ABSTRACT Progressive hip displacement is a common problem in children with neurodevelopmental conditions, often leading to painful dislocation and impaired function. Hip reconstruction may be necessary to maintain containment but these reconstructions are major surgery in this vulnerable population. Effective pain management during and after hip reconstruction is crucial but challenging due to comorbidities and communication difficulties. Current practices vary widely, risking inadequate pain control. Epidural analgesia shows superior outcomes compared to local anesthesia, though optimal regimens remain unclear. This study aims to evaluate pain protocols used during and after hip reconstruction and propose a uniform protocol. This retrospective study analyzed records of children with neurodevelopmental conditions who underwent hip surgery at Erasmus MC from 2017 to 2021. Data included surgical details, pain management during and after the operations and pain scores using various validated tools. Pain assessments considered developmental level, using observational scales for non‐verbal children and self‐reports for others. Ninety‐one patients were included. Epidural analgesia was the main method of analgesia in 81 patients (89.0%). The group of patients who received intermittent epidural boluses after the loading dose had a higher number of high pain scores on the day of surgery, compared to those receiving continuous epidural infusion (p = 0.045). Patients who had undergone previous surgery had significantly higher median pain scores on the day of surgery compared to patients undergoing their first operation (p = 0.020). This study shows a wide variety in perioperative pain management. Patients who received intermittent epidural boluses instead of continuous epidural infusion during anesthesia experienced higher pain scores on the day of surgery. Next to that, patients who had undergone previous surgery experienced higher pain scores on the day of surgery, suggesting pain sensitization. This study has led to the development of a new uniform protocol.

Objectives: Complex regional pain syndrome (CRPS) is a heterogeneous pain disorder with incompletely understood immunoinflammatory features. This study investigated whether autonomic receptor autoantibodies differentiate CRPS from other chronic pain conditions and healthy controls. Methods: We conducted a cross-sectional analysis of serum samples from patients referred with suspected CRPS. Patients were subsequently classified as having either CRPS or another chronic pain condition, based on the Budapest criteria. Healthy controls were included for comparison. Serum levels of autoantibodies targeting the muscarinic M2 receptor (M2R), β1-adrenergic receptor (β1AR), and the β2-adrenergic receptor (β2AR) were assessed using enzyme-linked immunosorbent assay. All analyses were performed blinded to group assignment. Results: Seventy participants were analyzed (CRPS = 22, other chronic pain = 25, healthy controls = 23). M2R autoantibody levels were higher in both CRPS and other chronic pain compared with healthy controls (mean difference [MD] = 0.37, 95%CI 0.22–0.51; and MD = 0.31 95%CI 0.19–0.44, respectively). β2AR levels were higher in other chronic pain compared with healthy controls (MD = 0.29, 95%CI 0.04–0.54), whereas no significant difference was observed in CRPS (MD = 0.21 95%CI −0.01–0.42). No meaningful differences were observed between CRPS and other chronic pain for any receptor. β1AR levels did not differ between groups. Seropositivity for any autoantibody was 55% in CRPS, 44% in other chronic pain, and 22% in healthy controls. Conclusions: Elevated autonomic receptor autoantibody levels were observed across chronic pain conditions but were not specific for CRPS.

