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Cecilie Siggaard Knoph,1,2 Rasmus Bach Nedergaard,1 Søren Schou Olesen,1,2 Louise Kuhlmann,1 Asbjørn Mohr Drewes1,2 1Center for Pancreatic Diseases & Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; 2Department of Clinical Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Asbjørn Mohr Drewes, Center for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Mølleparkvej 4, Aalborg, 9000, Denmark, Tel +45 97663562, Email amd@rn.dkPurpose: Abdominal pain is common in patients with chronic pancreatitis (CP), but management is challenging – possibly due to altered pain processing within the central nervous system rendering conventional treatments ineffective. We hypothesized that many patients with painful CP have generalized hyperalgesia correlating with central neuronal hyperexcitability.Patients and Methods: Seventeen CP patients with pain and 20 matched healthy controls underwent experimental pain testing, including repeated pain stimuli (temporal summation), pressure algometry performed in dermatomes with same spinal innervation as the pancreatic gland (pancreatic areas) and remote dermatomes (control areas), a cold pressor test and a conditioned pain modulation paradigm. To probe central neuronal excitability, the nociceptive withdrawal reflex was elicited by electrical stimulation of the plantar skin, and electromyography was obtained from the ipsilateral anterior tibial muscle together with somatosensory evoked brain potentials.Results: Compared to healthy controls, patients with painful CP had generalized hyperalgesia as evidenced by 45% lower pressure pain detection thresholds (P< 0.05) and decreased cold pressor endurance time (120 vs 180 seconds, P< 0.001). In patients, reflex thresholds were lower (14 vs 23 mA, P=0.02), and electromyographic responses were increased (16.4 vs 9.7, P=0.04) during the withdrawal reflex, reflecting predominantly spinal hyperexcitability. Evoked brain potentials did not differ between groups. A positive correlation was found between reflex thresholds and cold pressor endurance time (ρ=0.71, P=0.004).Conclusion: We demonstrated somatic hyperalgesia in patients with painful CP associated with spinal hyperexcitability. This highlights that management should be directed at central mechanisms using, eg, gabapentinoids or serotonin-noradrenaline reuptake inhibitors.Keywords: pain, hyperalgesia, nociceptive withdrawal reflex, electroencephalography, electromyography

Tine Maria Hansen,1,2 Esben Bolvig Mark,1,3 Søren Schou Olesen,2,3 Mikkel Gram,3 Jens Brøndum Frøkjær,1,2 Asbjørn Mohr Drewes2,3 1Mech-Sense, Department of Radiology, Aalborg University Hospital, 2Department of Clinical Medicine, Aalborg University, 3Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark Objective: The aim of the present study was to characterize the cortical source generators evoked by experimental tonic pain. Methods: Electroencephalography (EEG) was recorded on two separate days during rest and with immersion of the hand in ice water for 2 minutes (cold pressor test). Exact low-resolution brain electromagnetic tomography source localization was performed in 31 healthy volunteers to characterize the cortical source generators. Results: Reliability was high in all eight frequency bands during rest and cold pressor conditions (intraclass coefficients =0.47–0.83 in the cingulate and insula). Tonic pain increased cortical activities in the delta (1–4 Hz), theta (4–8 Hz), beta1 (12–18 Hz), beta2 (18–24 Hz), beta3 (24–32 Hz), and gamma (32–60 Hz) bands (all P

Jacob Juel,1 Christina Brock,1–4 Søren S Olesen,1,2 Adnan Madzak,5 Adam D Farmer,5–7 Qasim Aziz,7 Jens B Frøkjær,2,5 Asbjørn Mohr Drewes1,2 1Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, 2Department of Clinical Medicine, Aalborg University, Aalborg, 3Department of Rheumatology, Aarhus University Hospital, Aarhus, 4Drug Design and Pharmacology, University of Copenhagen, Copenhagen, 5Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark; 6Department of Gastroenterology, University Hospitals of North Midlands, Stoke-on-Trent, 7Centre for Neuroscience and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK Background: The effective management of pain in chronic pancreatitis (CP) remains a therapeutic challenge. Analgesic drugs, such as opioids, and the underlying pathology can impair gut function. The autonomic nervous system influences hormone secretion and gut motility. In healthy volunteers, electrical (using noninvasive transcutaneous vagal nerve stimulation [t-VNS]) and physiological (using deep slow breathing [DSB]) modulation of parasympathetic tone results in pain attenuation and enhanced gut motility. Thus, the aims were to investigate whether t-VNS and DSB could enhance the parasympathetic tone, decrease pain sensitivity and improve gut motility in CP.Patients and methods: A total of 20 patients (12 males, mean age=61 years, range: 50–78 years) with CP were randomized to short-term (60 minutes) t-VNS and DSB, or their placebo equivalent, in a crossover design. Cardiometrically derived parameters of autonomic tone, quantitative sensory testing of bone and muscle pain pressure, conditioned pain modulation (CPM) and assessments of gastroduodenal motility with ultrasound were performed.Results: In comparison to sham, t-VNS and DSB increased cardiac vagal tone (CVT) (P

Stefan AW Bouwense,1 Søren S Olesen,2 Asbjørn M Drewes,2 Harry van Goor,1 Oliver HG Wilder-Smith31Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud university medical center, Nijmegen, The Netherlands; 2Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; 3Pain and Nociception Neuroscience Research Group, Department of Anaesthesiology, Pain and Palliative Medicine, Radboud university medical center, Nijmegen, The NetherlandsBackground: Pain control in chronic pancreatitis is a major challenge; the mechanisms behind analgesic treatment are poorly understood. This study aims to investigate the differences in pain sensitivity and modulation in chronic pancreatitis patients, based on their clinical response (responders vs nonresponders) to placebo or pregabalin treatment. Methods: This study was part of a randomized, double-blind, placebo-controlled trial evaluating the analgesic effects of pregabalin and placebo in chronic pancreatitis. Post hoc, patients were assigned to one of four groups, ie, responders and nonresponders to pregabalin (n=16; n=15) or placebo (n=12; n=17) treatment. Responders were defined as patients with >30% pain reduction after 3 weeks of treatment. We measured change in pain sensitivity before and after the treatment using electric pain detection thresholds (ePDT) in dermatomes C5 (generalized effects) and Ventral T10 (segmental effects). Descending endogenous pain modulation was quantified via conditioned pain modulation (CPM) paradigm. Results: Sixty patients were analyzed in a per-protocol analysis. ePDT change in C5 was significant vs baseline and greater in pregabalin (1.3 mA) vs placebo responders (−0.1 mA; P=0.015). This was not so for ePDT in Ventral T10. CPM increased more in pregabalin (9%) vs placebo responders (−17%; P

