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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

Laura JGM van Weerdenburg,1 Christina Brock,2,3 Asbjørn Mohr Drewes,2 Harry van Goor,1 Marjan de Vries,1 Oliver HG Wilder-Smith4 1Department of Surgery, Radboud University Medical Centre, Nijmegen, the Netherlands; 2Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, 3Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark; 4Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands Background and objectives: Contradictory results have been found about the effect of different exercise modalities on pain. The aim of this study was to investigate the early effects of aerobic and isometric exercise on different types of experimental pain, including visceral pain, compared to an active control condition. Methods: Fifteen healthy subjects (6 women, mean [standard deviation] age 25 [6.5] years) completed 3 interventions consisting of 20 minutes of aerobic cycling, 12 minutes of isometric knee extension and a deep breathing procedure as active control. At baseline and after each intervention, psychophysical tests were performed, including electrical stimulation of the esophagus, pressure pain thresholds and the cold pressor test as a measure for conditioned pain modulation. Participants completed the Medical Outcome Study Short-Form 36 and State-Trait Anxiety Inventory prior to the experiments. Data were analyzed using two-way repeated measures analysis of variance. Results: No significant differences were found for the psychophysical tests after the interventions, compared to baseline pain tests and the control condition. Conclusion: No hypoalgesic effect of aerobic and isometric exercise was found. The evidence for exercise-induced hypoalgesia appears to be not as consistent as initially thought, and caution is recommended when interpreting the effects of exercise on pain. Keywords: motor activity, breathing exercises, pain measurement, pain perception

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

Anne Estrup Olesen,1,2 Christina Brock,1,2 Eva Sverrisdóttir,2 Isabelle Myriam Larsen,1 Asbjørn Mohr Drewes1,3 1Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; 2Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 3Department of Clinical Medicine, Aalborg University, Aalborg, Denmark Introduction: Opioid analgesia can be explored with quantitative sensory testing, but most investigations have used models of phasic pain, and such brief stimuli may be limited in the ability to faithfully simulate natural and clinical painful experiences. Therefore, identification of appropriate experimental pain models is critical for our understanding of opioid effects with the potential to improve treatment. Objectives: The aim was to explore and compare various pain models to morphine analgesia in healthy volunteers. Methods: The study was a double-blind, randomized, two-way crossover study. Thirty-nine healthy participants were included and received morphine 30 mg (2 mg/mL) as oral solution or placebo. To cover both tonic and phasic stimulations, a comprehensive multi-modal, multi-tissue pain-testing program was performed. Results: Tonic experimental pain models were sensitive to morphine analgesia compared to placebo: muscle pressure (F=4.87, P=0.03), bone pressure (F=3.98, P=0.05), rectal pressure (F=4.25, P=0.04), and the cold pressor test (F=25.3, P0.05). Conclusion: Pain models with deep tonic stimulation including C fiber activation and and/or endogenous pain modulation were more sensitive to morphine analgesia. To avoid false negative results in future studies, we recommend inclusion of reproducible tonic pain models in deep tissues, mimicking clinical pain to a higher degree. Keywords: pain, opioid, experiment pain model

Jakob Lykke Poulsen,1 Christina Brock,1,2 Anne Estrup Olesen,1,2 Matias Nilsson,1 Asbjørn Mohr Drewes1,3 1Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; 2Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark; 3Department of Clinical Medicine, Aalborg University, Aalborg, DenmarkAbstract: Opioid-induced bowel dysfunction (OIBD) is a burdensome condition which limits the therapeutic benefit of analgesia. It affects the entire gastrointestinal tract, predominantly by activating opioid receptors in the enteric nervous system, resulting in a wide range of symptoms, such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation. The majority of studies evaluating OIBD focus on constipation experienced in approximately 60% of patients. Nevertheless, other presentations of OIBD seem to be equally frequent. Furthermore, laxative treatment is often insufficient, which in many patients results in decreased quality of life and discontinuation of opioid treatment. Novel mechanism-based pharmacological approaches targeting the gastrointestinal opioid receptors have been marketed recently and even more are in the pipeline. One strategy is prolonged release formulation of the opioid antagonist naloxone (which has limited systemic absorption) and oxycodone in a combined tablet. Another approach is peripherally acting, µ-opioid receptor antagonists (PAMORAs) that selectively target µ-opioid receptors in the gastrointestinal tract. However, in Europe the only PAMORA approved for OIBD is the subcutaneously administered methylnaltrexone. Alvimopan is an oral PAMORA, but only approved in the US for postoperative ileus in hospitalized patients. Finally, naloxegol is a novel, oral PAMORA expected to be approved soon. In this review, the prevalence and pathophysiology of OIBD is presented. As PAMORAs seem to be a promising approach, their potential effect is reviewed with special focus on naloxegol's pharmacological properties, data on safety, efficacy, and patient-focused perspectives. In conclusion, as naloxegol is administered orally once daily, has proven efficacious compared to placebo, has an acceptable safety profile, and can be used as add-on to existing pain treatment, it is a welcoming addition to the targeted treatment possibilities for OIBD.Keywords: opioids, gut, dysfunction, constipation, naloxegol, opioid antagonists

