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Thomas JP Mangnus, Maaike Dirckx, Frank JPM Huygen Department of Anesthesiology, Center for Pain Medicine, Erasmus MC University Medical Center, Rotterdam, the NetherlandsCorrespondence: Thomas JP Mangnus, Email t.mangnus@erasmusmc.nlAbstract: 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.Keywords: CRPS, nociceptive pain, neuropathic pain, nociplastic pain, mixed pain, personalized medicine

Corinne van den Berg, Maaike Dirckx, Frank JPM Huygen, Jitske Tiemensma Department of Anesthesiology, Center for Pain Medicine, Erasmus University Medical Center, Rotterdam, the NetherlandsCorrespondence: Corinne van den Berg, Department of Anesthesiology, Center for Pain Medicine, Erasmus University Medical Center, Postbus 2040, Rotterdam, 3000CA, the Netherlands, Tel +31 107040140, Fax +31 107035184, Email c.vandenberg.6@erasmusmc.nlPurpose: 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.Keywords: complex regional pain syndrome, CRPS, TNF-α inhibitors, treatment, inflammation, anti-inflammatories

KD Bharwani,1,* AB Kersten,1,* AL Stone,2 F Birklein,3 S Bruehl,2 M Dirckx,1 PD Drummond,4 J Gierthmühlen,5 A Goebel,6 L Knudsen,7 FJPM Huygen1 1Center for Pain Medicine, Department of Anesthesiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; 2Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA; 3Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 4Discipline of Psychology, College of Science, Health, Engineering and Education, Murdoch University, Perth, WA, Australia; 5Division of Neurological Pain Research and Therapy, Department Neurology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany; 6Director of the Pain Research Institute Reader in Pain Medicine, University of Liverpool Honorary Consultant in Pain Medicine, Walton Centre NHS Foundation Trust, Liverpool, UK; 7The National Rehabilitation Centre for Neuromuscular Diseases, Aarhus, Denmark*These authors contributed equally to this workCorrespondence: KD Bharwani Tel +31107040704Email bharwani.kd@gmail.comPurpose: Several articles have claimed that complex regional pain syndrome (CRPS) does not exist. Although a minority view, it is important to understand the arguments presented in these articles. We conducted a systematic literature search to evaluate the methodological quality of articles that claim CRPS does not exist. We then examined and refuted the arguments supporting this claim using up-to-date scientific literature on CRPS.Methods: A systematic search was conducted in MEDLINE, EMBASE and Cochrane CENTRAL databases. Inclusion criteria for articles were (a) a claim made that CRPS does not exist or that CRPS is not a distinct diagnostic entity and (b) support of these claims with subsequent argument(s). The methodological quality of articles was assessed if possible.Results: Nine articles were included for analysis: 4 narrative reviews, 2 personal views, 1 letter, 1 editorial and 1 case report. Seven points of controversy were used in these articles to argue that CRPS does not exist: 1) disagreement with the label “CRPS”; 2) the “unclear” pathophysiology; 3) the validity of the diagnostic criteria; 4) CRPS as a normal consequence of immobilization; 5) the role of psychological factors; 6) other identifiable causes for CRPS symptoms; and 7) the methodological quality of CRPS research.Conclusion: The level of evidence for the claim that CRPS does not exist is very weak. Published accounts concluding that CRPS does not exist, in the absence of primary evidence to underpin them, can harm patients by encouraging dismissal of patients’ signs and symptoms.Keywords: complex regional pain syndrome, pathophysiology, treatment, chronic pain