Objectives: Noncancer chronic pain is a clinical challenge because pharmacological treatment often fails to relieve pain. Transcranial direct current stimulation (tDCS) is a treatment that could have the potential for pain relief and improvement in quality of life. However, there is a lack of clinical trials evaluating the effects of tDCS on the pain system. The aim of the present study was to evaluate the effect of 5 days of anodal tDCS treatment on the pain system in patients with chronic noncancer pain using quantitative sensory testing and quality of life questionnaires: (1) Brief Pain Inventory-short form, (2) European Organization for Research and Treatment of Life Questionnaire-C30, and (3) Hospital Anxiety Depression Scale., Methods: Eleven patients with noncancer chronic pain (51 ± 13.6 y old, 5M) participated in the study. Anodal tDCS was applied for 5 consecutive days, followed by sham stimulation after a washout period of at least 2 weeks. Pressure pain thresholds and pain tolerance thresholds (PTT) were assessed in different body regions on days 1 and 5., Results: Anodal tDCS appeared to maintain PTT at C5 (clavicle) on day 5, but sham stimulation decreased PTT ( P = 0.007). In addition, anodal tDCS increased PTT compared with sham at day 5 at Th10 ventral dermatomes ( P = 0.014). Both anodal and sham tDCS decreased the Brief Pain Inventory-short form total and interference scores, and the European Organization for Research and Treatment of Life Questionnaire-C30 fatigue score, but no interaction effect was observed., Conclusion: This study adds to the evidence in the literature that tDCS may be a potential therapeutic tool for the management of noncancer chronic pain., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Opioids used to manage severe pain in acute pancreatitis (AP) might exacerbate the disease through effects on gastrointestinal and immune functions. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, may counteract these effects without changing analgesia., Methods: This double-blind, randomized, placebo-controlled trial included adult patients with AP and systemic inflammatory response syndrome at 4 Danish centers. Patients were randomized to receive 5 days of continuous intravenous methylnaltrexone (0.15 mg/kg/d) or placebo added to the standard of care. The primary end point was the Pancreatitis Activity Scoring System score after 48 hours of treatment. Main secondary outcomes included pain scores, opioid use, disease severity, and mortality., Results: In total, 105 patients (54% men) were randomized to methylnaltrexone (n = 51) or placebo (n = 54). After 48 hours, the Pancreatitis Activity Scoring System score was 134.3 points in the methylnaltrexone group and 130.5 points in the placebo group (difference 3.8, 95% confidence interval [CI] -40.1 to 47.6; P = 0.87). At 48 hours, we found no differences between the groups in pain severity (0.0, 95% CI -0.8 to 0.9; P = 0.94), pain interference (-0.3, 95% CI -1.4 to 0.8; P = 0.55), and morphine equivalent doses (6.5 mg, 95% CI -2.1 to 15.2; P = 0.14). Methylnaltrexone also did not affect the risk of severe disease (8%, 95% CI -11 to 28; P = 0.38) and mortality (6%, 95% CI -1 to 12; P = 0.11). The medication was well tolerated., Discussion: Methylnaltrexone treatment did not achieve superiority over placebo for reducing the severity of AP., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background and Objective: The aim of this study was to develop and validate explainable prediction models based on continuous glucose monitoring (CGM) and baseline data to identify a week-to-week risk of CGM key metrics (hyperglycemia, hypoglycemia, glycemic variability). By having a weekly prediction of CGM key metrics, it is possible for the patient or health care personnel to take immediate preemptive action., Methods: We analyzed, trained, and internally tested three prediction models (Logistic regression, XGBoost, and TabNet) using CGM data from 187 type 1 diabetes patients with long-term CGM monitoring. A binary classification approach combined with feature engineering deployed on the CGM signals was used to predict hyperglycemia, hypoglycemia, and glycemic variability based on consensus targets (time above range ≥5%, time below range ≥4%, coefficient of variation ≥36%). The models were validated in two independent cohorts with a total of 223 additional patients of varying ages., Results: A total of 46 593 weeks of CGM data were included in the analysis. For the best model (XGBoost), the area under the receiver operating characteristic curve (ROC-AUC) was 0.9 [95% confidence interval (CI) = 0.89-0.91], 0.89 [95% CI = 0.88-0.9], and 0.8 [95% CI = 0.79-0.81] for predicting hyperglycemia, hypoglycemia, and glycemic variability in the interval validation, respectively. The validation test showed good generalizability of the models with ROC-AUC of 0.88 to 0.95, 0.84 to 0.89, and 0.80 to 0.82 for predicting the glycemic outcomes., Conclusion: Prediction models based on real-world CGM data can be used to predict the risk of unstable glycemic control in the forthcoming week. The models showed good performance in both internal and external validation cohorts., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The research was funded by i-SENS, Inc (Seoul, South Korea) and SLC’s involvement with the company did not influence the design, implementation, or interpretation of the study. SLC have received research funding from i-SENS, Inc (Seoul, South Korea), which manufactures some of the product types discussed in this paper. However, the study was conducted independently, and the authors declare that their involvement with i-SENS, Inc (Seoul, South Korea) did not influence the findings or conclusions of the study.

