How Do We Treat Children with Anterior Cutaneous Nerve Entrapment Syndrome and Is the Biopsychosocial Model Also Being Applied? A Scoping Review.

Background: Evidence-based guidelines for managing anterior cutaneous nerve entrapment syndrome (ACNES) in children are absent. The primary aim of this review was to scrutinize the evidence supporting currently used treatment interventions. In accordance with the World Health Organization (WHO) guidelines for managing chronic pain in children, these patients and their families and caregivers should be treated within the context of the biopsychosocial model; pain should not be treated purely as a biomedical problem. Therefore, our second aim was to evaluate whether these interventions are applied within the context of the biopsychosocial model, utilizing an inter- or multidisciplinary approach. Materials and Methods: A scoping review of the literature was conducted to explore treatment strategies for ACNES in children. To ensure a comprehensive overview of published literature on this topic, the search was not restricted based on study type. Two reviewers independently assessed titles and abstracts. After excluding records unrelated to children, full texts were screened for inclusion. Any discrepancies in judgement were resolved through discussion with a third reviewer. Results: Out of 35 relevant titles, 22 were included in this review. Only 4 articles provided information on long-term outcomes. The overall quality of the review was deemed low. The majority of reports did not address treatment or education within the psychological and social domains. A structural qualitative analysis was not feasible due to the substantial heterogeneity of the data. Conclusion: The evidence supporting current treatment strategies in children with ACNES is of low quality. More research is needed to establish an evidence-based treatment algorithm for patients with this challenging pain problem. In line with the WHO recommendation, greater emphasis should be placed on a biopsychosocial approach. The ultimate goal should be the development of a generic treatment algorithm outlining an approach to ACNES applicable to all professionals involved.

Is there an association between serum soluble interleukin-2 receptor levels and syndrome severity in persistent Complex Regional Pain Syndrome?

OBJECTIVE: A potentially useful biomarker for Complex Regional Pain Syndrome (CRPS) is the serum soluble interleukin-2 receptor (sIL-2R) level, which is a marker for T-cell activation. Elevated serum sIL-2R levels have been described in CRPS patients compared to healthy controls. In T-cell mediated inflammatory diseases such as sarcoidosis and rheumatoid arthritis, the serum sIL-2R levels correlate with disease severity. In this study, we investigate whether an association exists between serum sIL-2R levels in CRPS patients and CRPS severity. METHODS: A cross-sectional cohort study was conducted in a tertiary pain referral center in the Netherlands. Adult CRPS patients diagnosed by the IASP criteria were included between October 2018 until October 2022. The main study parameters were serum sIL-2R levels and the CRPS severity score. RESULTS: Fifty-three CRPS patients were included with a mean syndrome duration of 84 months (Q3 - Q1:180 - 48). The majority had persistent CRPS with a syndrome duration >1 year (n = 52, 98%). The median pain Numerical Rating Score (NRS) was 7 (Q3 - Q1: 8 - 5) and the mean CRPS severity score was 11 (SD ± 2.3). The median serum sIL-2R level was 330 U/mL (Q3 - Q1:451 - 256). No statistically significant correlation was observed between serum sIL-2R levels and the CRPS severity score (rs = 0.15, P = .28). CONCLUSIONS: Our findings suggest that serum sIL-2R levels cannot be used as a biomarker for syndrome severity in persistent CRPS (syndrome duration >1 year). Serial measurements of serum sIL-2R from early CRPS to persistent CRPS are needed to investigate whether serum sIL-2R levels can be used to monitor T-cell mediated inflammatory syndrome activity.

Effectiveness of Infliximab in Patients with Complex Regional Pain Syndrome: A Case Series.

Purpose: Complex regional pain syndrome (CRPS) is a multi-mechanism disease, with an exaggerated inflammatory response as an important underlying mechanism. Auto-inflammation can theoretically be combated by anti-inflammatories, such as TNF-α inhibitors. This study's aim was to assess the effectiveness of intravenous infliximab, a TNF-α inhibitor, in patients with CRPS. Patients and Methods: CRPS patients treated with infliximab between January 2015 and January 2022 were approached to participate in this retrospective study. Medical records were screened for age, gender, medical history, CRPS duration, and CRPS severity score. Additionally, treatment effect, dose and duration, and side effects were extracted from medical records. Patients who still receive infliximab completed a short global perceived effect survey. Results: Eighteen patients received infliximab, and all but two gave consent. Trial treatment with three sessions of 5 mg/kg intravenous infliximab was completed in 15 patients (93.7%). Eleven patients (73.3%) were categorized as responders with a positive treatment effect. Treatment was continued in nine patients, and seven patients are currently treated. Infliximab dose is 5 mg/kg, and frequency is every four to six weeks. Seven patients completed a global perceived effect survey. All patients reported improvement (median 2, IQR 1-2) and treatment satisfaction (median 1, IQR 1-2). One patient described side effects such as itching and rash. Conclusion: Infliximab proved effective in 11 out of 15 CRPS patients. Seven patients are still being treated. Further research is needed on the role of infliximab in the treatment of CRPS and possible predictors of response to treatment.

