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Background/objectives: There is scarce information about risk factors for exocrine pancreas insufficiency (EPI) in chronic pancreatitis (CP), and how it associates with other complications. The aim of the present study was to examine risk factors for EPI and associations to procedures and other CP related complications in a large, Northern European cohort.Patients and methods: We retrieved cross-sectional data on demographics, status on EPI, aetiological risk factors for CP, CP related complications as well as surgical and endoscopic treatment from the Scandinavian Baltic Pancreatic Club Database. Associations were assessed by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals.Results: We included 1869 patients with probable or definitive CP in the study. Exocrine pancreas insufficiency was present in 849 (45.4%) of patients. In multivariate analyses, EPI associated with smoking aetiology (OR 1.47 (1.20-1.79), p < 0.001), and nutritional/metabolic aetiology (OR 0.52 (0.31-0.87), p = 0.01) to CP. Pancreatic or common bile duct stenting procedure and pancreatic resection were both associated with EPI (ORs 1.44 (1.15-1.80), p = 0.002 and 1.54 (1.02-2.33), p = 0.04, respectively). The presence of diabetes mellitus (OR 2.45 (1.92-3.15), p < 0.001), bile duct stenosis (OR 1.48 (1.09-2.00), p = 0.02) and underweight (2.05 (OR 1.40-3.02), p < 0.001) were all associated with presence of EPI.Conclusions: Smoking, bile duct stenosis, previous stenting and resection procedures are all associated with EPI in patients with CP. Presence of EPI were also associated with malnutrition and diabetes mellitus. Hence, intensive nutritional surveillance is needed in these patients. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC.

ObjectivePrevious neuroimaging studies have shown that patients with chronic pain display altered functional connectivity across distributed brain areas involved in the processing of nociceptive stimuli. The aim of the present study was to investigate how pain chronification modulates whole-brain functional connectivity during evoked clinical and tonic pain.MethodsPatients with osteoarthritis of the hip (n = 87) were classified into 3 stages of pain chronification (Grades I–III, Mainz Pain Staging System). Electroencephalograms were recorded during 3 conditions: baseline, evoked clinical hip pain, and tonic cold pain (cold pressor test). The effects of both factors (recording condition and pain chronification stage) on the phase-lag index, as a measure of neuronal connectivity, were examined for different frequency bands.ResultsIn women, we found increasing functional connectivity in the low-frequency range (delta, 0.5–4 Hz) across pain chronification stages during evoked clinical hip pain and tonic cold pain stimulation. In men, elevated functional connectivity in the delta frequency range was observed in only the tonic cold pain condition.ConclusionsAcross pain chronification stages, we found that widespread cortical networks increase their synchronization of delta oscillations in response to clinical and experimental nociceptive stimuli. In view of previous studies relating delta oscillations to salience detection and other basic motivational processes, our results hint at these mechanisms playing an important role in pain chronification, mainly in women. ObjectivePrevious neuroimaging studies have shown that patients with chronic pain display altered functional connectivity across distributed brain areas involved in the processing of nociceptive stimuli. The aim of the present study was to investigate how pain chronification modulates whole-brain functional connectivity during evoked clinical and tonic pain.MethodsPatients with osteoarthritis of the hip (n = 87) were classified into 3 stages of pain chronification (Grades I–III, Mainz Pain Staging System). Electroencephalograms were recorded during 3 conditions: baseline, evoked clinical hip pain, and tonic cold pain (cold pressor test). The effects of both factors (recording condition and pain chronification stage) on the phase-lag index, as a measure of neuronal connectivity, were examined for different frequency bands.ResultsIn women, we found increasing functional connectivity in the low-frequency range (delta, 0.5–4 Hz) across pain chronification stages during evoked clinical hip pain and tonic cold pain stimulation. In men, elevated functional connectivity in the delta frequency range was observed in only the tonic cold pain condition.ConclusionsAcross pain chronification stages, we found that widespread cortical networks increase their synchronization of delta oscillations in response to clinical and experimental nociceptive stimuli. In view of previous studies relating delta oscillations to salience detection and other basic motivational processes, our results hint at these mechanisms playing an important role in pain chronification, mainly in women.

In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea. In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea.