Background: Spinal cord stimulation (SCS) has emerged as a treatment option for patients with chronic pancreatitis (CP) who experience pain that does not respond to standard interventions. However, there is a lack of sham-controlled trials to support its efficacy., Methods: This randomized, double-blinded, sham-controlled, cross-over trial enrolled 16 CP patients with insufficient pain relief from standard therapies. Patients underwent high-frequency (1000 Hz) paraesthesia-free SCS or sham for two 10-day stimulation periods, separated by a 3-day washout period. The primary outcome was daily pain intensity registered in a pain diary based on a numeric rating scale (NRS). Secondary outcomes included various questionnaires. Quantitative sensory testing was used to probe the pain system before and after interventions., Results: The average daily pain score on the NRS at baseline was 5.2 ± 1.9. After SCS, the pain score was 4.2 ± 2.1 compared to 4.3 ± 2.1 in the sham group (mean difference -0.1, 95% CI [-1.4 to 1.1]; P = 0.81). Similarly, no differences were observed between groups for the maximal daily pain score, secondary outcomes or quantitative sensory testing parameters. During an open-label, non-sham-controlled and non-blinded extension of the study, the average daily NRS was 5.2 ± 1.7 at baseline, 3.2 ± 1.8 at 3 months, 2.9 ± 1.9 at 6 months and 3.4 ± 2.2 at 12 months of follow-up (P = 0.001)., Conclusion: In this first sham-controlled trial of SCS in painful CP, we did not find evidence of short-term pain relief with paraesthesia-free high-frequency (1000 Hz) stimulation. However, evaluation of the long-term effect by larger sham-controlled trials with long-term follow-up is warranted., Significance Statement: In this first sham-controlled trial to apply high-frequency (1000 Hz) spinal cord stimulation in patients with visceral pain due to chronic pancreatitis, we did not find evidence for clinically relevant pain relief. Taken together with potential procedure-related complications, adverse effects and costs associated with spinal cord stimulation, our findings question its use for management of visceral pain., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background: Since there is no current international consensus on the optimal approach for pain management in acute pancreatitis (AP), analgesic practices may vary across different healthcare settings., Objective: This study explored global disparities in analgesic use, in particular opioids, during admission and at discharge in hospitalised AP patients., Methods: This was a post hoc analysis of the prospective PAINAP database, which included all admissions for AP between April and June 2022 with a 1-month follow-up. Demographic details, analgesic use, and clinical outcomes were recorded during admission and at discharge. Odds ratios (ORs) for opioid use during admission and at discharge were identified using multivariable regression analyses., Results: Amongst the 1864 patients (52% males, median age 56 (interquartile range, 41-71)) across three different continents, simple analgesics were predominantly used as the primary analgesic (70%). Opioid use during admission was lowest in European centres (67%). Admission in Asian (OR, 2.53 (95% confidence interval (CI), 1.59-4.04), p < 0.001), and Australian (OR, 5.81 (95% CI, 3.19-10.56), p < 0.001) centres was associated with opioid administration during admission compared with European centres. Increased pain severity, longer pre-admission pain duration, organ failure, and longer length of admission increased opioid use during admission. At discharge, Asian (OR, 2.01 (95% CI, 1.40-2.88), p < 0.001) and Australian (OR, 1.91 (95% CI, 1.28-2.85), p = 0.002) centres were associated with opioid prescription compared with European centres. Increased pain severity, longer pre-admission pain duration, acute necrotic collections, and walled-off necrosis also increased the likelihood of opioid prescription at discharge., Conclusion: There are substantial intercontinental differences in opioid use for AP pain. Accordingly, there is a need for international guidelines on pain management in AP., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Introduction: Pain is the foremost complication of chronic pancreatitis (CP), affecting about 70% of patients. However, the pathophysiological understanding and management of CP-related pain is complex, likely as patients have diverse "pain phenotypes" responding differently to treatment. This study aims to develop a bedside test panel to identify distinct pain phenotypes, investigate the temporal evolution, and determine whether they can be used to predict treatment response., Method: The INPAIN study is an international, multi-center, observational, longitudinal cohort study comprised of 4 sub-studies. The studies will prospectively enroll 400 CP patients (50 without pain and 350 with pain) and 50 control subjects, conducting biannual observations for four years. The test panel is comprised of comprehensive subjective and objective assessment parameters. Statistical analysis strategies differ across the sub-studies. A model to predict treatment efficacy will be developed using various machine learning techniques, including an artificial intelligence approach, with internal cross-validation. Trajectories in pain parameters will be characterized by graphical analysis and mixed effect models., Discussion: The INPAIN study aims to comprehensively understand pain in CP through a test panel developed for routine clinical use. This tool has the potential to personalize treatments, improve clinical practice, enhance patient care, improve quality of life, and minimize treatment side effects., Competing Interests: Funding: Professor Asbjørn Mohr Drewes initiated this research project. Researchers behind this study declare no conflicts of interest. This study is economically supported by the INPAIN study sponsored by Aalborg University Hospital (“ForskningsKUBE”). This grant will be used to cover expenses related to equipment and salary for study personnel. Various funds will be applied to cover any additional financial expenses. Conflict of interest: The involved researchers will conduct the trial of general scientific interest without personal financial gain., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To study social disparity in acute pancreatitis (AP) and chronic pancreatitis (CP).We also aimed at exploring whether an interaction exists between alcohol intake and socioeconomic factors., Methods: Prospective cohort study based on data from 271 696 men and women participating in the Danish National Health Surveys 2010, and 2013. Information on alcohol and smoking parameters, body mass index (BMI), diet, and education, were self-reported and information on family income was obtained from administrative registers. Outcome variables (acute and chronic pancreatitis) were obtained from national health registers., Results: The incidence rate ratio (IRR) of developing AP and CP increased with decreasing family income. Compared to participants in the highest income quintile, participants in the lowest income quintile had 43 (95% CI: 14-80%), 99 (95% CI: 26-214%), and 56% (95% CI: 26-94%) higher incidence rates of AP, CP, and all pancreatitis, respectively. The associations persisted after adjustment for alcohol intake, smoking, BMI, and diet.Likewise, participants with only primary school education had an IRR for an AP of 1.30 (95% CI: 1.06-1.59) compared to those with higher education after adjustment for baseline year, age, and sex. We found no interactions between alcohol intake and income or between alcohol intake and education in relation to neither AP, CP, nor all pancreatitis., Conclusion: This large prospective population study showed a significant social disparity in incidence rates of pancreatitis by family income, with higher rates among those with the lowest income and education independent of risk factors such as alcohol intake, smoking, BMI, and diet., (© The Author(s) 2024. Medical Council on Alcohol and Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: No randomized controlled trials have substantiated endoscopic decompression of the pancreatic duct in patients with painful chronic pancreatitis., Objective: To investigate the pain-relieving effect of pancreatic duct decompression in patients with chronic pancreatitis and intraductal stones., Design: 24-week, parallel-group, randomized controlled trial (ClinicalTrials.gov: NCT03966781)., Setting: Asian Institute of Gastroenterology in India from February 2021 to July 2022., Participants: 106 patients with chronic pancreatitis., Intervention: Combined extracorporeal shock-wave lithotripsy (ESWL) and endoscopic retrograde pancreatography (ERP) compared with sham procedures., Measurements: The primary end point was pain relief on a 0- to 10-point visual analog scale (VAS) at 12 weeks. Secondary outcomes were assessed after 12 and 24 weeks and included 30% pain relief, opioid use, pain-free days, questionaries, and complications to interventions., Results: 52 patients in the ESWL/ERP group and 54 in the sham group were included. At 12 weeks, the ESWL/ERP group showed better pain relief compared with the sham group (mean difference in change, -0.7 [95% CI, -1.3 to 0] on the VAS; P  = 0.039). The difference between groups was not sustained at the 24-week follow-up, and no differences were seen for 30% pain relief at 12- or 24-week follow-up. The number of pain-free days was increased (median difference, 16.2 days [CI, 3.9 to 28.5 days]), and the number of days using opioids was reduced (median difference, -5.4 days [CI, -9.9 to -0.9 days]) in the ESWL/ERP group compared with the sham group at 12-week follow-up. Safety outcomes were similar between groups., Limitation: Single-center study and limited duration of follow-up., Conclusion: In patients with chronic pancreatitis and intraductal stones, ESWL with ERP provided modest short-term pain relief., Primary Funding Source: Asian Institute of Gastroenterology and Aalborg University Hospital., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0210.