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

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

Different Types of Pain in Complex Regional Pain Syndrome Require a Personalized Treatment Strategy.

Complex regional pain syndrome (CRPS) is a debilitating painful state of an extremity that can develop after trauma. CRPS is diagnosed by the new International Association for the Study of Pain (IASP) diagnostic criteria for CRPS. The syndrome is characterized by continuing regional pain with abnormal sensory, motor, sudomotor, vasomotor, edema, and/or trophic signs. The clinical presentation of CRPS can be very heterogeneous because CRPS is a multi-mechanism syndrome. Therefore, mechanism-based subgroups have been suggested to personalize treatment for CRPS. Additionally, the presentation of symptom pain may also be able to identify different subgroups of CRPS. In this review, the types of pain recognized by the IASP-nociceptive, neuropathic, and nociplastic pain-will be discussed as possible subgroups for CRPS. Each pain type should be identified in CRPS patients, with a thorough history taking, physical examination, and diagnostic tests or (novel) biomarkers to optimize treatment effectiveness. Over the course of the syndrome, patients with CRPS probably experience more than one distinct pain type. Therefore, pain specialists should be alert to not only adjust their treatment if underlying pathophysiologic mechanisms tend to change but also to personalize the treatment of the associated type of pain in the CRPS patient.

From a Symptom-Based to a Mechanism-Based Pharmacotherapeutic Treatment in Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) is a debilitating painful condition of a distal extremity that can develop after tissue damage. CRPS is thought to be a multimechanism syndrome and ideally the most prominent mechanism(s) should be targeted by drugs in an individually tailored manner. This review gives an overview of the action and evidence of current and future pharmacotherapeutic options for CRPS. The available options are grouped in four categories by their therapeutic actions on the CRPS mechanisms, i.e. inflammation, central sensitisation, vasomotor disturbances and motor disturbances. More knowledge about the underlying mechanisms of CRPS helps to specifically target important CRPS mechanisms. In the future, objective biomarkers could potentially aid in selecting appropriate mechanism-based drugs in order to increase the effectiveness of CRPS treatment. Using this approach, current and future pharmacotherapeutic options for CRPS should be studied in multicentre trials to prove their efficacy. The ultimate goal is to shift the symptom-based selection of therapy into a mechanism-based selection of therapy in CRPS.

Ketamine therapy for chronic pain in The Netherlands: a nationwide survey.

OBJECTIVES: Ketamine is used to treat chronic refractory pain. However, there are no scientific guidelines for ketamine use in the Netherlands. The aim of this survey was to provide an overview of the use of ketamine for chronic pain in the Netherlands. METHODS: All pain clinics in the Netherlands were contacted. A digital survey, available from June 2019 to January 2020, was sent to 68 pain clinics. The survey was completed by one pain physician as a representative of the entire pain department. The survey included questions about ketamine treatment indications, administration, dose, duration, treatment repetition and the inpatient or outpatient setting. RESULTS: The survey was completed by 51 pain clinics (75.0%). Thirty-one clinics used ketamine for chronic pain treatment. The most common indication was Complex Regional Pain Syndrome (83.9%). Pain clinics administered ketamine via intravenous infusions (96.8%), iontophoresis (61.3%), subcutaneous (3.2%) or oral administration (3.2%). Intravenous ketamine treatment was offered in an inpatient setting in 14 pain clinics, in both an inpatient and outpatient setting in 11 pain clinics and in six pain clinics in an outpatient setting. In the outpatient setting, the median starting dose was 5 mg/h (IQR=17.5-5). The median maximum dose was 27.5 mg/h (IQR=100-11.9). The median infusion duration was 6 h (IQR=8-4). In the inpatient setting, the median starting dose was 5 mg/h (IQR=5-1.5) and the median maximum dose was 25 mg/h (IQR=25-14). Patients were admitted to hospital for a median of 4 days (IQR=5-1). CONCLUSIONS: The results of this Dutch nationwide survey study show that there are heterogeneous treatment protocols with different indications, treatment setting and dosing regimen for the treatment of chronic pain with ketamine. This study encourages the formulation of a broader consensus and the development of evidence based guidelines for ketamine treatment.