BACKGROUND: Bowel dysfunction following treatment of pelvic organ cancer is prevalent and impacts the quality of life (QoL). The present study aimed to evaluate the feasibility and effects of treating bowel dysfunction in two nurse-led late sequelae clinics.MATERIAL AND METHODS: Treatment effects were monitored prospectively by patient-reported outcome measures collected at baseline and discharge. Change in bowel function was evaluated by 15 bowel symptoms, the St. Mark's Incontinence Score, the Patients Assessment of Constipation-Symptoms (PAC-SYM) score and self-rated bowel function. QoL was evaluated by the EuroQol 5-dimension 5-level (EQ-5D-5L) utility score and by measuring the impact of bowel function on QoL.RESULTS: From June 2018 to December 2021, 380 cancer survivors (46% rectal, 15% gynaecological, 13% anal, 12% colon, 12% prostate, and 2% other cancers) completed a baseline questionnaire and started treatment for bowel dysfunction. At referral, 96% of patients were multisymptomatic. The most frequent symptoms were faecal urgency (95%), fragmented defaecation (93%), emptying difficulties (92%), flatus/faecal incontinence (flatus 89%, liquid 59%, solid 33%), and obstructed defaecation (79%). In total, 169 patients were discharged from the clinics in the follow-up period. At discharge, 69% received conservative treatment only and 24% also received transanal irrigation; 4% were surgically treated; 3% discontinued treatment. Improvements were seen in all 15 bowel symptoms ( p CONCLUSION: Treatment of bowel dysfunction in nurse-led late sequelae clinics is feasible and significantly improved bowel function and QoL.

BACKGROUND: Acute pancreatitis (AP) has variable clinical courses. This systematic review and meta-analysis aimed to determine the safety, efficacy, and impact of epidural anaesthesia (EA) use in AP.METHODS: The PubMed, EMBASE, SCOPUS and Cochrane library databases were systematically searched between 1980 and 2022 using the PRISMA guidelines, to identify observational and comparative studies reporting on EA in AP. The meta-analysis was performed in R Foundation for Statistical Computing using the meta R Package for Meta-Analysis.RESULTS: A total of 9 studies with 2006 patients of which 726 (36%) patients had EA were included. All studies demonstrated high safety and feasibility of EA in AP with no reported major local or neurological complications. One randomised controlled trial demonstrated an improvement in pain severity using a 0-10 visual analogue scale (VAS) at the outset (1.6 in EA vs 3.5 in non-EA, P = 0.02) and on day 10 (0.2 in EA vs 2.33 in non-EA, P = 0.034). There was also improvement in pancreatic perfusion with EA measured with computerised tomography 13 (43%) in EA vs 2 (7%) in non-EA, P = 0.003. The need for ventilatory support and overall mortality was lower in EA patients 40 (19%) vs 285 (24%) P = 0.025 (OR: 0.49, 95% CI: 0.28-0.84) and 16 (7%) vs 214 (20%), P = 0.050 (OR: 0.39, 95% CI: 0.15-1.00), respectively.CONCLUSION: EA is infrequently used for pain management in AP and yet the available evidence suggests that it is safe and effective in reducing pain severity, improving pancreatic perfusion, and decreasing mortality.

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.

BACKGROUND: Diabetes type 1 and type 2 may develop gastrointestinal complications e.g., gastroparesis and gastroenteropathy. Concomitant celiac disease and pancreatic exocrine insufficiency occur with high prevalence in diabetes and with symptomatic overlap. Consequently, it is a challenge to disentangle symptoms of these conditions and separate them from functional dyspepsia. We aim to develop a clinical decision-support tool to differentiate the underlying disease in a plethora of gastrointestinal symptoms.METHODS: An internet-based computerized survey will collect basic characteristics (diabetes type, age, gender, duration, HbA1c, treatment) and patient reported outcomes by validated questionnaires focusing on (1) gastroparesis using Gastroparesis Cardinal Symptom Index; (2) gastroenteropathy using Gastrointestinal Symptom Rating Scale; (3) celiac disease using Celiac Symptom Index and (4) pancreatic exocrine insufficiency with Pancreatic Exocrine Insufficiency Questionnaire. Logistic regression and multiple regression analyses will identify risk factors and gastrointestinal complications. Cluster analyses and machine learning will classify different symptoms and co-existing presentations, into a likely diagnosis. We seek biomarkers for autonomic neuropathy by characterizing development of retinopathy using the Visual Function Questionnaire-25 and peripheral neuropathy by the Michigan neuropathy questionnaire. Participants are re-examined yearly for disease progression over time.RESULTS: From focus group studies gastrointestinal symptoms are of major concern in diabetes. Potentially, estimates of symptom prevalence, risk factor identification and classifications of gastrointestinal complications can be unraveled for feedback to health care providers.CONCLUSION: The web-based DICODI project will open up possibilities to detect gastrointestinal complications of diabetes in a societal setting, benefitting people living with diabetes, health care professionals, and society.

