 stimuli; b) lack of habituation with permanence of the stimuli greater than 67.2%. RESULTS: Age 55.4±8.57 years. Complex regional pain syndrome was more frequent in women (90.9%), more common in upper limbs (68.2%) than lower limbs (31.8%). In SSR, we have observed normal response (<67.2%) in 2 patients (11.1%), lack of SSR in 2 patients (11.1%) and lack of habituation (>67.2%) in 14 patients (77.8%). In total, 16 patients presented abnormal or absent responses (88.8%). The diagnostic sensitivity of scintigraphy is similar to that of SSR (89.5% vs 88.8%), with no statistical difference (P=.6721). CONCLUSION: Scintigraphy has shown similar sensitivity to SSR, although the simplicity, security, low cost, non-ionizing and non-invasiveness of the latter technique suggest that it could be more cost-effective. The lack of habituation and the absence of response could identify response patterns and localize the involvement in the afferent, central, efferent or post-ganglionic pathways.

Impact of different CRPS phenotypes and diagnostic criteria on quantitative sensory testing outcomes: systematic review and meta-analysis.

OBJECTIVES: This review and meta-analysis evaluated the impact of diagnostic criteria and clinical phenotypes on quantitative sensory testing (QST) outcomes in patients with complex regional pain syndrome (CRPS). METHODS: Eight databases were searched based on a previously published protocol. Forty studies comparing QST outcomes between CRPS-I vs II, warm vs cold CRPS, upper vs lower limb CRPS, males vs females, or using Budapest vs older IASP criteria were included. RESULTS: Studies investigating QST differences between CRPS-I vs II (n = 4), between males vs females (n = 2), and between upper and lower limb CRPS (n = 2) showed no significant differences. Four studies compared QST outcomes in warm vs cold CRPS, showing heat hyperalgesia in warm CRPS, with thermal and mechanical sensory loss in cold CRPS. Although CRPS diagnosed using the Budapest criteria (24 studies) vs 1994 IASP criteria (13 studies) showed similar sensory profiles, there was significant heterogeneity and low quality of evidence in the latter. CONCLUSIONS: Based on the findings of this review, classifying CRPS according to presence or absence of nerve lesion into CRPS-I and II, location (upper or lower limb) or according to sex might not be clinically relevant as all appear to have comparable sensory profiles that might suggest similar underlying mechanisms. In contrast, warm vs cold phenotypes exhibited clear differences in their associated QST sensory profiles. To the extent that differences in underlying mechanisms might lead to differential treatment responsiveness, it appears unlikely that CRPS-I vs II, CRPS location, or patient sex would prove useful in guiding clinical management.

The role of diet and non-pharmacologic supplements in the treatment of chronic neuropathic pain: A systematic review.