Intravenous ketamine is used for complex regional pain syndrome (CRPS), but variable response and uncertain durability limit patient selection. This systematic review evaluated reported predictors of response to intravenous ketamine in CRPS and quantified the extent and duration of pain relief. The protocol is registered in PROSPERO (CRD420250655066). Databases were searched from inception through March 26, 2026. Randomized trials and observational studies reporting intravenous ketamine in CRPS were included. Pain scores were rescaled to a 0-10 scale, and the mean difference in change from baseline was pooled for the earliest post-infusion assessment within 14 days using inverse-variance random-effects meta-analysis. Random-effects meta-regression modeled outcomes at 14 days or later. Predictors of response were synthesized narratively. Twenty-one studies (3 randomized trials) included 605 ketamine-treated patients, with most studies having a moderate to high risk of bias. The pooled mean baseline pain score was 7.4. At the earliest post-infusion assessment within 14 days, the mean change in pain was -3.6 (95%CI -4.7 to -2.5). Limited longer-term data up to 90 days suggested attenuation of effect, with a gradual return toward baseline. Responder definitions varied widely, with a median responder rate of 65% (range 0-100%). Only 3 studies formally evaluated predictors, and quantitative synthesis was not feasible. Reported associations included sympathetically maintained pain (aOR 6.54, 95%CI 1.83-23.44) and obesity (aOR 8.75, 95%CI 1.45-52.73). Other exploratory predictors included bone scintigraphy phase ratios and baseline microRNAs. Intravenous ketamine may reduce pain, but limited predictor evidence precludes firm conclusions for individualized treatment selection. PERSPECTIVE: This systematic review supports intravenous ketamine as a potential interventional option for complex regional pain syndrome, while emphasizing that standardized outcome reporting and validated predictors are needed before treatment can be reliably individualized.

Purpose:Pamidronate is a nitrogen-containing bisphosphonate with immunomodulatory and anti-osteoclastic properties that has shown benefit in early-onset complex regional pain syndrome (CRPS), yet evidence in persistent CRPS remains limited. Given that chronicity may attenuate therapeutic response, this study evaluates the effectiveness and tolerability of intravenous pamidronate in CRPS patients managed in routine clinical practice. Patients and Methods:We conducted a single-center retrospective observational study, including all adult CRPS patients treated with pamidronate between 2014 and 2024 at our tertiary referral center. Data were collected from medical records at baseline, during treatment and at routine follow-up at approximately 1-, 3-, 6-, and 12-months post-treatment. The primary outcome was the pain trajectory, analyzed using a linear mixed-effects model. Responders were defined by a ≥2-point NRS reduction or subjective benefit when NRS data were unavailable. Results:Of 110 eligible patients, 97 were included with a median age of 45 (IQR 32-54), and a median disease duration of 31 months (IQR 9-97). Baseline mean NRS was 7.95 (95% CI: 7.66 to 8.25), declining by 1.10 points (95% CI: -1.49 to -0.70; p<0.001) at 1 month and by 0.66 points (95% CI: -1.13 to -0.20; p<0.01) at 3 months. Responder rates were 34% and 22%, respectively. Treatment-related adverse events occurred in 91% of patients but led to discontinuation in only 6%. Conclusion:In patients with predominantly persistent CRPS, intravenous pamidronate was well tolerated and associated with a modest, short-term pain relief up to 3 months. No sustained analgesic benefit was evident at later timepoints.

Background Sympathetic interventions are frequently used in complex regional pain syndrome (CRPS). However, the evidence is inconclusive, and the response may depend on phenotype, anatomical target, and treatment durability. For upper-extremity CRPS, clinical data on thoracic sympathetic block (TSB) with botulinum toxin type A (BoNT-A) are lacking. Objective To describe patient characteristics, procedural details, and clinical and thermographic outcomes after computed tomography (CT)-guided TSB with BoNT-A in upper-extremity CRPS. Methods We performed a retrospective single-center case series of consecutive adults with upper-extremity CRPS who underwent CT-guided TSB with BoNT-A between January 2023 and March 2026. For each procedure, medical records were reviewed to descriptively assess pain change, duration of effect, repeat procedures, thermographic change, and adverse events. Results Six patients underwent 7 procedures. Most suffered from persistent, treatment-refractory CRPS. Responses varied: 3 patients experienced a clinically meaningful analgesic benefit, 1 had thermographic improvement without clear analgesic benefit, and 2 had no meaningful response. No serious procedure-related complications were observed. Conclusion CT-guided TSB with BoNT-A was feasible in this small retrospective series of refractory upper-extremity CRPS. Responses were heterogeneous, and thermographic improvement was not always accompanied by pain relief. The findings may prompt hypotheses regarding phenotype-based patient selection and the role of thermography.