Purpose: The need for incorporation of quantitative imaging biomarkers of pancreatic parenchymal and ductal structures has been highlighted in recent proposals for new scoring systems in chronic pancreatitis (CP). To quantify inter- and intra-observer variability in CT-based measurements of ductal- and gland diameters in CP patients. Materials and Methods: Prospectively acquired pancreatic CT examinations from 50 CP patients were reviewed by 12 radiologists and four pancreatologists from 10 institutions. Assessment entailed measuring maximum diameter in the axial plane of four structures: (1) pancreatic head (PDhead), (2) pancreatic body (PDbody), (3) main pancreatic duct in the pancreatic head (MPDhead), and (4) body (MPDbody). Agreement was assessed by the 95% limits of agreement with the mean (LOAM), representing how much a single measurement for a specific subject may plausibly deviate from the mean of all measurements on the specific subject. Bland–Altman limits of agreement (LoA) were generated for intra-observer pairs. Results: The 16 observers completed 6400 caliper placements comprising a first and second measurement session. The widest inter-observer LOAM was seen with PDhead (± 9.1 mm), followed by PDbody (± 5.1 mm), MPDhead (± 3.2 mm), and MPDbody (± 2.6 mm), whereas the mean intra-observer LoA width was ± 7.3, ± 5.1, ± 3.7, and ± 2.4 mm, respectively. Conclusion: Substantial intra- and inter-observer variability was observed in pancreatic two-point measurements. This was especially pronounced for parenchymal and duct diameters of the pancreatic head. These findings challenge the implementation of two-point measurements as the foundation for quantitative imaging scoring systems in CP. Graphical abstract: [Figure not available: see fulltext.]

Background Long-term gastrointestinal sequelae are common after colorectal cancer surgery, but the impact of type 2 diabetes (T2D) is unknown. Methods In a cross-sectional design, questionnaires regarding bowel function and quality of life (QoL) were sent to all Danish colorectal cancer survivors, who had undergone surgery between 2001 and 2014 and had more than 2 years follow-up without relapse. The prevalence of long-term gastrointestinal sequelae among colorectal cancer survivors with and without T2D were compared while stratifying for type of surgical resection and adjusting for age, sex, and time since surgery. Results A total of 8747 out of 14 488 colorectal cancer survivors answered the questionnaire (response rate 60 per cent), consisting of 3116 right-sided colonic, 2861 sigmoid, and 2770 rectal resections. Of these, 690 (7.9 per cent) had a diagnosis of T2D before surgery. Survivors with T2D following rectal resection had a 15 per cent (95 per cent c.i. 7.8 to 22) higher absolute risk of major low anterior resection syndrome, whereas survivors with T2D following right-sided and sigmoid resection had an 8 per cent higher risk of constipation (P Conclusion T2D at time of surgery was associated with a higher risk of long-term bowel dysfunction after rectal resection, but not after colon resection excluding a higher risk of constipation. T2D was associated with a slightly higher frequency of severe pain and inferior QoL after both rectal and colonic cancer resection.

