Complex Regional Pain Syndrome Pain Research Articles

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

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

The Role of Neuroinflammation in Complex Regional Pain Syndrome: A Comprehensive Review.

Complex Regional Pain Syndrome (CRPS) is an excess and/or prolonged pain and inflammation condition that follows an injury to a limb. The pathogenesis of CRPS is multifaceted that remains incompletely understood. Neuroinflammation is an inflammatory response in the peripheral and central nervous systems. Dysregulated neuroinflammation plays a crucial role in the initiation and maintenance of pain and nociceptive neuronal sensitization, which may contribute to the transition from acute to chronic pain and the perpetuation of chronic pain in CRPS. The key features of neuroinflammation encompass infiltration and activation of inflammatory cells and the production of inflammatory mediators in both the central and peripheral nervous systems. This article reviews the role of neuroinflammation in the onset and progression of CRPS from six perspectives: neurogenic inflammation, neuropeptides, glial cells, immune cells, cytokines, and keratinocytes. The objective is to provide insights that can inform future research and development of therapeutic targets for CRPS.

Algorithm for multimodal medication therapy in patients with complex regional pain syndrome.

Complex regional pain syndrome (CRPS), previously known as reflex sympathetic dystrophy and causalgia, is a clinical entity characterized by classic neuropathic pain, autonomic involvement, motor symptoms, and trophic changes in the skin, nails, and hair. Although various therapeutic modalities are used to control CRPS-related pain, severe pain due to CRPS often persists and progresses to the chronic phase. In this study, we constructed an algorithm for multimodal medication therapy for CRPS based on the established pathology of CRPS. Oral steroid pulse therapy is recommended for initial pain management in patients with CRPS. Oral steroid therapy can reduce peripheral and central neuroinflammation, contributing to the development of neuropathic pain during the acute and chronic phases. If steroid pulse therapy offers poor relief or is ineffective, treatment to control central sensitization in the chronic phase should be initiated. If pain persists despite all drug adjustments, ketamine with midazolam 2 mg before and after ketamine injection can be administered intravenously to inhibit the N-methyl D-aspartate receptor. If this treatment fails to achieve sufficient efficacy, intravenous lidocaine can be administered for 2 weeks. We hope that our proposed drug treatment algorithm to control CRPS pain will help clinicians appropriately treat patients with CRPS. Further clinical studies assessing patients with CRPS are warranted to establish this treatment algorithm in clinical practice.

Sub-anaesthetic dose of propofol attenuates mechanical allodynia in chronic post-ischaemic pain via regulation of PTEN/PI3K/IL-6 signalling.

Background: Propofol is an intravenous anaesthetic drug that has been shown to reduce inflammatory pain. Complex regional pain syndrome (CRPS) type I is a pain condition characterized by autonomic, motor and sensory disturbance. The chronic post-ischaemic pain (CPIP) model is a well-established model to recapture CRPS-I syndromes pre-clinically by non-invasive ischaemic-reperfusion (IR) injury. In this study, we investigated the analgesic effects of propofol and underlying mechanisms in mitigating CRPS pain using the CPIP model. Methods: Sub-anaesthetic dose of propofol (25mg/kg) was intravenously delivered to the CPIP model and sham control. Nociceptive behavioural changes were assayed by the von Frey test. Molecular assays were used to investigate expression changes of PTEN, PI3K, AKT and IL-6 underlying propofol-mediated analgesic effects. Pharmacological inhibition was applied for PTEN/PI3K/AKT pathway manipulation. Results: Both pre- and post-operative administration of propofol attenuated mechanical allodynia induced by CPIP. Propofol could modulate PTEN/PI3K/AKT signalling pathway by increasing active PTEN and reducing phosphorylated PI3K, phosphorylated AKT and IL-6 expression in the spinal dorsal horn, which promoted pain relief in the CPIP model. Inhibition of PTEN with bpV abolished the analgesic effects produced by propofol in CPIP mice. Conclusion: Sub-anaesthetic dose of propofol administration resulted in the activation of PTEN, inhibition of both PI3K/AKT signalling and IL-6 production in the spinal cord, which dramatically reduced CPIP-induced pain. Our findings lay the foundation in using propofol for the treatment of CRPS with great therapeutic implications.