Background Anterior cutaneous nerve entrapment syndrome (ACNES) is a chronic pain syndrome that also occurs in children. The European Pain Federation EFIC recommends the application of the biopsychosocial model of pain. In children with suspected ACNES, the use of this model in diagnosis and treatment appears underused. Most publications focus on invasive interventions. These are potentially harming patients due to this one-dimensional approach. We aimed to assess the use of the biopsychosocial model during the diagnosis and treatment of children with chronic abdominal pain and suspected ACNES before referral to a tertiary paediatric pain centre (PPC) and diagnosis and treatment outcomes in the PPC using the biopsychosocial model.Design Single-centre retrospective cohort study of patients referred to a tertiary PPC with (suspected) diagnosis of ACNES between November 2017 and March 2024.Primary outcome Use of the biopsychosocial model and treatments performed before referral to the PPC.Secondary outcomes Confirmation of the diagnosis of ACNES on assessment and results of therapeutic interventions performed in the PPC.Results 31 patients were included. In less than 25% of the patients, the biopsychosocial model was used before referral. The treatments performed were diverse. At the PCC, in none of the cases could the diagnosis of ACNES be solidly confirmed. After treatment using the biopsychosocial model in the PPC, 20 patients (64.5%) reported less or absence of pain.Conclusion Failure to use the biopsychosocial model in the treatment of suspected ACNES in children might lead to unnecessary invasive interventions with a risk of persistence of pain while the pain-maintaining factors are inadequately addressed. Therefore, a diagnostic-treatment algorithm is proposed.

BACKGROUND:Several studies point towards the involvement of the immune system (especially the monocyte-macrophage system) in the pathophysiology of Complex Regional Pain Syndrome (CRPS), as shown by increased levels of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6. These cytokines are primarily released from pro-inflammatory M1 macrophages, but are difficult to measure in a clinical setting. Investigating the activity of tissue-resident macrophages by measuring soluble CD163 (sCD163) in serum is much more clinically applicable. sCD163 could potentially be a biomarker for determining inflammation in CRPS and would have direct consequences for the choice of therapy. The aim of this study is to investigate the tissue-resident macrophage activation in CRPS with sCD163 and explore the relationship between soluble IL-2R, which is a marker for T-cell activation, and sCD163. METHODS:The sCD163 levels were determined in this retrospective cohort study (MEC-2020-0716) in serum of CRPS patients (n = 22) and healthy controls (n = 27). ELISA kits were used to measure the levels of these markers. Data on demographics, pain scores (11-point Numeric Rating Scale: NRS), sIL-2R levels, signs and symptoms, and CRPS disease severity were also recorded. RESULTS:The median serum sCD163 level was significantly higher in CRPS patients (CRPS 960.5 pg/mL [Q3-Q1: 1211.5-623.9] than in healthy controls 677.0 pg/mL [Q3-Q1: 828.0-469.5], p = 0.008). There was a statistically significant positive correlation between sCD163 and sIL-2R in the CRPS group (rs = 0.577; p = 0.005), but not in the healthy control group (rs = 0.359; p = 0.066). CONCLUSION:Our findings indicate that pro-inflammatory activation of tissue-resident macrophages and thus the monocyte-macrophage system is part of CRPS pathogenesis. The monocyte-macrophage system is an interesting new target for future research into the pathogenesis of CRPS, but also has potential for diagnosis, particularly for assessing the involvement of the immune system and choice of therapy in the individual CRPS patient. Measurement of the sCD163 could be a potential biomarker for inflammation in CRPS. TRIAL REGISTRATION:This retrospective cohort study was approved by the Medical Ethics Committee of the Erasmus MC University Medical Center (MEC-2020-0716).