Tine Maria Hansen,1 Anne Estrup Olesen,2 Carsten Wiberg Simonsen,1 Asbjørn Mohr Drewes,2,3 Jens Brøndum Frøkjær11Mech-Sense, Department of Radiology, 2Mech-Sense, Department of Gastroenterology, 3Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, DenmarkBackground: Experimental investigation of cerebral mechanisms underlying pain and analgesia are important in the development of methods for diagnosis and treatment of pain. The aim of the current study was to explore brain metabolites in response to pain and treatment with morphine.Methods: Proton magnetic resonance spectroscopy of the anterior cingulate cortex was performed in 20 healthy volunteers (13 males and seven females, aged 24.9±2.6 years) during rest and acute pain before and during treatment with 30 mg of oral morphine or placebo in a randomized, double-blinded, cross-over study design. Pain was evoked by skin stimulation applied to the right upper leg using a contact heat-evoked potential stimulator.Results: Data from 12 subjects were valid for analysis. Painful stimulation induced an increase in N-acetylaspartate/creatine compared with rest (F=5.5, P=0.04). During treatment with morphine, painful stimulation induced decreased glutamate/creatine (F=7.3, P=0.02), myo-inositol/creatine (F=8.38, P=0.02), and N-acetylaspartate/creatine (F=13.8, P=0.004) concentrations, whereas an increase in the pain-evoked N-acetylaspartate/creatine concentration (F=6.1, P=0.04) was seen during treatment with placebo.Conclusion: This explorative study indicates that neuronal metabolites in the anterior cingulate cortex, such as N-acetylaspartate, glutamate, and myo-inositol, could be related to the physiology of pain and treatment with morphine. This experimental method has the potential to enable the study of brain metabolites involved in pain and its treatment, and may in the future be used to provide further insight into these mechanisms.Keywords: magnetic resonance imaging, spectroscopy, pain, morphine, anterior cingulate cortex

Frederik Hvid-Jensen,1 Rikke B Nielsen,2 Lars Pedersen,2 Peter Funch-Jensen,3 Asbjørn Mohr Drewes,4 Finn B Larsen,5 Reimar W Thomsen2 1Department of Surgical Gastroenterology L, Aarhus University Hospital, Aarhus, 2Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, 3Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, 4Mech-Sense Centre, Department of Gastroenterology, Aarhus University Hospital, Aalborg, 5Public Health and Quality Improvement, Central Denmark Region, Denmark Purpose: Lifestyle factors may influence observed associations between proton pump inhibitor (PPI) usage and health outcomes. The aim of the study reported here was to examine characteristics and differences in lifestyle among PPI users and nonusers. Methods: This cross-sectional study utilized data from a 2006 population-based health survey of 21,637 persons in the Central Danish Region. All persons using prescribed PPIs were identified through linkage to a population-based prescription database. Biometric measures and prevalence of smoking, excessive alcohol consumption, diet, and physical exercise were analyzed, comparing PPI users with nonusers. Results: Among 10,129 (46.8%) male and 11,508 (53.2%) female survey respondents, 1,356 (13.4%) males and 1,691 (14.7%) females reported ever use of PPIs. PPI users were more obese (16.7%) than nonusers (13.1%), with an age- and sex-standardized prevalence ratio (PR) of 1.3 (95% confidence interval [CI]: 1.2–1.4). The prevalence of smokers was also higher in the PPI group (26.2% vs 22.3% [PR =1.2, 95% CI: 1.1–1.3]), as was the prevalence of ex-smokers (41.0% vs 32.0% [PR =1.2, 95% CI: 1.1–1.2]). Unhealthy diet was slightly more common among PPI users than among nonusers (15.4% vs 13.0%), with a PR of 1.2 (95% CI: 1.1–1.3). Physical exercise level and alcohol consumption were similar in the two groups. Hospital-diagnosed comorbidity was observed in 35% of PPI users (a Charlson Comorbidity Index score of 1 or more) compared with only 15% among nonusers. Conclusion: PPI users are more obese, smoke more, and have significantly more comorbidities than PPI nonusers. These data are important when evaluating unmeasured confounding in observational studies of PPI effects. Keywords: PPI, obesity, smoking, reflux, population-based, gastroesophageal reflux