Effect of intravenous low-dose S-ketamine on pain in patients with Complex Regional Pain Syndrome: A retrospective cohort study.

OBJECTIVE: The objective of this study was to assess the effectiveness of a low-dose intravenous S-ketamine treatment on refractory pain in patients with Complex Regional Pain Syndrome (CRPS). METHODS: In this retrospective study, patients with CRPS who received intravenous S-ketamine from March 2010 to April 2019 were included. According to our inpatient protocol, S-ketamine dose was increased until pain reduction was achieved or side effects were observed. Maximum dose was 14 mg/h and treatment duration was 7 days. Primary outcome parameters were pain scores (Numeric Rating Scale) at baseline (T0), end of infusion (T1), and approximately 4 weeks postinfusion (T2). Patients were categorized as responder/nonresponder at T1 and T2. Patients were considered a responder in case there was pain score reduction of greater than or equal to 2 points or if treatment was reported as successful. RESULTS: Forty-eight patients were included. Mean disease duration was 5 years (interquartile range [IQR] = 6 years). Median pain score significantly decreased from 8 (IQR = 2) at T0 to 6 (IQR = 4) at T1 (p < 0.001). At T1, 62% of the patients were responders. At T2, 48% of the patients remained a responder. A significant proportion of the responders at T1 turned into nonresponders at T2 (p = 0.03). CONCLUSION: In a group of patients with CRPS with refractory pain, low-dose intravenous S-ketamine treatment resulted in effective pain relief during infusion. Although a significant proportion of initial responders became nonresponders at follow-up, half of the patients were still a responder at ~ 4 weeks postinfusion. Further research is needed to investigate mechanisms responsible for pain relief by S-ketamine infusions and to ascertain possible predictors of response to the treatment.

Highlighting the Role of Biomarkers of Inflammation in the Diagnosis and Management of Complex Regional Pain Syndrome.

Complex regional pain syndrome (CRPS) is characterized by continuous pain that is often accompanied by sensory, motor, vasomotor, sudomotor, and trophic disturbances. If left untreated, it can have a significant impact on the quality of life of patients. The diagnosis of CRPS is currently based on a set of relatively subjective clinical criteria: the New International Association for the Study of Pain clinical diagnostic criteria for CRPS. There are still no objective laboratory tests to diagnose CRPS and there is a great need for simple, objective, and easily measurable biomarkers in the diagnosis and management of this disease. In this review, we discuss the role of inflammation in the multi-mechanism pathophysiology of CRPS and highlight the application of potential biomarkers of inflammation in the diagnosis and management of this disease.

The use of dipyrone (metamizol) as an analgesic in children: What is the evidence? A review.

Dipyrone has analgesic, spasmolytic, and antipyretic effects and is used to treat pain. Due to a possible risk of agranulocytosis with the use of dipyrone, it has been banned in a number of countries. The most commonly used data for the use of dipyrone are related to adults. Information relating to the use of dipyrone in children is scarce. Given the potential added value of dipyrone in the treatment of pain, a review of the literature was conducted to obtain more insight into the analgesic efficacy of dipyrone in children as well as the safety of dipyrone in terms of adverse events. A literature search was done for original articles (in English, German, or Spanish language) which met the following criteria: the use of dipyrone for pain and children up to the age of 17 years old. All titles and abstracts retrieved were reviewed, independently, by two of the authors, for their suitability for inclusion. The references of the selected articles were also checked for additional relevant papers. The publications were categorized into case reports, observational studies, or randomized controlled trials. To assess the methodological quality of the studies, the Jadad score was used. In the limited available data, the analgesic efficacy of intravenous dipyrone appears similar to that of intravenous paracetamol. Evidence is lacking to support the claim that dipyrone is equivalent or even superior to Non-Steroid-Anti-Inflammatory-Drugs in pediatric pain. While the absolute risk of agranulocytosis with dipyrone in children, based on available literature, cannot be determined, case reports suggest that this risk is not negligible.

Elevated Plasma Levels of sIL-2R in Complex Regional Pain Syndrome: A Pathogenic Role for T-Lymphocytes?