BACKGROUND/IMPORTANCE: Dietary interventions, vitamins, and nutritional supplementation are playing an increasingly important role in the management of neuropathic pain. Current pharmacological treatments are poorly tolerated and ineffective in many cases. OBJECTIVE: This systematic review aims to study the efficacy of dietary interventions, vitamins, and nutritional supplementation in the management of chronic neuropathic pain in adults. EVIDENCE REVIEW: The review followed PRISMA guidelines and was registered with PROSPERO (#CRD42022300312). Ten databases and gray literature, including Embase.com, MEDLINE and Web of Science, were systematically searched using a combination of keywords and controlled vocabulary related to chronic neuropathic pain and oral non-pharmacological supplements. Studies on adult humans published between 2000 and 2021 were considered for inclusion. The Cochrane Handbook was used to assess risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation was used to determine overall quality of evidence. FINDINGS: Forty studies were included in the final review, and results were categorized according to pain type including pain related to chemotherapy-induced peripheral neuropathy (CIPN, 22 studies, including 3 prospective cohorts), diabetic peripheral neuropathy (DPN, 13 studies, including 2 prospective), complex regional pain syndrome (CRPS-I, 3 studies, including 1 prospective), and other (2 studies, both RCT). The CIPN studies used various interventions including goshajinkigan (4 studies), vitamin E (5), vitamin B12 (3), glutamine (3), N-acetyl-cysteine (2), acetyl-l-carnitine (2), guilongtonluofang (1), ninjin'yoeito (1), alpha-lipoic acid (1), l-carnosine (1), magnesium and calcium (1), crocin (1), and antioxidants (1), with some studies involving multiple interventions. All CIPN studies involved varying cancers and/or chemotherapies, advising caution for generalizability of results. Interventions for DPN included alpha-lipoic acid (5 studies), vitamin B12 (3), acetyl-l-carnitine (3), vitamin E (1), vitamin D (2), and a low-fat plant-based diet (1). Vitamin C was studied to treat CRPS-I (3 studies, including 1 prospective). Magnesium (1) and St. John's wort (1) were studied for other or mixed neuropathologies. CONCLUSIONS: Based on the review, we cannot recommend any supplement use for the management of CIPN, although further research into N-acetyl-cysteine, l-carnosine, crocin, and magnesium is warranted. Acetyl-l-carnitine was found to be likely ineffective or harmful. Alpha-lipoic acid was not found effective. Studies with goshajinkigan, vitamin B12, vitamin E, and glutamine had conflicting results regarding efficacy, with one goshajinkigan study finding it harmful. Guilongtonluofang, ninjin'yoeito, and antioxidants showed various degrees of potential effectiveness. Regarding DPN, our review supports the use of alpha-lipoic acid, acetyl-l-carnitine, and vitamin D. The early use of vitamin C prophylaxis for the development of CRPS-I also seems promising. Further research is warranted to confirm these findings.

Neural Correlates of Pain-Autonomic Coupling in Patients With Complex Regional Pain Syndrome Treated by Repetitive Transcranial Magnetic Stimulation of the Motor Cortex.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a chronic pain condition involving autonomic dysregulation. In this study, we report the results of an ancillary study to a larger clinical trial investigating the treatment of CRPS by neuromodulation. This ancillary study, based on functional magnetic resonance imaging (fMRI), evaluated the neural correlates of pain in patients with CRPS in relation to the sympathetic nervous system and for its potential relief after repetitive transcranial magnetic stimulation of the motor cortex. MATERIALS AND METHODS: Eleven patients with CRPS at one limb (six women, five men, aged 52.0 ± 9.6 years) were assessed before and one month after the end of a five-month repetitive transcranial magnetic stimulation (rTMS) therapy targeting the motor cortex contralateral to the painful limb, by means of electrochemical skin conductance (ESC) measurement, daily pain intensity scores on a visual numerical scale (VNS), and fMRI with motor tasks (alternation of finger movements and rest). The fMRI scans were analyzed voxelwise using ESC and VNS pain score as regressors to derive their neural correlates. The criterion of response to rTMS therapy was defined as ≥30% reduction in VNS pain score one month after treatment compared with baseline. RESULTS: At baseline, ESC values were reduced in the affected limb vs the nonaffected limb. There was a covariance of VNS with brain activation in a small region of the primary somatosensory cortex (S1) contralateral to the painful side on fMRI investigation. After rTMS therapy on motor cortex related to the painful limb, the VNS pain scores significantly decreased by 22% on average. The criterion of response was met in six of 11 patients (55%). In these responders, at one month after treatment, ESC value increased and returned to normal in the CRPS-affected limb, and overall, the increase in ESC correlated with the decrease in VNS after motor cortex rTMS therapy. At one month after treatment, there also was a covariance of both variables (ESC and VNS) with fMRI activation of the S1 region previously mentioned. The fMRI activation of other brain regions (middle frontal gyrus and temporo-parietal junction) showed correlation with ESC values before and after treatment. Finally, we found a positive correlation at one month after treatment (not at baseline) between VNS pain score and fMRI activation in the temporo-parietal junction contralateral to painful side. CONCLUSIONS: This study first shows a functional pain-autonomic coupling in patients with CRPS, which could involve a specific S1 region. However, the modulation of sympathetic sudomotor activities expressed by ESC changes was rather correlated with functional changes in other brain regions. Finally, the pain relief observed at one month after rTMS treatment was associated with a reduced activation of the temporo-parietal junction on the side in which rTMS was performed. These findings open perspectives to define new targets or biomarkers for using rTMS to treat CRPS-associated pain. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02817880.