The risk of developing chronic pain is twice as high among people with a history of childhood maltreatment compared to those without these experiences. It is unclear, however, whether childhood maltreatment might lead to lower or higher perception of pain. In this paper, we investigate the association between childhood maltreatment and pain sensitivity. A sample of 187 Dutch adolescents (ages 16.7 to 20.5) was used from a population-based cohort at high-risk for emotional and behavioral problems screened at age 13. The Childhood Trauma Questionnaire short form (CTQ-SF) was completed to measure emotional, physical, sexual abuse, and emotional and physical neglect. To asses pain sensitivity, a thermal quantitative sensory testing procedure was used which measured pain from hot and cold stimuli. Individuals reporting childhood sexual abuse, emotional abuse or neglect and physical neglect could on average withstand hot and cold pain of 1.03 degrees C [0.13, 1.84] to 3.20 degrees C [0.62, 5.97] more across different types of abuse compared to those with no emotional abuse or (physical) neglect history. Physical abuse was not associated with pain sensitivity. The current findings suggest that childhood maltreatment might lead to habituation to painful stimuli as opposed to increased pain sensitivity.

INTRODUCTION:Amputation in patients with complex regional pain syndrome (CRPS) remains controversial, with variable outcomes in quality of life (QoL), disability, pain reduction, and complications. This study aims to evaluate long-term outcomes in CRPS patients who underwent amputation. METHODS:We conducted a single-center retrospective observational study combined with a cross-sectional survey of all CRPS patients who underwent limb amputation between 2003 and 2023 at the Erasmus MC University Medical Center. Preamputation and short-term postamputation outcomes were extracted from medical records, with short-term pain scores reflecting measurements within the first year after amputation. Long-term outcomes, including QoL, disability, pain, and satisfaction, were assessed through patient-reported questionnaires. Subgroup analyses were performed based on the presence of a neurostimulator implant. RESULTS:A total of 39 patients with a median CRPS Severity Score of 12 (IQR 11-13) were included. 34 patients (87%) completed the survey a median of 6.4 years (IQR 3.0-11.7) after amputation. The 36-Item Short Form Health Survey yielded mean physical and mental health summary scores of 45.4 (±26.1) and 67.7 (±22.3), respectively. The mean Pain Disability Index score was 29.3 (±15.1). Pain decreased by a mean of 3.54 points (95% CI: 2.46 to 4.62) at short-term follow-up (median 5 months, IQR 2-6) and 2.71 points (95% CI: 1.76 to 3.65) at long-term follow-up. Residual limb pain occurred in 77%, phantom limb pain in 85%, and CRPS recurrence in the stump in 10%. Overall, 94% of respondents were satisfied and would choose amputation again. Neurostimulator status did not influence measured outcomes. CONCLUSIONS:In this cohort of severe, therapy-resistant CRPS, amputation was associated with meaningful improvements in QoL, disability, and pain in carefully selected cases, although complications remained common. Amputation should, therefore, be reserved as a last-resort intervention, offered only in specialized multidisciplinary centers.

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.

INTRODUCTION:Complex regional pain syndrome (CRPS) is a clinical disorder that can develop following surgery or trauma. Based on the most prominent underlying pathophysiological mechanisms, CRPS can be classified into different subtypes, namely inflammatory, nociplastic/neuropathic, vasomotor, and motor. Depending on the subtype, personalized treatment can be applied. If conservative treatments are insufficient or ineffective, more invasive treatments may be recommended. This article provides an overview of the most recent insights into CRPS and discusses the most common invasive treatments. METHODS:The literature regarding interventional treatments for CRPS has been systematically reviewed and summarized. RESULTS:Bisphosphonates are effective in treating the inflammatory subtype, while ketamine can provide pain relief for the nociplastic/neuropathic subtype. Sympathetic blocks are effective in addressing vasomotor disturbances. For patients with refractory symptoms, neurostimulation is a viable option due to its multimechanistic properties for all subtypes. End-of-line motor disturbances may benefit from intrathecal baclofen. CONCLUSIONS:CRPS is a debilitating condition with an unpredictable course. The effectiveness of treatment varies from patient to patient. When conservative approaches prove insufficient, gradual progression to invasive treatments based on the underlying subtype is recommended.