The need for incorporation of quantitative imaging biomarkers of pancreatic parenchymal and ductal structures has been highlighted in recent proposals for new scoring systems in chronic pancreatitis (CP). To quantify inter- and intra-observer variability in CT-based measurements of ductal- and gland diameters in CP patients.Prospectively acquired pancreatic CT examinations from 50 CP patients were reviewed by 12 radiologists and four pancreatologists from 10 institutions. Assessment entailed measuring maximum diameter in the axial plane of four structures: (1) pancreatic head (PDhead), (2) pancreatic body (PDbody), (3) main pancreatic duct in the pancreatic head (MPDhead), and (4) body (MPDbody). Agreement was assessed by the 95% limits of agreement with the mean (LOAM), representing how much a single measurement for a specific subject may plausibly deviate from the mean of all measurements on the specific subject. Bland-Altman limits of agreement (LoA) were generated for intra-observer pairs.The 16 observers completed 6400 caliper placements comprising a first and second measurement session. The widest inter-observer LOAM was seen with PDhead (± 9.1 mm), followed by PDbody (± 5.1 mm), MPDhead (± 3.2 mm), and MPDbody (± 2.6 mm), whereas the mean intra-observer LoA width was ± 7.3, ± 5.1, ± 3.7, and ± 2.4 mm, respectively.Substantial intra- and inter-observer variability was observed in pancreatic two-point measurements. This was especially pronounced for parenchymal and duct diameters of the pancreatic head. These findings challenge the implementation of two-point measurements as the foundation for quantitative imaging scoring systems in CP.

OBJECTIVE Postpancreatitis diabetes mellitus (PPDM) is a frequent complication of pancreatitis and associates with poor glycemic control. We investigated the risk of adverse diabetes-related outcomes in PPDM compared with type 2 diabetes. RESEARCH DESIGN AND METHODS In this Danish population-based cohort study, we included adults (>18 years) with incident PPDM or type 2 diabetes between 1998 and 2018 through national health registries. PPDM was further divided into acute (PPDM-A) and chronic (PPDM-C) subtypes. We ascertained risk of major adverse cardiovascular events (MACE), severe hypoglycemia, and all-cause mortality as well as incidence rates of severe hypoglycemia. We compared risk and incidence rates across diabetes subgroups using multivariate Cox and Poisson regression analyses. RESULTS We identified 383,325 people with incident type 2 diabetes, 3,418 with PPDM-A, and 2,461 with PPDM-C. Compared with type 2 diabetes, PPDM-C was associated with increased risks of severe hypoglycemia (hazard ratio [HR] 5.27, 95% CI 4.62–6.00, P < 0.001) and all-cause mortality (HR 1.54, 95% CI 1.45–1.64, P < 0.001). Similar patterns were observed for people with PPDM-A. Incidence rate ratios (IRRs) for severe hypoglycemia were increased in both PPDM-C (IRR 7.38, 95% CI 6.75–8.08, P < 0.001) and PPDM-A (IRR 3.76, 95% CI 3.36–4.21, P < 0.001) compared with type 2 diabetes. Findings were consistent in an analysis restricted to people on insulin and in an analysis including pancreatitis patients without diabetes as comparator group. CONCLUSIONS Compared with type 2 diabetes, PPDM is associated with excess risk of adverse diabetes-related outcomes. This has important implications for management.

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.

Gastrointestinal (GI) pain - a form of visceral pain - is common in some disorders, such as irritable bowel syndrome, Crohn's disease and pancreatitis. However, identifying the cause of GI pain frequently represents a diagnostic challenge as the clinical presentation is often blurred by concomitant autonomic and somatic symptoms. In addition, GI pain can be nociceptive, neuropathic and associated with cancer, but in many cases multiple aetiologies coexist in an individual patient. Mechanisms of GI pain are complex and include both peripheral and central sensitization and the involvement of the autonomic nervous system, which has a role in generating the symptoms that frequently accompany pain. Treatment of GI pain depends on the precise type of pain and the primary disorder in the patient but can include, for example, pharmacological therapy, cognitive behavioural therapies, invasive surgical procedures, endoscopic procedures and lifestyle alterations. Owing to the major differences between organ involvement, disease mechanisms and individual factors, treatment always needs to be personalized and some data suggest that phenotyping and subsequent individual management of GI pain might be options in the future.

Gastrointestinal (GI) pain - a form of visceral pain - is common in some disorders, such as irritable bowel syndrome, Crohn's disease and pancreatitis. However, identifying the cause of GI pain frequently represents a diagnostic challenge as the clinical presentation is often blurred by concomitant autonomic and somatic symptoms. In addition, GI pain can be nociceptive, neuropathic and associated with cancer, but in many cases multiple aetiologies coexist in an individual patient. Mechanisms of GI pain are complex and include both peripheral and central sensitization and the involvement of the autonomic nervous system, which has a role in generating the symptoms that frequently accompany pain. Treatment of GI pain depends on the precise type of pain and the primary disorder in the patient but can include, for example, pharmacological therapy, cognitive behavioural therapies, invasive surgical procedures, endoscopic procedures and lifestyle alterations. Owing to the major differences between organ involvement, disease mechanisms and individual factors, treatment always needs to be personalized and some data suggest that phenotyping and subsequent individual management of GI pain might be options in the future.