The immune system has long been thought to be involved in the pathophysiology of complex regional pain syndrome (CRPS). However, not much is known about the role of the immune system and specifically T-cells in the onset and maintenance of this disease. In this study, we aimed to evaluate T-cell activity in CRPS by comparing blood soluble interleukin-2 receptor (sIL-2R) levels between CRPS patients and healthy controls. CRPS patients had statistically significant elevated levels of sIL-2R as compared to healthy controls (median sIL-2R levels: 4151 pg/ml (Q3 - Q1 = 5731 pg/ml - 3546 pg/ml) versus 1907 pg/ml (Q3 - Q1: 2206 pg/ml - 1374 pg/ml), p < 0.001, resp.). Furthermore, sIL-2R level seems to be a good discriminator between CRPS patients and healthy controls with a high sensitivity (90%) and specificity (89.5%). Our finding indicates increased T-cell activity in patients with CRPS. This finding is of considerable relevance as it could point towards a T-cell-mediated inflammatory process in this disease. This could pave the way for new anti-inflammatory therapies in the treatment of CRPS. Furthermore, sIL-2R could be a promising new marker for determining inflammatory disease activity in CRPS.

The prevalence of autoantibodies in complex regional pain syndrome type I.

Autoimmunity has been suggested as one of the pathophysiologic mechanisms that may underlie complex regional pain syndrome (CRPS). Screening for antinuclear antibodies (ANA) is one of the diagnostic tests, which is usually performed if a person is suspected to have a systemic autoimmune disease. Antineuronal antibodies are autoantibodies directed against antigens in the central and/or peripheral nervous system. The aim of this study was to compare the prevalence of these antibodies in CRPS patients with the normal values of those antibodies in the healthy population. Twenty seven (33%) of the 82 CRPS patients of whom serum was available showed a positive ANA test. This prevalence is significantly higher than in the general population. Six patients (7.3%) showed a positive result for typical antineuronal antibodies. This proportion, however, does not deviate from that in the general population. Our findings suggest that autoantibodies may be associated with the pathophysiology of CRPS, at least in a subset of patients. Further research is needed into defining this subset and into the role of autoantibodies in the pathogenesis of CRPS.

Report of a preliminary discontinued double-blind, randomized, placebo-controlled trial of the anti-TNF-α chimeric monoclonal antibody infliximab in complex regional pain syndrome.

OBJECTIVE: Inflammation appears to play a role in CRPS as, for example, cytokines (like TNF-α) are involved in the affected limb. The ongoing inflammation is probably responsible for the central sensitization that sometimes occurs in CRPS. Thus, early start of a TNF-α antagonist may counteract inflammation, thereby preventing rest damage and leading to recovery of the disease. DESIGN: Patients (n = 13) were randomly assigned to infliximab 5 mg/kg or placebo, both administered at week 0, 2, and 6. OUTCOME MEASURES: The aim was to confirm a reduction in clinical signs of regional inflammation (based on total impairment level sumscore: ISS) after systemic administration of infliximab. Also, levels of mediators in the fluid of induced blisters were examined in relation to normalization and improvement in quality of life. RESULTS: Six patients received infliximab and 7, placebo. There was no significant change in total ISS score between the two groups. Similarly, no significant difference in change in cytokine levels was found between infliximab compared with placebo. However, there was a trend toward a greater reduction of TNF-α in the intervention group compared with the placebo group. A subscale of the EuroQol (ie EuroQol VAS) revealed significant decrease in health status in the intervention group compared with the placebo group. CONCLUSIONS: This study was terminated before the required number of participants had been reached for sufficient statistical power. Nevertheless, a trend was found toward an effect of infliximab on the initially high TNF-α concentration.

Mast cells: a new target in the treatment of complex regional pain syndrome?

There is convincing evidence that inflammation plays a pivotal role in the pathophysiology of complex regional pain syndrome (CRPS). Besides inflammation, central sensitization is also an important phenomenon. Mast cells are known to be involved in the inflammatory process of CRPS and also play a role (at least partially) in the process of central sensitization. In the development of a more mechanism-based treatment, influencing the activity of mast cells might be important in the treatment of CRPS. We describe the rationale for using medication that counteracts the effects of mast cells in the treatment of CRPS.

Effect of immunomodulating medications in complex regional pain syndrome: a systematic review.