Introduction: The purpose of this study was to investigate the risk of metabolic sequelae and all-cause mortality in a population-based cohort of chronic pancreatitis (CP) patients with and without prior acute pancreatitis (AP)., Methods: We used nationwide health registries to identify all Danish residents (18 years and older) with incident CP from 2000 to 2018. Information on AP/CP diagnoses, metabolic sequelae (post-pancreatitis diabetes mellitus [PPDM], exocrine pancreatic dysfunction, and osteoporosis), and all-cause mortality were obtained from Danish national health registries. CP cases were stratified based on the presence of AP before CP diagnosis. The risk of metabolic sequelae and all-cause mortality was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), calculated using multivariate Cox proportional hazards models., Results: A total of 9,655 patients with CP were included. Among patients with CP, 3,913 (40.5%) had a prior AP diagnosis. Compared with patients without a history of AP, patients with prior AP had a decreased risk of death (HR 0.79, 95% CI 0.74-0.84), which was largely confined to the initial period after CP diagnosis. Patients with prior AP had an increased risk of PPDM (HR 1.53, 95% CI 1.38-1.69), which persisted for up to a decade after CP diagnosis. No overall differences in risk were observed for exocrine pancreatic dysfunction (HR 0.97, 95% CI 0.87-1.07) and osteoporosis (HR 0.87, 95% CI 0.74-1.02)., Discussion: This nationwide study revealed that most of the patients with CP have no prior episode(s) of AP, indicating that an attack of AP sensitizing the pancreas is not essential for CP development. CP patients with and without prior AP have different risk profiles of PPDM and all-cause mortality., (Copyright © 2024 by The American College of Gastroenterology.)

Objective: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP)., Methods: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups., Results: In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10., Conclusion: CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens., Methods: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP., Results: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose., Conclusions: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The effect of analgesic modalities on short-term outcomes in acute pancreatitis remains unknown. However, preclinical models have raised safety concerns regarding opioid use in patients with acute pancreatitis., Objective: This study aimed to assess the association between analgesics, particularly opioids, and severity and mortality in hospitalised patients with acute pancreatitis., Methods: This prospective multicentre cohort study recruited consecutive patients admitted with a first episode of acute pancreatitis between April 1 and 30 June 2022, with a 1-month follow-up. Data on aetiology, clinical course, and analgesic treatment were collected. The primary outcome was the association between opioid analgesia and acute pancreatitis severity, which was analysed using univariate and multivariate analyses., Results: Among a total of 1768 patients, included from 118 centres across 27 countries, 1036 (59%) had opioids administered on admission day, and 167 (9%) received opioids after admission day. On univariate analysis, moderately severe or severe acute pancreatitis was associated with male sex, Asian ethnicity, alcohol aetiology, comorbidity, predicted severe acute pancreatitis, higher pain scores, longer pain duration and opioid treatment (all p < 0.001). On multivariate analysis, comorbidity, alcohol aetiology, longer pain duration and higher pain scores increased the risk of moderately severe or severe acute pancreatitis (all p < 0.001). Furthermore, opioids administered after admission day (but not on admission day) doubled the risk of moderately severe or severe disease (OR 2.07 (95% CI, 1.29-3.33); p = 0.003). Opioid treatment for 6 days or more was an independent risk factor for moderately severe or severe acute pancreatitis (OR 3.21 (95% CI, 2.16-4.79; p < 0.001). On univariate analysis, longer opioid duration was associated with mortality., Conclusion: Opioid treatment increased the risk of more severe acute pancreatitis only when administered after admission day or for 6 days or more. Future randomised studies should re-evaluate whether opioids might be safe in acute pancreatitis., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Introduction: Treatment for abdominal pain in patients with chronic pancreatitis (CP) remains challenging in the setting of central nervous system sensitisation, a phenomenon of remodelling and neuronal hyperexcitability resulting from persistent pain stimuli. This is suspected to render affected individuals less likely to respond to conventional therapies. Endotherapy or surgical decompression is offered to patients with pancreatic duct obstruction. However, the response to treatment is unpredictable. Pancreatic quantitative sensory testing (P-QST), an investigative technique of standardised stimulations to test the pain system in CP, has been used for phenotyping patients into three mutually exclusive groups: no central sensitisation, segmental sensitisation (pancreatic viscerotome) and widespread hyperalgesia suggestive of supraspinal central sensitisation. We will test the predictive capability of the pretreatment P-QST phenotype to predict the likelihood of pain improvement following invasive treatment for painful CP., Methods and Analysis: This observational clinical trial will enrol 150 patients from the University of Pittsburgh, Johns Hopkins and Indiana University. Participants will undergo pretreatment phenotyping with P-QST. Treatment will be pancreatic endotherapy or surgery for clearance of painful pancreatic duct obstruction., Primary Outcome: average pain score over the preceding 7 days measured by Numeric Rating Scale at 6 months postintervention. Secondary outcomes will include changes in opioid use during follow-up, and patient-reported outcomes in pain and quality of life at 3, 6 and 12 months after the intervention. Exploratory outcomes will include creation of a model for individualised prediction of response to invasive treatment., Ethics and Dissemination: The trial will evaluate the ability of P-QST to predict response to invasive treatment for painful CP and develop a predictive model for individualised prediction of treatment response for widespread use. This trial was approved by the University of Pittsburgh Institutional Review Board. Data and results will be reported and disseminated in conjunction with National Institutes of Health policies., Trial Registration Number: NCT04996628., Competing Interests: Competing interests: AEP: Board Member, National Pancreas Foundation. VKS: Consultant to Abbvie, Ariel Precision Medicine, Horizon Therapeutics and Panafina; Medical Advisory Board participant to Organon; Scientific advisory board participant for Kyttaro, Origin Endoscopy and Solv Endoscopy; Equity holder in Kyttaro, Origin Endoscopy, Solv Endoscopy. The other authors have no financial or personal competing interests to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop a machine-learning model that can predict the risk of pancreatic ductal