[This corrects the article DOI: 10.1371/journal.pone.0171723.].

Opioids are known to affect gastrointestinal motility, but their effect on fluid absorption and secretion is poorly understood in humans.To investigate the effect of oxycodone on colonic fecal volume and stool dryness by using a novel MRI-based technique.Prospective, randomized, double-blinded, crossover study.Twenty-five healthy male volunteers (median age: 24 years [range: 21-56]; mean body mass index [BMI]: 23.9 kg/mTSubjects were treated for 5 days with prolonged-release oxycodone or a placebo. Imaging was performed on the first and last study day in each period. Images of the colon were analyzed with semiautomatic k-means-based segmentation software. Regional colonic fecal volumes were quantified excluding gas volume and colon wall. Two-point Dixon and TIntraclass correlation coefficients were used to test the reliability of measurements between days, while repeated measures mixed models were applied to test treatment effects.After oxycodone treatment, total colonic fecal volume was significantly increased compared with placebo (mean change 100 mL vs. -13 mL; P = 0.001), with the largest increase (24%) observed in the ascending colon/cecum (P = 0.001). Dixon signal increased (less water in colon content) after oxycodone treatment compared with placebo (mean 0.09 vs. -0.02; P0.001). TThe 5-day oxycodone treatment increased colonic fecal volume and increased stool dryness compared with placebo. This imaging-based method for noninvasive analysis of colon content has the potential to characterize gastrointestinal symptoms in general, such as in constipation.2 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:733-745.

Item does not contain fulltext BACKGROUND: In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed European guidelines for the management of chronic pancreatitis using an evidence-based approach. METHODS: Recommendations of multidisciplinary review groups based on systematic literature reviews to answer predefined clinical questions are summarised. Recommendations are graded using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Recommendations covered topics related to the clinical management of chronic pancreatitis: aetiology, diagnosis of chronic pancreatitis with imaging, diagnosis of pancreatic exocrine insufficiency, surgical therapy, medical therapy, endoscopic therapy, treatment of pancreatic pseudocysts, pancreatic pain, nutrition and malnutrition, diabetes mellitus and the natural course of the disease and quality of life. CONCLUSIONS: The HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research. This article summarises the HaPanEU recommendations and statements.

Treatment of esophageal pain remains a major challenge for the clinician. Although many patients have heartburn and may respond to proton pump inhibitors, there in an unmet need for other treatment modalities in patients where there are no obvious pathological findings. Although analgesics are the mainstay in esophageal pain treatment, many patients are nonresponders to these drugs. The current concise review focuses on other systems affecting pain processing, where better understanding may serve as a framework for therapy. These are the parasympathetic nervous system, exercise, and personality profiles. Finally, treatment with analgesics for functional chest pain remains a challenge, and an overview of treatment with antidepressive drugs is provided.

To compare results from analysis of averaged and single-sweep evoked brain potentials (EPs) by visual inspection and spectral analysis in order to identify an objective measure for the analgesic effect of buprenorphine and fentanyl.Twenty-two healthy males were included in a randomized study to assess the changes in EPs after 110 sweeps of painful electrical stimulation to the median nerve following treatment with buprenorphine, fentanyl or placebo patches. Bone pressure, cutaneous heat and electrical pain ratings were assessed. EPs and pain assessments were obtained before drug administration, 24, 48, 72 and 144 h after beginning of treatment. Features from EPs were extracted by three different approaches: (i) visual inspection of amplitude and latency of the main peaks in the average EPs, (ii) spectral distribution of the average EPs and (iii) spectral distribution of the EPs from single-sweeps.Visual inspection revealed no difference between active treatments and placebo (all P0.05). Spectral distribution of the averaged potentials showed a decrease in the beta (12-32 Hz) band for fentanyl (P = 0.036), which however did not correlate with pain ratings. Spectral distribution in the single-sweep EPs revealed significant increases in the theta, alpha and beta bands for buprenorphine (all P0.05) as well as theta band increase for fentanyl (P = 0.05). For buprenorphine, beta band activity correlated with bone pressure and cutaneous heat pain (both P = 0.04, r = 0.90).In conclusion single-sweep spectral band analysis increases the information on the response of the brain to opioids and may be used to identify the response to analgesics.

Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physician's use of opioids to morphine. Although this approach is recognized as cost-effective in most cases there is solid evidence that, on an individual patient basis, opioids are not all equal. Therefore it is important to have an armamentarium of strong analgesics in clinical practice to ensure a personalized approach in patients who do not respond to standard treatment. In this review we highlight differences between opioids in human studies from a pharmacological, experimental, clinical and health economics point of view. We provide evidence that individuals respond differently to opioids, and that general differences between classes of opioids exist. We recommend that this recognition is used to individualize treatment in difficult cases allowing physicians to have a wide range of treatment options. In the end this will reduce pain and side effects, leading to improved quality of life for the patient and reduce the exploding pain related costs.

To identify electroencephalographic (EEG) biomarkers for the analgesic effect of pregabalin in patients with chronic visceral pain.This was a double-blind, placebo-controlled study in 31 patients suffering from visceral pain due to chronic pancreatitis. Patients received increasing doses of pregabalin (75mg-300mg twice a day) or matching placebo during 3 weeks of treatment. Pain scores were documented in a diary based on a visual analogue scale. In addition, brief pain inventory-short form (BPI) and quality of life questionnaires were collected prior to and after the study period. Multi-channel resting EEG was recorded before treatment onset and at the end of the study. Changes in EEG spectral indices were extracted, and individual changes were classified by a support vector machine (SVM) to discriminate the pregabalin and placebo responses. Changes in individual spectral indices and pain scores were correlated.Pregabalin increased normalized intensity in low spectral indices, most prominent in the theta band (3.5-7.5Hz), difference of -3.18, 95% CI -3.57, -2.80; P= 0.03. No changes in spectral indices were seen for placebo. The maximum difference between pregabalin and placebo treated patients was seen in the parietal region, with a classification accuracy of 85.7% (P= 0.009). Individual changes in EEG indices were correlated with changes in pain diary (P= 0.04) and BPI pain composite scores (P= 0.02).Changes in spectral indices caused by slowing of brain oscillations were identified as a biomarker for the central analgesic effect of pregabalin. The developed methodology may provide perspectives to assess individual responses to treatment in personalized medicine.

The effects of morphine on brain potentials after experimental gut pain have never been investigated. This study explored whether multi-channel-evoked brain potentials (EP) and corresponding dipole sources in the brain would reflect the effects of morphine on experimental oesophageal pain. In a crossover study, the effects of oral morphine (30 mg) or corresponding placebo on pain from electrical oesophageal stimulation were tested in 12 healthy male volunteers. The electroencephalographic (EEG) activity was monitored with 64 surface recordings. Pain was assessed by subjective scores on a visual analogue scale, amplitude and latency of the vertex-EP as well as on multi-channel recordings of EPs. Finally, electrical brain sources after pain stimuli were modelled from the EEG data. Morphine attenuated subjective pain scores (p = 0.008). The amplitude of the P2 peak (230 msec. post-stimulus) in the vertex EPs was unaltered after treatment with morphine, whereas after placebo treatment, it decreased (p = 0.03). However, the overall topography changed and the source of P1 (100 msec. post-stimulus), possibly originating from areas near the cingulate gyrus, changed localization in an upward, posterior direction (p = 0.04). The length of the vector describing this shift correlated inversely with the magnitude of the subjective pain relief (r = -0.7; p = 0.02). With the potential of becoming a useful biomarker in analgesic trials, the localization of the dipole sources reflected the analgesic action of morphine after pain stimuli of the gut. Even though further evaluation of the method is necessary, it has the potential to be a valid objective biomarker for opioid analgesia.