BACKGROUND: Different mechanisms are involved in a complex network of interactions resulting in the painful and impairing disorder, complex regional pain syndrome (CRPS). There is convincing evidence that inflammation plays a pivotal role in the pathophysiology of CRPS. Immunomodulating medication reduces the manifestation of inflammation by acting on the mediators of inflammation. Therefore, as inflammation is involved in the pathophysiology of CRPS, immunomodulating medication in CRPS patients may prove beneficial. OBJECTIVES: To describe the current empirical evidence for the efficacy of administering the most commonly used immunomodulating medication (ie, glucocorticoids, tumor necrosis factor-α antagonists, thalidomide, bisphosphonates, and immunoglobulins) in CRPS patients. METHODS: PubMed was searched for original articles that investigated CRPS and the use of one of the abovementioned immunomodulating agents. RESULTS: The search yielded 39 relevant articles: from these, information on study design, sample size, duration of disease, type and route of medication, primary outcome measures, and results was examined. DISCUSSION: Theoretically, the use of immunomodulating medication could counteract the ongoing inflammation and might be an important step in improving a disabled hand or foot, leading to further recovery. However, more high-quality intervention studies are needed.

Remifentanil as a single drug for extracorporeal shock wave lithotripsy: a comparison of infusion doses in terms of analgesic potency and side effects.

UNLABELLED: This randomized, double-blind study was designed to evaluate analgesic effectiveness and side effects of two remifentanil infusion rates in patients undergoing extracorporeal shock wave lithotripsy (ESWL) for renal stones. We included 200 patients who were administered remifentanil either 0.05 microg x kg(-1) x min(-1) (n = 100) or 0.1 microg x kg(-1) x min(-1) (n = 100) plus demand bolus of 10 microg of remifentanil via a patient-controlled analgesia (PCA) device. No other sedating drugs were given. The frequencies of PCA demands and deliveries were recorded. Arterial blood pressure, oxygen saturation, and respiratory rate were recorded throughout the procedure; postoperative nausea and vomiting (PONV), dizziness, itching, agitation, and respiratory depression were measured posttreatment. Visual analog scale (VAS) scores were taken preoperatively, directly postoperatively, and 30 min after finishing the procedure. There were no statistically significant differences in the frequency of PCA demands and delivered boluses or among perioperative VAS scores. The extent of PONV and frequency of dizziness and itching immediately after and dizziness 30 min after the end of treatment were significantly reduced in the smaller dose group. We conclude that a remifentanil regimen of 0.05 microg x kg(-1) x min(-1) plus 10 microg demands is superior to 0.1 microg x kg(-1) x min(-1) plus demands, as there was no difference in the VAS scores recorded between groups and it has a less frequent incidence of side effects in patients receiving ESWL. IMPLICATIONS: Remifentanil is an appropriate analgesic choice for patients undergoing extracorporeal shock wave lithotripsy (ESWL) therapy, as it has both fast onset and offset times. We studied remifentanil as a sole drug for ESWL and have shown that an infusion rate of 0.05 microg x kg-1 x min-1 plus patient-controlled analgesia demands of 10 microg provides adequate analgesia and has significantly less side effects than a dose of 0.1 microg x kg-1 x min-1 plus 10 microg demands.

Propofol-induced injection pain: comparison of a modified propofol emulsion to standard propofol with premixed lidocaine.

Propofol is well known for its association with pain on injection. The most frequently used method to reduce this pain is premixture with lidocaine. Recently, a modified lipid emulsion of propofol containing medium-chain triglycerides (MCT) with long-chain triglycerides (LCT), in contrast to the usual LCT formulation, has been advocated to alleviate pain. In a randomized, prospective, controlled, double-blind study on 222 surgical patients, we compared the effect of the two solutions on the incidence and intensity of injection pain. Patients were randomly allocated to receive either propofol MCT/LCT (group M; n = 109) or standard propofol LCT with the addition of 20 mg of lidocaine (2 mL of lidocaine 1%) to 200 mg of propofol (group L; n = 113). Pain scores were assessed using a verbal analog scale (VAS) ranging from 0-10. Group L was found to have significantly less pain on the injection of propofol (mean VAS, 2.5 +/- 2.9) (mean +/- sd) than group M (mean VAS, 3.8 +/- 3.2; P = 0.002). Regarding postoperative recall of pain on injection, patients in group L indicated significantly less pain (mean VAS, 2.2 +/- 2.4) than patients in group M (mean VAS, 3.0 +/- 2.7; P = 0.02). Premixing of 20 mg of lidocaine (2 mL of lidocaine 1%) to 200 mg of standard propofol LCT causes less pain on injection than propofol MCT/LCT and thus increases patient comfort.