adenocarcinoma (PDAC) in people with new-onset diabetes (NOD)., Methods: From a population-based sample of individuals with NOD aged >50 years, patients with pancreatic cancer-related diabetes (PCRD), defined as NOD followed by a PDAC diagnosis within 3 years, were included (n = 716). These PCRD patients were randomly matched in a 1:1 ratio with individuals having NOD. Data from Danish national health registries were used to develop a random forest model to distinguish PCRD from Type 2 diabetes. The model was based on age, gender, and parameters derived from feature engineering on trajectories of routine biochemical variables. Model performance was evaluated using receiver operating characteristic curves (ROC) and relative risk scores., Results: The most discriminative model included 20 features and achieved a ROC-AUC of 0.78 (CI:0.75-0.83). Compared to the general NOD population, the relative risk for PCRD was 20-fold increase for the 1 % of patients predicted by the model to have the highest cancer risk (3-year cancer risk of 12 % and sensitivity of 20 %). Age was the most discriminative single feature, followed by the rate of change in haemoglobin A1c and the latest plasma triglyceride level. When the prediction model was restricted to patients with PDAC diagnosed six months after diabetes diagnosis, the ROC-AUC was 0.74 (CI:0.69-0.79)., Conclusion: In a population-based setting, a machine-learning model utilising information on age, sex and trajectories of routine biochemical variables demonstrated good discriminative ability between PCRD and Type 2 diabetes., Competing Interests: Declaration of Competing Interest No potential conflicts of interest relevant to this article were reported, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: This pilot study seeks to identify serum immune signatures across clinical stages of patients with chronic pancreatitis (CP)., Methods: We performed a cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies-study. CP subjects were categorised into three clinical stages based on the presence/absence of metabolic complications: (1) CP with no diabetes and exocrine pancreatic dysfunction (EPD), (2) CP with either diabetes or EPD, and (3) CP with diabetes and EPD. Blinded samples were analysed using an 80-plex Luminex assay of cytokines/chemokines/adhesion molecules. Group and pairwise comparisons were performed to characterise immune signatures across CP subgroups., Results: A total of 135 CP subjects (evenly distributed between clinical stages) and 50 controls were studied. Interleukin-6 (IL-6), interleukin-8 (IL-8), and soluble intercellular adhesion molecule 1 (sICAM-1) were significantly elevated in CP subjects compared to controls. The levels of IL-6 and IL-8 increased with advancing disease stages, with the highest levels observed in CP with diabetes and EPD (clinical stage 3). Furthermore, hepatocyte growth factor and macrophage-derived chemokine were significantly increased in clinical stage 3 compared to controls., Conclusion: Our study reveals a progressive elevation in pro-inflammatory cytokines and chemokines with advancing clinical stages of CP. These findings indicate potential targets for the development of disease-modifying interventions., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Post-pancreatitis diabetes mellitus (PPDM) is a frequent complication of pancreatitis and is associated with an increased risk of adverse outcomes. Metformin is recommended for the treatment of PPDM, but evidence of its risk-benefit profile is limited. In a pharmaco-epidemiologic study, we investigated the association between metformin treatment and adverse outcomes in patients with PPDM., Design and Methods: In a Danish nationwide population-based cohort study, we included adults (≥18 years) with incident PPDM or type 2 diabetes between 2009 and 2018. Post-pancreatitis diabetes mellitus was categorised into acute and chronic subtypes (PPDM-A and PPDM-C). Associations between metformin treatment and severe hypoglycaemia, major adverse cardiovascular events (MACE), and all-cause mortality were examined across the diabetes subgroups using Cox regression analysis. Treatments with metformin, insulin, and other glucose-lowering therapies were handled as time-varying exposures., Results: We included 222 337 individuals with new-onset type 2 diabetes and 3781 with PPDM, of whom 2305 (61%) were classified as PPDM-A and 1476 (39%) as PPDM-C. Treatment with metformin was associated with a lower risk of severe hypoglycaemia (adjusted hazard ratio [HR] 0.41, 95% CI 0.27-0.62, P < .0001), MACE (HR 0.74, 95% CI 0.60-0.92, P = .0071), and all-cause mortality (HR 0.56, 95% CI 0.49-0.64, P < .0001) in patients with PPDM. In sensitivity analyses and among individuals with type 2 diabetes, metformin treatment exhibited comparable trends of risk reduction., Conclusions: Metformin is associated with a lower risk of adverse outcomes, including all-cause mortality in patients with PPDM, supporting the use of metformin as a glucose-lowering therapy for these patients., Competing Interests: Conflict of interest: M.H.J. is an employee at Novo Nordisk and holds shares in Novo Nordisk. Co-author F.K.K. is on the editorial board of EJE. He was not involved in the review or editorial process for this paper, on which he is listed as author. No other potential conflicts of interest relevant to this article were reported., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To investigate the co-existence of hepatic and pancreatic fibrosis using magnetic resonance elastography (MRE) in chronic pancreatitis (CP), including the association between hepatic and pancreatic MRE-derived stiffness and exploration of potential etiological risk factors., Materials and Methods: Fifty-four CP patients and 35 healthy controls underwent hepatic and pancreatic MRE with measurements of tissue stiffness. Clinical parameters including stage (probable or definite CP), etiology of CP, the presence of diabetes or exocrine insufficiency, and previous history of common bile duct stenosis were assessed. Uni- and multivariate regression models were used to investigate risk factors associated with hepatic fibrosis/stiffness in CP patients., Results: Fifteen percent of CP patients and none of the controls had abnormal liver stiffness (>2.5 kPa), p  = 0.02. 5.6% of CP patients had liver stiffness indicating F1 fibrosis (>2.93 kPa). However, hepatic stiffness was not higher in patients than in healthy controls (2.20 ± 0.41 vs 2.08 ± 0.21 kPa, p  = 0.10). In patients, a positive association was seen between hepatic and pancreatic stiffness ( r  = 0.270, p  = 0.048). In the multivariate analysis (adjusted for age, gender and BMI), liver stiffness was significantly associated with alcoholic etiology of CP ( p  = 0.029). In contrast, stage of CP, history of common bile duct stenosis, and the presence of diabetes or exocrine insufficiency were not associated with liver stiffness (all p  > 0.14)., Conclusions: Only a modest co-existence of hepatic and pancreatic fibrosis was observed in CP. However, the positive association between hepatic and pancreatic stiffness indicates some level of common pathophysiology. Especially, alcoholic etiology of CP was related to increased hepatic stiffness.