Anxiety, Disability, and Pain Predict Outcomes of Complex Regional Pain Syndrome: An 8-year Follow-up of a Prospective Cohort

Factors contributing to the varied outcomes of complex regional pain syndrome (CRPS) are not well known. This study aimed to determine whether baseline psychological factors, pain, and disability influence long-term CRPS outcomes. We conducted an 8-year follow-up from a previous prospective study of CRPS outcomes. Sixty-six people diagnosed with acute CRPS were previously assessed at baseline, 6 months, and 12 months and in the current study, 45 were followed up after 8 years. At each timepoint, we measured signs and symptoms of CRPS, pain, disability, and psychological factors. Mixed-model repeated measures were used to identify baseline predictors of CRPS severity, pain, and disability at 8 years. Predictors of greater CRPS severity at 8 years were female sex, greater baseline disability, and greater baseline pain. Predictors of greater pain at 8 years were greater baseline anxiety and disability. The only predictor of greater disability at 8 years was greater baseline pain. Findings suggest CRPS is best understood from a biopsychosocial perspective, and baseline anxiety, pain, and disability may influence the trajectory of CRPS outcomes as far as 8 years later. These variables could be used to identify those at risk of poor outcomes or form targets for early interventions. PerspectiveThis paper presents the findings of the first study to prospectively investigate predictors of CRPS outcomes over 8 years. Baseline anxiety, pain, and disability predicted greater CRPS severity, pain, and disability over 8 years. These factors could identify those at risk of poor outcomes or form targets for early interventions.

Signs and symptoms of pediatric complex regional pain syndrome - type 1: A retrospective cohort study

ABSTRACT Background Complex regional pain syndrome (CRPS) presents with an array of symptoms that can vary from child to child, making it difficult to diagnose and differentiate from other pain conditions such as chronic musculoskeletal (MSK) pain. Thirteen symptoms and signs are outlined in the Budapest criteria for CRPS (developed and validated for adults) but have not been well described in pediatrics. Aims The aim of this study was to describe the signs and symptoms of pediatric CRPS type 1 (CRPS 1) and determine whether a cluster of symptoms can differentiate CRPS 1 from chronic MSK pain. Methods A retrospective cohort study of pediatric patients with CRPS 1 and MSK pain in a pediatric pain program was conducted. Descriptive statistics were used to report demographics and pain characteristics. The chi-square test was used to evaluate differences in signs and symptoms between patients with CRPS and MSK pain. A logistic regression model was used to evaluate whether a cluster of symptoms could predict a diagnosis of CRPS 1. Results The sample included 187 patients (99 with CRPS 1 and 88 with MSK pain); 81% were female with a mean age 14.1 years. The most prevalent CRPS symptoms were hyperalgesia (54%) and allodynia (52%). A cluster of symptoms (hyperalgesia, color changes, and range of motion) predicted the probability of a diagnosis of CRPS 1. Conclusions A cluster of symptoms may be critical in differentiating pediatric CRPS 1 and MSK pain. Future research is needed to determine if this model is valid in external populations and to explore whether a similar model can differentiate CRPS 1 from other pain conditions (e.g., neuropathic pain).

Aberrant sensorimotor coupling and movement planning in complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is characterized by inflammation and a failure of multimodal signal integration in the central nervous system (CNS). Central nervous system reorganization might account for sensory deficits, pain, and motor symptoms in CRPS, but it is not clear how motor control is affected by CNS mechanisms. The present study characterized the motor performance and related cortical activity of 16 CRPS patients and 16 control participants during the planning of visually guided unimanual grips, in patients with either the unaffected left or the affected right hand, and investigated resting-state sensorimotor coupling in MRI. Patients started isometric movements further in advance of the "go" cue and earlier than control participants. Even when accounting for this different timing, results showed side-independent overactivation in planning-related sensorimotor regions in CRPS during manual grips and increased functional coupling between those regions at rest. Fear of movement or individual pain scores contributed only marginally to the observed effects. The study suggests that changes in planning-related sensorimotor CNS regions may explain difficulties with force exertion and motor control in CRPS.Perspective : Functional changes in motor planning-related brain regions might indicate that feedback-enhanced functional motor training may be effective for CRPS rehabilitation.

Pain-autonomic measures reveal nociceptive sensitization in complex regional pain syndrome.