Wound catheter infusion (WCI) with local anesthetics (LA) is a regional anesthesia technique, which has shown to produce effective postoperative analgesia in adults, without any adverse effects on wound healing. To investigate the efficacy and safety of WCI with LA for the treatment of postoperative pain in children, we conducted a systematic review of literature published until 2020. The literature search included articles concerning subcutaneous WCI with LA, in the surgical wound, as treatment of postoperative pain, in children <18 years of age. Exclusion criteria were studies describing peripheral nerve blocks, intercostal, abdominal or thoracic wall blocks and single local anesthetic infiltration of the surgical wound. The articles were appraised for quality and only randomized controlled trials with a Jadad score ≥3 were included for evaluation of results concerning postoperative pain scores and opioid use. All relevant original studies, including observational studies and case reports, were assessed for adverse events and measurements of LA plasma concentrations during WCI. A total of 1907 articles were found, leading to 92 relevant abstracts selected for further review. After exclusion of articles of which full texts could not be retrieved or because of exclusion criteria, 28 articles remained. Thirteen articles described randomized controlled trials, of which 10 were assessed as good or excellent in quality. Due to the small number and heterogeneity of the studies, the data could not be pooled. Instead, results were described per type of procedure: abdominal surgery, extremity surgery, thoracic surgery and iliac crest bone harvesting. Reduced pain scores and opioid needs were demonstrated after abdominal and extremity surgery. In five studies, plasma levels of LA were measured, which all remained below toxic thresholds. In all relevant studies, no serious adverse events concerning the use of WCI were reported.

Neurostimulation, for example dorsal root ganglion stimulation (DRGS), is increasingly used for managing chronic pain, including among women of reproductive age. We present the case of a 33-year-old patient with complex regional pain syndrome (CRPS) implanted with DRGS who subsequently became pregnant twice. Both pregnancies resulted in the delivery of healthy newborns via caesarean section under successful spinal anaesthesia, with no (device) complications. This case highlights the special considerations for managing pregnant patients with neurostimulation implants, including the differences between DRGS implants and other neurostimulators in the context of neuraxial anaesthesia and the continued use of neurostimulation during pregnancy.

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.

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-a inhibitors. This study's aim was to assess the effectiveness of intravenous infliximab, a TNF-a 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.

Lung cancer is the leading cause of cancer-related death and the second most common malignancy in the world. NonSmall Cell Lung Cancer (NSCLC) accounts for approximately 85 percent of newly diagnosed lung cancer cases. The discovery of particular driver mutations and the development of targeted therapy are major breakthroughs in the treatment of advanced NSCLC. Cancer-related pain is a common and devastating symptom, and it is important to achieve adequate analgesia in all cancer patients. As new cancer treatments are being developed, clinicians must be aware of unknown and potentially disastrous drug-drug interactions when choosing an analgesic treatment. Here, we introduce a case of a 62-year-old female patient with advanced NSCLC who had a slow progression of the disease on previous anticancer therapy. The tumor had a Kirsten Rat Sarcoma Virus (KRAS) G12C mutation and the patient was therefore able to start sotorasib. The patient complained of left hip pain, which increased markedly after starting sotorasib. She required increased doses of oxycodone and received radiation therapy. Suspecting a radiation flare, the patient was hospitalized with unbearable pain. An opioid rotation to fentanyl had no effect on the pain. With suspected interaction between sotorasib and fentanyl, an opioid rotation to morphine was performed, after which the patient received almost immediate pain relief. Strong opioids, including oxycodone, are the cornerstone of pharmacological treatment of cancer-related pain. This case highlights the need for ongoing education about potential interactions between the cancer treatment and the analgesic treatment.

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.

Abstract 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.