Background & Aims: Understanding the nature of inflammatory pancreatic diseases is essential for planning health care system requirements and interventions. The aim of this study was to quantify the trajectories of inflammatory pancreatic diseases and their association with pancreatic cancer in a population-based setting., Methods: National health registries were used to identify all Danish residents (18 years or older) in the period from 2000 through 2018 with incident cases of acute pancreatitis (AP), recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic cancer. We used a multistate model to examine transitions from a healthy state to intermediate states of acute pancreatic inflammation (AP and RAP) to chronic states (CP and pancreatic cancer) and, ultimately, death. Results were reported as transition incidence rates per 1000 person-years with 95% CIs., Results: There were 4,663,864 individuals included (mean age, 46 years; 51% were women). During a mean follow-up of 16.8 years, 31,396 individuals were diagnosed with incident AP, 5546 with RAP, 8898 with CP, and 18,182 with pancreatic cancer. The cumulative incidence of pancreatitis (acute and chronic) during the study period was 0.80% (95% CI, 0.79%-0.80%). The transition incidence rates to CP were 12.1 (95% CI, 8.1-18.1) from AP, 46.8 (95% CI, 31.6-69.3) from RAP, and 0.07 (95% CI, 0.04-0.13) from a healthy state. Similar patterns were observed for transitions to pancreatic cancer. Most patients diagnosed with CP (64.2%) and pancreatic cancer (96.4%) transitioned directly from a healthy state. Among patients with pancreatitis, 41.0% (95% CI, 40.5%-41.5%) died during follow-up., Conclusions: The study findings revealed an increased risk of CP and pancreatic cancer in patients with a history of AP. However, most patients with CP and pancreatic cancer transitioned directly from a healthy state., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Autoimmune pancreatitis [AIP] is rarely associated with inflammatory bowel disease [IBD]. The long-term outcomes of AIP and IBD in patients with coexisting AIP-IBD and predictors of complicated AIP course have rarely been reported., Methods: An ECCO COllaborative Network For Exceptionally Rare case reports project [ECCO-CONFER] collected cases of AIP diagnosed in patients with IBD. Complicated AIP was defined as a composite of endocrine and/or exocrine pancreatic insufficiency, and/or pancreatic cancer. We explored factors associated with complicated AIP in IBD., Results: We included 96 patients [53% males, 79% ulcerative colitis, 72% type 2 AIP, age at AIP diagnosis 35 ± 16 years]. The majority of Crohn's disease [CD] cases [78%] had colonic/ileocolonic involvement. In 59%, IBD preceded AIP diagnosis, whereas 18% were diagnosed simultaneously. Advanced therapy to control IBD was used in 61% and 17% underwent IBD-related surgery. In total, 82% of patients were treated with steroids for AIP, the majority of whom [91%] responded to a single course of treatment. During a mean follow-up of 7 years, AIP complications occurred in 25/96 [26%] individuals. In a multivariate model, older age at AIP diagnosis was associated with a complicated AIP course (odds ratio [OR] = 1.05, p = 0.008), whereas family history of IBD [OR = 0.1, p = 0.03], and CD diagnosis [OR = 0.2, p = 0.04] decreased the risk of AIP complications. No IBD- or AIP-related deaths occurred., Conclusions: In this large international cohort of patients with concomitant AIP-IBD, most patients have type 2 AIP and colonic IBD. AIP course is relatively benign and long-term outcomes are favourable, but one-quarter develop pancreatic complications. Age, familial history of IBD, and CD may predict uncomplicated AIP course., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Holistic management of pancreatitis means that gastroenterologists in the 21st Century should think beyond improving in-hospital outcomes of pancreatitis alone. In particular, there is considerable room for optimizing the management of new-onset diabetes, exocrine pancreatic insufficiency, and other metabolic sequelae of pancreatitis. The present article provides state-of-the-art information on classification, terminology, and burden of the common sequelae of pancreatitis. A high-risk group of patients with pancreatitis is identified, which is positioned to benefit the most from the metabolic sequelae surveillance program introduced in this article. The program involves continuous follow-up after pancreatitis diagnosis, with the focus on early identification of new-onset diabetes after pancreatitis and exocrine pancreatic insufficiency. The metabolic sequelae surveillance program is scalable and has the potential to reduce the burden of pancreatitis through tertiary prevention in the decades to come., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Chronic Pancreatitis (CP) causes morphological changes in the pancreatic tissue, leading to complications and pain, which may require endoscopic interventions., Objective: Our aim was to determine the frequency of endoscopic procedures (EP) in CP patients and to analyse pain and quality of life (QoL) in these patients after their EP., Methods: This study included 1327 CP patients from the Scandinavian Baltic Pancreatic Club (SBPC) database including four countries and eight centres. We analysed patients undergoing EPs and gathered information on the EP, pancreatic function, pain, disease and duration. The EORTC C-30 QoL questionnaire was gathered prospectively and multivariable analysis was conducted on independent parameters between the groups. The reference population had no interventions (n = 870)., Results: 260 CP patients (22%) underwent EPs, median one year (range 0-39 years) after CP diagnosis. 68% were males. The median age was 59 (20-90) years. Most common aetiological factors were alcohol in 65% and smoking in 71%. Extracorporeal shock wave lithotripsy (ESWL) was used in 6% of the CP population and in 21% of the EP group. Biliary duct stenting was performed on 37% and pancreatic stenting was performed on 56% of the patients. There was no difference in pain patterns between patients who had pancreatic stenting and the reference population. The EP group had slightly better QoL (p = 0.047), functioning and fewer symptoms than the reference population, in the multivariable analysis there was no interaction effect analysis between the groups. The pancreatic stent group had better QoL and the same amount of pain than the reference group. The patients who needed later surgery (23%) had more pain (p = 0.043) and fatigue (p = 0.021)., Conclusions: One in five of the CP patients underwent EP. These patients scored higher on QoL responses and had better symptom scores. CP patients who had pancreatic stenting performed had the same pain patterns as the reference population. Randomised prospective trials are needed to determine the effect of endoscopy procedures on CP patients., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: New onset diabetes (NOD) in people 50 years or older may indicate underlying pancreatic ductal adenocarcinoma (PDAC). The cumulative incidence of PDAC among people with NOD remains uncertain on a population-based level., Methods: This was a nationwide population-based retrospective cohort study based on the Danish national health registries. We investigated the 3-year cumulative incidence of PDAC in people 50 years or older with NOD. We further characterised people with pancreatic cancer-related diabetes (PCRD) in relation to demographic and clinical characteristics, including trajectories of routine biochemical parameters, using people with type 2 diabetes (T2D) as a comparator group., Results: During a 21-year observation period, we identified 353,970 people with NOD. Among them, 2105 people were subsequently diagnosed with pancreatic cancer within 3 years (0.59%, 95% CI [0.57-0.62%]). People with PCRD were older than people with T2D at diabetes diagnosis (median age 70.9 vs. 66.0 years (P < 0.001) and had a higher burden of comorbidities (P = 0.007) and more prescriptions of medications used to treat cardiovascular diseases (all P < 0.001). Distinct trajectories of HbA1c and plasma triglycerides were observed in PCRD vs. T2D, with group differences observed for up to three years prior to NOD diagnosis for HbA1c and up to two years for plasma triglyceride levels., Conclusions: The 3-year cumulative incidence of PDAC is approximately 0.6% among people 50 years or older with NOD in a nationwide population-based setting. Compared to T2D, people with PCRD are characterised by distinct demographic and clinical profiles, including distinctive trajectories of plasma HbA1c and triglyceride levels., Competing Interests: Declaration of competing interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: The aim was to analyze the effects of drinking pattern and type of alcohol on risk of acute and chronic pancreatitis., Methods: Prospective cohort study based on data from 316,751 men and women participating in the Danish National Health Surveys 2010 and 2013. Self-reported questionnaire-based alcohol parameters and information on pancreatitis was obtained from national health registers. Cox regression models were used adjusting for baseline year, gender, age, smoking, Body Mass Index, diet and education., Results: Development of acute and chronic pancreatitis increased with alcohol intake with a significant increase among abstainers and those drinking >14 drinks per week compared with individuals drinking 1-7 drinks per week. Frequent binge drinking and frequent drinking (every day) was associated with increased development of acute and chronic pancreatitis compared with those drinking 2-4 days per week. Problematic alcohol use according to the CAGE-C questionnaire was associated with increased development of acute and chronic pancreatitis.Intake of more than 14 drinks of spirits per week was associated with increased development of acute and chronic pancreatitis, and more than 14 drinks of beer per week were associated with increased development of chronic pancreatitis, whereas drinking wine was not associated with development of pancreatitis., Conclusion: This large prospective population study showed a J-shaped association between alcohol intake and development of pancreatitis. Drinking every day, frequent binge drinking and problematic alcohol use were associated with increased development of pancreatitis and drinking large amounts of beer and spirits might be more harmful than drinking wine., (© The Author(s) 2023. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Blueberries beneficially modulate physiologic mechanisms relevant to the pathogenesis of functional gastrointestinal disorders (FGID). Forty-three patients with FGID received freeze-dried blueberries (equivalent to 180 g fresh blueberries) or sugar and energy-matched placebo in a double-blind, randomized, cross-over study. After 6 weeks of treatment, the differences in Gastrointestinal Clinical Rating Scale (GSRS) scores and abdominal symptom relief were compared as primary outcome measures. The quality of life and life functioning ratings (OQ45.2 questionnaire), Bristol stool scales, and fructose breath test results constituted secondary outcome measures. Blueberry treatment resulted in more patients with relevant abdominal symptom relief compared to placebo (53% vs. 30%, p = 0.03). Total and pain GSRS scores improved insignificantly (mean treatment differences [95% CI]: -3.4 [-7.4 to 0.6] ( p = 0.09) and -1.0 [-2.2 to 0.1] ( p = 0.08), respectively). OQ45.2 scores improved during blueberry treatment compared to placebo (treatment difference -3.2 [95% CI: -5.6 to -0], p = 0.01). Treatment effect differences for the further measures did not reach statistical significance. Blueberries relieved abdominal symptoms and improved general markers of well-being, quality of life, and life functioning more than placebo in patients with FGID. Consequently, the polyphenol and fiber components of blueberries exert broad beneficial effects separate from the sugars present in both treatments.

Background: Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression., Methods: The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis., Discussion: This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes., Trial Registration: EudraCT no. 2021-000069-34., Clinicaltrials: gov NCT04966559. Registered on July 8, 2021., (© 2023. The Author(s).)

Background: Non-invasive modalities for assessing chronic pancreatitis (CP) are needed in clinical practice., Purpose: To investigate the correlation between magnetic resonance elastography (MRE)-derived stiffness and T1 relaxation times (as proxies of fibrosis) and explore their relationships to gland volume and pancreatic functions in patients with CP and healthy controls (HCs)., Material and Methods: In 49 patients with CP and 35 HCs, pancreatic stiffness, T1 relaxation times, and gland volume were assessed. Fecal elastase and the presence of diabetes were used to evaluate pancreatic exocrine and endocrine functions. Uni- and multivariable linear regression models were used to analyze correlations between imaging parameters., Results: There was a positive correlation between MRE-derived stiffness and T1 relaxation times in patients with CP (R 2  = 0.42; P  < 0.001) and HCs (R 2  = 0.14; P  = 0.028). There was no correlation between MRE-derived stiffness and gland volume in patients (R 2  = 0.007; P  = 0.065) or HCs (R 2  = 0.010; P  = 0.57). T1 relaxation time was correlated to gland volume (R 2  = 0.19; P  = 0.002) in patients with CP but not in the HCs ( P  = 0.056). Severity of pancreatic functional impairment was reflected by increased fibrosis-related parameters in patients without functional impairment, followed by a further increase in fibrosis-related parameters and reduction in gland volume in patients with pancreatic functional impairments., Conclusion: Pancreatic MRE-derived stiffness and T1 relaxation times might reflect early pathophysiological changes in CP. The dynamic correlation with pancreatic function suggests that these parameters may be useful for the non-invasive and early identification of CP.