Allodynia and hyperalgesia are common signs in individuals with complex regional pain syndrome (CRPS), mainly attributed to sensitization of the nociceptive system. Appropriate diagnostic tools for the objective assessment of such hypersensitivities are still lacking, which are essential for the development of mechanism-based treatment strategies. This study investigated the use of pain-autonomic readouts to objectively detect sensitization processes in CRPS. Twenty individuals with chronic CRPS were recruited for the study alongside 16 age- and sex-matched healthy controls (HC). All individuals underwent quantitative sensory testing and neurophysiological assessments. Sympathetic skin responses (SSRs) were recorded in response to 15 pinprick and 15 noxious heat stimuli of the affected (CRPS hand/foot) and a control area (contralateral shoulder/hand). Individuals with CRPS showed increased mechanical pain sensitivity and increased SSR amplitudes compared with HC in response to pinprick and heat stimulation of the affected (p< 0.001), but not in the control area (p> 0.05). Habituation of pinprick-induced SSRs was reduced in CRPS compared to HC in both the affected (p= 0.018) and slightly in the control area (p= 0.048). Habituation of heat-induced SSR was reduced in CRPS in the affected (p= 0.008), but not the control area (p= 0.053). This is the first study demonstrating clinical evidence that pain-related autonomic responses may represent objective tools to quantify sensitization processes along the nociceptive neuraxis in CRPS (e.g. widespread hyperexcitability). Pain-autonomic readouts could help scrutinize mechanisms underlying the development and maintenance of chronic pain in CRPS and provide valuable metrics to detect mechanism-based treatment responses in clinical trials. This study provides clinical evidence that autonomic measures to noxious stimuli can objectively detect sensitization processes along the nociceptive neuraxis in complex regional pain syndrome (CRPS) (e.g. widespread hyperexcitability). Pain-autonomic readouts may represent valuable tools to explore pathophysiological mechanisms in a variety of pain patients and offer novel avenues to help guide mechanism-based therapeutic strategies.

Prognostic factors for persistent pain after a distal radius fracture: a systematic review.

The aim of this systematic review was to synthesize the evidence regarding prognostic factors for persistent pain, including Complex Regional Pain Syndrome (CRPS), after a distal radius fracture (DRF), a common condition after which persistent pain can develop. Medline, Pubmed, Embase, Psychinfo, CINAHL, BNI, AMED and the Cochrane Register of Clinical Trials were searched from inception to May 2021 for prospective longitudinal prognostic factor studies investigating persistent pain in adults who had sustained a DRF. The Quality in Prognostic Studies (QUIPS) tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework were used to assess the strength of evidence. A search yielded 440 studies of which 7 studies met full eligibility criteria. From five studies we found low evidence for high baseline pain or an ulnar styloid fracture as prognostic factors for persistent pain, and very low evidence for diabetes or older age. From two studies, investigating an outcome of CRPS, there was low evidence for high baseline pain, slow reaction time, dysynchiria, swelling and catastrophising as prognostic factors, and very low evidence for depression. Sex was found not to be a prognostic factor for CRPS or persistent pain. The associations between prognostic factors and persistent pain following a DRF are unclear. The small number of factors investigated in more than one study, along with poor reporting and methodological limitations contributed to an assessment of low to very low strength of evidence. Further prospective studies, investigating psychosocial factors as candidate predictors of multidimensional pain outcomes are recommended.

Physiotherapy for pain and disability in adults with complex regional pain syndrome (CRPS) types I and II.