Pharmacokinetic/pharmacodynamic (PK/PD) modelling can be used to characterize the relationship between dose regimen of opioids, plasma concentration and effect of opioids, which in turn can lead to more rational treatment regimens of pain. The aim of this study was to investigate the concentration-effect relationship for transdermal buprenorphine and fentanyl in experimentally induced pain. Twenty-two healthy volunteers were randomized to receive transdermal patches with fentanyl (25 μg/hr, 72 hr), buprenorphine (20 μg/hr, 144 hr) or placebo. The experimental pain tests were pressure at the tibial bone, cutaneous thermal stimulation, cold pressor test (conditioning stimulus (3 ± 0.3°C cold water), nerve growth factor-induced muscle soreness and intradermal capsaicin-induced hyperalgesia and allodynia. Experiments were carried out at baseline, 24, 48, 72 and 144 hr after application of patches. Time-course of placebo was described first and was afterwards added to the description of the time-courses of buprenorphine and fentanyl. This was either described by zero (no drug effect), linear or E(max) model concentration-effect relationships. Time-dependent changes in pain measures in the placebo arm were described by linear or quadratic functions. The time-course of fentanyl and buprenorphine plasma concentrations was complex but could be represented by cubic spline interpolation in the models. Buprenorphine significantly attenuated bone-associated pain, heat pain, nerve growth factor-induced soreness and cold pressor pain. Fentanyl significantly attenuated cold pressor pain for the administered dose regimens. Although the PK/PD relationship for both drugs could be described with similar models, tissue-differentiated analgesic effects between buprenorphine and fentanyl was shown.

Acute hyperglycaemia is known to increase gastrointestinal (GI) sensitivity in healthy subjects and may contribute to the increased prevalence of GI symptoms in diabetes patients. The aim of this study was to evaluate the effect of acute hyperglycaemia on perception and brain responses to painful visceral and somatic stimuli in diabetic patients.The sensitivity and evoked brain potentials (EPs) to electrical oesophageal and median nerve stimulations were assessed in 14 type-1 diabetes patients with autonomic neuropathy and GI symptoms using a hyperinsulinaemic clamp at 6 and 15 mM.No differences between the normo- and hyperglycaemic conditions were found in sensitivity to both oesophageal (P=0·72) and median nerve (P=0·66) stimulations. The latencies and amplitudes of EPs did not differ between the normo- and hyperglycaemic conditions following oesophageal (P=0·53 and 0·57) and median nerve (P=0·78 and 0·52) stimulations.Acute hyperglycaemia itself does not contribute to the sensations in patients with longstanding diabetes and autonomic neuropathy. Any potential sensory effects of acute hyperglycaemia can likely be blurred by the neuropathic-like changes in the sensory nervous system.

Udgivelsesdato: 2009-null BACKGROUND: Autoimmune pancreatitis (AIP) is a relatively newly recognized type of pancreatitis that is characterized by diffuse or focal swelling of the pancreas due to lymphoplasmacytic infiltration and fibrosis of the pancreatic parenchyma. MATERIAL AND METHODS: A PubMed literature search was performed using the keywords "autoimmune pancreatitis". Sometimes, bibliographies were cross-referenced and related article searches were performed once an article of interest was identified. RESULTS: Pathologically, AIP shows narrowing of the pancreatic ducts and the intrapancreatic portion of the common bile duct. Obstructive jaundice is a common symptom at presentation, and pancreatic cancer represents an important clinical differential diagnosis. In late stages of the disease, the normal pancreatic parenchyma is often replaced by large amounts of fibrosis. Histologically, there seem to be two subtypes of the disease-one showing infiltration with IgG4-positive plasma cells but lacking granulocytic epithelial lesions (GELs), the other showing GELs but lacking strong IgG4 positivity. AIP is in at least some instances the pancreatic manifestation of a clinicopathological entity of IgG4-related systemic sclerosing disease. On the basis of pancreatic imaging, together with serological measurement of IgG4 and evaluation of other organ involvement, many AIP patients can be identified. The remaining patients require further diagnostic work-up. In these patients, pancreatic core needle biopsy and, as AIP responds to steroid treatment, also a trial with steroids, can help to differentiate AIP from pancreatic cancer. OUTLOOK AND DISCUSSION: This review presents the pathological, radiologic and laboratory findings of AIP. Moreover, the treatment and pathogenesis are discussed.

Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide kappa-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid).The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order: (1) CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain detection and tolerance thresholds, (3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing.Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P0.001) and cuff pressure pain tolerance threshold (P0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P0.001) and thermal stimulation (P0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007).CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.

The value of opioid pharmacotherapy in the management of chronic pancreatitis pain is described. The role of kappa receptor opioid agonists and specifically oxycodone as compared to other opioid agonists is discussed. Limitations in the published studies on this topic are delineated as are difficulties in extrapolating form animal studies to clinical care.