Background: Acute on chronic pancreatitis (ACP) is a relatively common condition, but there are significant gaps in our knowledge on the definition, incidence, diagnosis, treatment and prognosis., Methods: A systematic review that followed PICO (Population; Intervention; Comparator; Outcome) recommendation for quantitative questions and PICo (Population, Phenomenon of Interest, Context) for qualitative research was done to answer 10 of the most relevant questions about ACP. Quality of evidence was judged by the GRADE criteria (Grades of Recommendation, Assessment, Development and Evaluation). The manuscript was sent for review to 12 international experts from various disciplines and continents using a Delphi process., Results: The quality of evidence, for most statements, was low to very low, which means that the recommendations in general are only conditional. Despite that, it was possible to reach strong levels of agreement by the expert panel for all 10 questions. A new consensus definition of ACP was reached. Although common, the real incidence of ACP is not known, with alcohol as a major risk factor. Although pain dominates, other non-specific symptoms and signs can be present. Serum levels of pancreatic enzymes may be less than 3 times the upper limit of normal and cross-sectional imaging is considered more accurate for the diagnosis in many cases. It appears that it is less severe and with a lower mortality risk than acute pancreatitis., Conclusions: Although the evidence base is poor, this position statement provides a foundation from which to advance management of ACP., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Sympatico-vagal balance is essential for regulating cardiac electrophysiology and plays an important role in arrhythmogenic conditions. Various noninvasive methods, including electrocardiography (ECG), have been used for clinical assessment of the sympatico-vagal balance. This study aimed to use a custom-designed wearable device to record ECG and ECG-based cardiac function biomarkers to assess sympatico-vagal balance during tonic pain in healthy controls. Nineteen healthy volunteers were included for the ECG measurements using the custom-designed amplifier based on the Texas Instruments ADS1299. The ECG-based biomarkers of the sympatico-vagal balance, (including heart rate variability, deceleration capacity of the heart rate, and periodic repolarization dynamic), were calculated and compared between resting and pain conditions (tonic pain). The custom-designed device provided technically satisfactory ECG recordings. During exposure to tonic pain, the periodic repolarization dynamics increased significantly ( p = 0.02), indicating enhancement of sympathetic nervous activity. This study showed that custom-designed wearable devices can potentially be useful in healthcare as a new telemetry technology. The ECG-based novel biomarkers, including periodic repolarization dynamic and deceleration capacity of heart rate, can be used to identify the cold pressor-induced activation of sympathetic and parasympathetic systems, making it useful for future studies on pain-evoked biomarkers.

Purpose: The study aimed to determine the performance of advanced magnetic resonance imaging (MRI), including a multiparametric MRI-index, for diagnosing and severity grading of chronic pancreatitis (CP) at various functional stages with focus on detection of CP with preserved pancreatic function., Methods: Fifty-four CP patients and 35 healthy controls underwent MRI including assessment of pancreatic volume, main pancreatic duct (MPD) diameter, T1 relaxation time, magnetic resonance elastography (MRE) derived stiffness, and intravoxel incoherent motion (IVIM) diffusion-weighted imaging. Patients were categorized into three subgroups: Preserved pancreatic function (n = 14), partial pancreatic insufficiency (exocrine insufficiency or diabetes, n = 25), and complete pancreatic insufficiency (exocrine insufficiency and diabetes, n = 15). A multiparametric MRI-index was based on ordinal logistic regression analysis. Diagnostic performances of MRI parameters for diagnosing CP at different functional stages were determined using receiver operating characteristic (ROC) analysis., Results: All MRI parameters differed across CP subgroups and healthy controls (all P < 0.001), except for IVIM. T1 relaxation time (ROC area under the curve (ROC-AUC) 0.82), MRE (ROC-AUC 0.88), and MRI-index (ROC-AUC 0.86) showed the highest performance for detecting patients with preserved pancreatic function (early CP) vs. healthy controls. For detecting preserved pancreatic function vs. partial insufficiency, pancreatic volume, MRI-index, and T1 relaxation time performed best (all ROC-AUC > 0.75), with the MRI-index tending to outperform MRE (ROC-AUC 0.77 vs. 0.63; P = 0.10)., Conclusion: Quantitative assessments of T1 relaxation time and MRE-derived stiffness seem promising for diagnosing CP at different functional stages and may together with multiparametric MRI-index be used for early identification, staging and monitoring of CP., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Chronic pancreatitis (CP) may cause intermittent or continuous pain and complications requiring invasive interventions. No specific recommendations for surgical interventions have been presented. Our aim was to determine the surgical treatment strategies for the treatment of CP in the Scandinavian and Baltic countries., Methods: This multi-centre cross sectional study included 1327 CP patients from eight centres. The data was gathered from the Scandinavian Baltic Pancreatic Club (SBPC) database. Patients who underwent pancreatic surgery were analysed. The baseline CP population from the eight centres was used as a reference. The information registered included comorbidities, pancreatic function, previous interventions, time and type of surgery and the EORTC-30 quality of life (QOL) questionnaire., Results: Overall, 95/1327 (7%) patients underwent pancreatic surgery. Fifty-one (54%) of these underwent pancreatic surgery for chronic pain (PSCP) and formed the final study group. Median follow-up time was two (range 0-8) years after surgery and seven (1-46) years after diagnosis. The most common surgical procedures were pancreatic resection combined with drainage (54%) followed by pancreatic resections (32%) and drainage procedures (14%). Postoperatively, 47% of the patients were pain free with or without pain medication while 16% had chronic pain episodes, this did not differ from the base CP population. In QOL questionnaires, PSCP patients reported the same QOL but worse social functioning and more symptoms compared to the CP population., Conclusions: Pancreatic surgery for CP is rare: surgical procedures were performed on only 7% of the CP patients in the SBPC database. In half of the patients the indication was pain. Most of these patients underwent endoscopic procedures before surgery. Half of the patients reported being pain-free after surgery., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Introduction: Pancreatic duct obstruction is the primary indication for endoscopic and/or surgical therapy in patients with chronic pancreatitis (CP). However, the clinical course of medically managed patients in relation to pancreatic duct obstruction is largely unknown., Methods: This was a retrospective cohort study of medically managed patients with CP. We classified patients based on pancreatic duct obstruction from a stricture or stone using cross-sectional imaging (i.e., large vs small duct CP). We compared prevalence of diabetes and exocrine insufficiency (EPI) between subgroups at inclusion and investigated risk of new-onset diabetes, EPI, and all-cause mortality over a follow-up period of 5 years. Changes in pancreatic morphology were studied in patients who underwent follow-up imaging., Results: A total of 198 patients (mean age 58 ± 12 years, 70% male, 60% alcoholic etiology, 38% large duct CP) were evaluated. At inclusion, patients with large vs small duct CP had a higher prevalence of both diabetes (43% vs 24%, P = 0.004) and EPI (47% vs 28%, P = 0.007). There was an increased risk of new-onset EPI in patients with large duct CP (hazard ratio 1.72; 95% confidence interval [1.05-2.80], P = 0.031) and higher rates of pancreatic atrophy ( P < 0.001). No differences between groups were observed for new-onset diabetes and all-cause mortality. Conversion from small to large duct CP or vice versa during follow-up was observed in 14% of patients., Discussion: In a medically managed cohort of patients, large duct CP was associated with increased risk of EPI and pancreatic atrophy compared with small duct CP., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)