Complex regional pain syndrome (CRPS) is a painful and disabling condition that usually manifests in response to trauma or surgery and is associated with significant pain and disability. CRPS can be classified into two types: type I (CRPS I) in which a specific nerve lesion has not been identified and type II (CRPS II) where there is an identifiable nerve lesion. Guidelines recommend the inclusion of a variety of physiotherapy interventions as part of the multimodal treatment of people with CRPS. This is the first update of the review originally published in Issue 2, 2016. To determine the effectiveness of physiotherapy interventions for treating pain and disability associated with CRPS types I and II in adults. For this update we searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, PEDro, Web of Science, DARE and Health Technology Assessments from February 2015 to July 2021 without language restrictions, we searched the reference lists of included studies and we contacted an expert in the field. We also searched additional online sources for unpublished trials and trials in progress. We included randomised controlled trials (RCTs) of physiotherapy interventions compared with placebo, no treatment, another intervention or usual care, or other physiotherapy interventions in adults with CRPS I and II. Primary outcomes were pain intensity and disability. Secondary outcomes were composite scores for CRPS symptoms, health-related quality of life (HRQoL), patient global impression of change (PGIC) scales and adverse effects. Two review authors independently screened database searches for eligibility, extracted data, evaluated risk of bias and assessed the certainty of evidence using the GRADE system. We included 16 new trials (600 participants) along with the 18 trials from the original review totalling 34 RCTs (1339 participants). Thirty-three trials included participants with CRPS I and one trial included participants with CRPS II. Included trials compared a diverse range of interventions including physical rehabilitation, electrotherapy modalities, cortically directed rehabilitation, electroacupuncture and exposure-based approaches. Most interventions were tested in small, single trials. Most were at high risk of bias overall (27 trials) and the remainder were at 'unclear' risk of bias (seven trials). For all comparisons and outcomes where we found evidence, we graded the certainty of the evidence as very low, downgraded due to serious study limitations, imprecision and inconsistency. Included trials rarely reported adverse effects. Physiotherapy compared with minimal care for adults with CRPS I One trial (135 participants) of multimodal physiotherapy, for which pain data were unavailable, found no between-group differences in pain intensity at 12-month follow-up. Multimodal physiotherapy demonstrated a small between-group improvement in disability at 12 months follow-up compared to an attention control (Impairment Level Sum score, 5 to 50 scale; mean difference (MD) -3.7, 95% confidence interval (CI) -7.13 to -0.27) (very low-certainty evidence). Equivalent data for pain were not available. Details regarding adverse events were not reported. Physiotherapy compared with minimal care for adults with CRPS II We did not find any trials of physiotherapy compared with minimal care for adults with CRPS II. The evidence is very uncertain about the effects of physiotherapy interventions on pain and disability in CRPS. This conclusion is similar to our 2016 review. Large-scale, high-quality RCTs with longer-term follow-up are required to test the effectiveness of physiotherapy-based interventions for treating pain and disability in adults with CRPS I and II.

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. PerspectiveLow 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.

Substance P Serum Degradation in Complex Regional Pain Syndrome – Another Piece of the Puzzle?

In a previous study, we demonstrated that the serum peptidase system might be less efficient in complex regional pain syndrome (CRPS). Since the neuropeptide substanc P (SP) contributes to inflammation in CRPS, we now investigated the metabolism of SP in CRPS specifically. An SP metabolism assay was performed in 24 CRPS patients, which constitute a subgroup of our previous investigation on BK degradation. In addition, we included 26 healthy controls (24 newly recruited plus 2 from our previous investigation), and 13 patients after limb trauma, who did not fulfil the CRPS diagnostic criteria (trauma controls, TC) were included. We adapted a thin layer chromatography assay (TLC) to quantify SP disappearance after incubation with 7.5 µL of serum. These results were compared with bradykinin (BK) metabolization to BK1-8 and BK1-5 fragments from our previous study. In addition, TC were clinically and quantitative sensory testing (QST) phenotyped; the phenotyping of CRPS patients was retrieved from our existing database. SP metabolism was less efficient in CRPS and TC patient serum vs human control (HC) serum (P < .03) suggesting reduced activity of the neutral endopeptidase (NEP) and/or the angiotensin converting enzyme (ACE). Together with the decreased occurrence of BK1-5 fragment in CRPS and TC, this suggests a reduced activation of the angiotensin converting enzyme (ACE). There was no clear clinical phenotype related to impaired SP degradation; duration of disease and gender were also not associated. Most importantly, results in TC did not differ from CRPS. Collectively, our current and previous experimental results suggest that limb trauma reduces serum peptidase metabolism of SP ex vivo, specifically serum ACE activity. However, this finding is not CRPS-specific and seems to be rather a long-term consequence of the trauma itself. PerspectiveThe experimental data from this study further support the hypothesis that impaired metabolism of inflammatory peptides potentially contribute to the development of posttraumatic pain in CRPS or limb trauma patients.

Pupillary Reflexes in Complex Regional Pain Syndrome: Asymmetry to Arousal Stimuli Suggests an Ipsilateral Locus Coeruleus Deficit

Converging lines of evidence suggest that autonomic and nociceptive pathways linked with the locus coeruleus are disrupted in complex regional pain syndrome (CRPS). To investigate this, pupillary dilatation to arousal stimuli (which reflects neural activity in the locus coeruleus) and pupillary reflexes to light were assessed in a cross-sectional study of 33 patients with CRPS. Moderately painful electrical shocks were delivered to the affected or contralateral limb and unilateral 110 dB SPL acoustic startle stimuli were delivered via headphones. To determine whether the acoustic startle stimuli inhibited shock-induced pain, startle stimuli were also administered bilaterally 200 ms before or after the electric shock. The pupils constricted briskly and symmetrically to bright light (500 lux) and dilated symmetrically in dim light (5 lux). However, the pupil on the CRPS-affected side was smaller than the contralateral pupil before and after the delivery of painless and painful arousal stimuli. Auditory sensitivity was greater on the affected than unaffected side but acoustic startle stimuli failed to inhibit shock-induced pain. Together, these findings suggest that neural activity in pathways linked with the locus coeruleus is compromised on the affected side in patients with CRPS. This may contribute to autonomic disturbances, auditory discomfort and pain. PerspectiveThe locus coeruleus is involved not only in modulation of pain but also regulates sensory traffic more broadly. Hence, fatigue of neural activity in the ipsilateral locus coeruleus might not only exacerbate pain and hyperalgesia in CRPS but could also contribute more generally to hemilateral disturbances in sensory processing.

Direct Sciatic Nerve Electrical Stimulation for Complex Regional Pain Syndrome Type 1

Foot and leg pain in complex regional pain syndrome (CRPS) presents a challenge even with neuromodulation techniques such as spinal cord stimulation (SCS). We report our experience with a novo technique of direct sciatic nerve electrical stimulation (DISNES) for intractable foot and leg pain in CRPS I. Following Research Ethics Board (REB) approval, data were gathered for 16 patients (10 women and 6 men, age 26-61 years) who had been subjected to ipsilateral DISNES. All 16 patients had failed conventional medical management. As well, seven subjects were previously treated with SCS for CRPS I pain. These subjects reported pain relief in the thigh and leg, however the SCS was unable to alleviate the disabling foot pain despite varied and multiple programming techniques. The remaining nine subjects were treated primarily with DISNES. Evaluation was done using visual analog scale (VAS), Oswestry Disability Index version 2 (ODI), and quality of life (EQ-5D and SF-36) scores done both pre-DISNES and at two follow-ups. VAS scores decreased by 59% at follow-up (F/U) 1 (P=0.00001) and 46% F/U 2. ODI improving by 40% F/U 1 (P=0.0038) and 37% F/U 2. SF-36 scores improved by 69% F/U 1 (P=0.015) and 80% F/U 2. EQ-5D scores improved significantly by F/U 1 (P=0.00030) but insignificantly at F/U 2 (P=0.81). There was also a rapid resolution of autonomic features such as edema, hyperemia, and allodynia (within 7-10 days). Three subjects returned to work post-DISNES. Our study shows that DISNES helps to control the disabling foot pain in CRPS I, thus improving the quality of life, improving ambulation and decreasing disability. DISNES also alleviates autonomic features and dystonia in CRPS I. Further studies are needed to determine long-term efficacy as this study pool is limited in size and follow-up period.

Predictors of Self-Reported Neglect-like Symptoms and Involuntary Movements in Complex Regional Pain Syndrome Compared to Other Chronic Limb Pain Conditions

ObjectiveIn addition to pain, people with complex regional pain syndrome (CRPS) often report inattention to and disengagement from their affected limb (i.e., “neglect-like symptoms”). Understanding how these symptoms relate to other characteristics of CRPS, and chronic pain generally, could provide insights for preventing and treating CRPS.MethodsWe administered an online survey to people who received a diagnosis of CRPS (n = 335) and other chronic limb pain (n = 407). Neglect-like symptoms were assessed using the Neurobehavioral questionnaire.ResultsA principal component analysis identified two components: motor and cognitive neglect-like symptoms, and involuntary movements. Internal consistency of the components was acceptable. We conducted regression analyses with these as outcomes. Having CRPS, a painful lower limb, higher pain intensity, and somatic symptoms were associated with more motor and cognitive neglect-like symptoms. Having CRPS, higher pain intensity, depression, and somatic symptoms were associated with more involuntary movements. Age, gender, anxiety, disease duration, hours of pain per day, affected side, whether the limb was the most painful body part, and number of pain-related medical diagnoses were no predictors. Finally, motor and cognitive neglect-like symptoms were related to tremor; and involuntary movements to changes in skin color, swelling, sweating, toenails, weakness, and tremor.ConclusionsThis study confirms the specificity of inattention to and disengagement from the affected limb in CRPS, independent of other factors. Furthermore, two components of the Neurobehavioral questionnaire were disentangled: motor and cognitive neglect-like symptoms, and involuntary movements. Results could potentially help clinicians to better assess neglect-like symptoms in chronic pain .

Validation of the Leiden Visual Sensitivity Scale and Visual Discomfort Scale in Chronic Pain Conditions.

Discomfort provoked by normally innocuous visual stimuli has been reported by people with chronic pain. Visual discomfort may be higher in pain conditions in which central sensitization is implicated, such as Complex Regional Pain Syndrome (CRPS) and fibromyalgia. In an online study, we validated the Leiden Visual Sensitivity Scale (L-VISS) and Visual Discomfort Scale (VDS) in people with CRPS (n = 57), fibromyalgia (n = 75), and general chronic pain (n = 53); investigated whether these groups and pain-free controls (n = 125) differed in visual discomfort; and evaluated the effect of age. The L-VISS and VDS had good internal consistency. Both scales were positively related with experimentally induced visual distortions for mid-spatial frequency striped patterns, suggesting good construct validity. The scales were positively related with each other, and dissociated between the pain and pain-free groups in similar ways, suggesting good construct validity. There was no relationship between age and L-VISS scores and a small negative relationship between age and VDS scores. Visual discomfort was highest in the fibromyalgia group, followed by the CRPS group. This research confirms the utility of the L-VISS and VDS for measuring visual sensitivity in chronic pain and adds to evidence that central sensitization is an important mechanism of visual discomfort.

High frequency spinal cord stimulation can be more effective than traditional spinal cord stimulation in treating complex regional pain syndrome

Abstract Introduction: This case report demonstrates the effectiveness of high frequency 10 kHz spinal cord stimulation (HF10 therapy SCS) in the treatment of Complex Regional Pain Syndrome (CRPS) when compared with other treatment modalities including traditional SCS. Traditional SCS is believed to exert its action through stimulating the dorsal columns mitigating the hyperexcitable afferent signals from the periphery. Hf10 SCS delivers more stimulation to the dorsal horns targeting specifically the wide dynamic range neurons (pain projecting neurons). This creates a greater potential to suppress the sympathetic overactivity seen in CRPS while additionally removing the paresthesia's generated with dorsal column stimulation, which many find unpleasant. Patient concerns: 59-year-old Caucasian male presented with classic right lower limb symptoms of CRPS and longstanding low back pain with right-sided radiculopathy. Diagnosis: The patient developed CRPS after right leg open thrombectomy. Interventions: The patient received para-sagittal steroid epidural injections and lumbar sympathetic blocks with inadequate pain relief. He failed to improve using traditional SCS and was referred for evaluation using high frequency 10 kHz spinal cord stimulator, which the SENZA-RCT showed superior pain relief when compared to traditional stimulation. Outcome: This case is unique because the patient had no improvement with traditional SCS and reported 100% relief of CRPS pain and associated symptoms and 40% reduction in back pain while using HF10. This also is significant because back pain tends to be refractory when treated with traditional SCS. Conclusion: High frequency 10 kHz spinal cord stimulator might be an effective means of managing the symptoms of CRPS and reducing axial back pain.

Review of complex regional pain syndrome and the role of the neuroimmune axis.

BackgroundComplex regional pain syndrome (CRPS) is a progressive and painful disease of the extremities that is characterized by continuous pain inconsistent with the initial trauma. CRPS is caused by a multi-mechanism process that involves both the peripheral and central nervous system, with a prominent role of inflammation in CRPS pathophysiology. This review examines what is currently known about the CRPS inflammatory and pain mechanisms, as well as the possible impact of neurostimulation therapies on the neuroimmune axis of CRPS.Study designA narrative review of preclinical and clinical studies provided an overview of the pain and inflammatory mechanisms in CRPS and addressed the effect of neurostimulation on immunomodulation.MethodsA systematic literature search was conducted based on the PRISMA guidelines between September 2015 to September 2020. Data sources included relevant literature identified through searches of PubMed, Embase and the Cochrane Database of Systematic Reviews.ResultsSixteen preclinical and eight clinical studies were reviewed. Preclinical studies identified different mechanisms of pain development in the acute and chronic CRPS phases. Several preclinical and clinical studies investigating inflammatory mechanisms, autoimmunity, and genetic profiles in CRPS, supported a role of neuroinflammation in the pathophysiology of CRPS. The immunomodulatory effects of neurostimulation therapy is still unclear, despite clinical improvement in the CRPS patients.ConclusionsIncreasing evidence supports a role for inflammation and neuroinflammation in CRPS pathophysiology. Preliminary neurostimulation findings, together with the role of (neuro)inflammation in CRPS, seems to provide a compelling rationale for its use in CRPS pain treatment. The possible immunomodulatory effects of neurostimulation opens new therapeutic possibilities, however further research is needed to gain a better understanding of the working mechanisms.

Serum Soluble Interleukin-2 Receptor Does Not Differentiate Complex Regional Pain Syndrome from Other Pain Conditions in a Tertiary Referral Setting.

Previously, we showed that serum soluble interleukin-2 receptor (sIL-2R) levels, a marker for T-cell activation, were higher in complex regional pain syndrome (CRPS) patients than in healthy controls, suggesting pathogenic T-cell activation in CRPS. Additionally, sIL-2R levels discriminated well between CRPS and healthy controls with a high sensitivity (90%) and specificity (89.5%), suggesting a possible role for sIL-2R in the diagnosis of CRPS. In order to further validate this marker in the diagnostic workup of CRPS, we conducted this prospective cohort study in which we determined sIL-2R levels in patients that were referred to our tertiary referral center with a suspicion of CRPS in a limb, and subsequently compared sIL-2R levels between the patients that were diagnosed with CRPS (CRPS group) and those who were not (no CRPS group). A group of anonymous blood bank donors were used as a healthy control group. Furthermore, we explored the relationship between sIL-2R and CRPS disease severity using the CRPS severity score. Median sIL-2R levels of both the CRPS group (2809.0 pg/ml; Q3-Q1: 3913.0-1589.0) and no CRPS group (3654.0 pg/ml; Q3-Q1: 4429.0-2095.5) were significantly higher than that of the control group (1515.0 pg/ml; Q3-Q1: 1880.0-1150.0): CRPS vs. controls, p < .001; no CRPS vs. controls, p < 0.001. Serum sIL-2R levels did not differ significantly between the CRPS and no CRPS group. A statistically significant negative correlation was observed between sIL-2R levels and the CRPS severity score (rs = −0.468, p = 0.024). Our results confirm our previous findings of higher sIL-2R levels in CRPS patients than in healthy controls. We further showed that serum sIL-2R cannot differentiate between CRPS and other pain conditions of a limb in a tertiary referral setting. Interestingly, a negative correlation was found between sIL-2R and CRPS disease severity; this finding warrants further research into the relationship between sIL-2R and CRPS disease severity.

Effectiveness, Safety, and Predictive Potential in Ultrasound-Guided Stellate Ganglion Blockades for the Treatment of Sympathetically Maintained Pain.

Evaluating the effectiveness of stellate ganglion blockades (SGBs) proves challenging, since the criteria defining a successful blockade are controversial. This may be one reason for the scarcity of studies on this topic, thus forcing clinical guidelines to remain conservative in recommending SGBs. Moreover, factors to predict which patients will benefit from blockade series are not yet available. The objectives of this study were to evaluate through a clinical approach SGBs' effectiveness performed under ultrasound guidance (us-SGB) and to identify factors to predict effectiveness. We retrospectively analyzed 809 us-SGBs in 105 patients with complex regional pain syndrome (CRPS) and neuropathic pain syndromes (all potentially including sympathetically maintained pain) regarding pain reduction. Volume and type of local anesthetics, magnitude of pain, temperature of the dorsal hands, heart rate, blood pressure, and occurrence of Horner's syndrome or complications were assessed. Pain reduction after a blockade series was highly significant and showed no significant correlation with change of temperature, vital signs, or Horner's syndrome. For patients with neuropathic pain, the predictive potential for pain reduction following a blockade series lies within the range of pain reduction after the first blockade. In a literature comparison, incidences of complications (hoarseness 3.9%, dysphagia 3.4%, hematoma 0.6%) were lower than in non-ultrasound-guided techniques. Data indicate that us-SGBs are safe and effective in reducing sympathetically maintained pain in patients with CRPS and neuropathic pain syndromes. Pain reduction after the first blockade may predict total pain reduction after a blockade series. Other clinical measures seem unsuitable to predict effectiveness.