Objective: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease. Studies suggest that pro-inflammatory cytokines may be attenuated by the vagus nerve through the cholinergic anti-inflammatory pathway. We aimed to evaluate the anti-inflammatory effects of short-term transcutaneous non-invasive vagus nerve stimulation (n-VNS) applied to the cervical vagus nerve in patients with RA. Method: We conducted a single-centre, open-label, preliminary proof-of-concept study of n-VNS in two cohorts of participants with RA: one with high disease activity (n = 16) and one with low disease activity (n = 20). Disease Activity Score based on 28-joint count–C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines were measured at baseline and after 1 and 4 days of n-VNS. Results: In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02). In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone (p = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02). Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs 4.9 ± 3 linear vagal scale, p = 0.03). Cardiac vagal tone was negatively associated with DAS28-CRP (r = −0.37, p = 0.03). Overall, n-VNS was well tolerated. Conclusion: This study provides preliminary support for an anti-inflammatory effect of n-VNS in patients with RA. These findings warrant further investigation in larger placebo-controlled trials. [ABSTRACT FROM AUTHOR]

ObjectiveOpioid therapy is associated with altered secretion and motility of the gut. The relative contribution of decreased secretion to the development of opioid-induced constipation remains unknown.Materials and methodsTwenty-five healthy males were treated with oxycodone for 5 d in a placebo-controlled, randomised cross-over design. Gastrointestinal adverse effects were assessed with validated questionnaires (bowel function index and gastrointestinal symptom rating scale). Rectosigmoid mucosal biopsies were taken at baseline and on day 5 during both treatments and mounted in Ussing chambers. Electrogenic ion transport parameters (short circuit current (SCC) and slope conductance) were measured after addition of secretagogues (prostaglandin E2(PGE2) (6 μm), theophylline (400 μm)), and an inhibitor (ouabain (200 μm)). Additionally, morphine (50 μm) was added to investigate the direct opioid effect on colonic mucosa.ResultsQuestionnaires showed pronounced bowel symptoms, including constipation during oxycodone treatment (eight-fold increase in bowel function index score from day 1 to day 5 (p < 0.001) while no significant change occurred during placebo treatment (p = 0.47). Basal SCC and slope conductance did not differ between treatments (allp > 0.05) and application with PGE2, theophylline, and ouabain yielded comparable results on all examinations (allp > 0.05). Morphine application consistently did not evoke a change in ion transport.ConclusionCompared to placebo, epithelial electrogenic ion transport is not altered in mucosal biopsies from the rectosigmoid colon following 5-d oxycodone treatment. The secretory mechanisms in isolated mucosa appear to play a negligible role in the development of opioid-induced constipation. [ABSTRACT FROM AUTHOR]

Background: Oxycodone is a strong opioid that acts at mu- and kappa-opioid receptors. It has pharmacological actions similar to strong opioids, but with a specific pharmacologic profile and greater analgesic potency to morphine. The efficacy of oxycodone in managing neuropathic and somatic pain, both of malignant and non-malignant origin, has been established in a wide range of settings.Scope: This review aims to provide a comprehensive evaluation of oxycodone and its role within clinical settings in order to provide an evidence-based perspective on its use in the clinic. Literature searches using Medline, EMBASE and Cochrane Databases were used to compile data for review. The review provides information on the pharmacokinetics and pharmacodynamics of oxycodone and also profiles established clinical data in neuropathic and somatic pain as well as emerging data to support the use of oxycodone in visceral pain, which may be due to its interaction with kappa-opioid receptors. Oxycodone is available in a range of formulations for oral, intraspinal and parenteral administration.Findings: The prolonged-release form of oxycodone offers a fast onset of analgesia, controlling pain for 12 hours and providing clinically meaningful relief of moderate to severe pain and improving quality of life across a broad spectrum of pain types.Conclusions: Oxycodone provides significant pain relief. It has relevant points of difference from other opioids and as such may be a suitable alternative to morphine. [ABSTRACT FROM AUTHOR]

The aim was to investigate biomechanical properties and sensory function of the duodenum in young and old volunteers using a previously developed impedance planimetric probe. A volume-controlled ramp distension protocol was used with subsequent evaluation of the circumferential wall tension and strain before and during administration of the relaxant drug butylscopolamine. Seven healthy young volunteers (mean age 26+/-2 years) and 5 healthy old volunteers (mean age 61+/-4 years) were studied. The pain threshold in the young group was significantly higher for most mechanical parameters than that in the old subjects. The luminal cross-sectional area (CSA) and strain of the young group were higher than those of the old group both without and with butylscopolamine administration (P<0.05 for all). In contrast, the pressure and tension of these 2 groups both without and with butylscopolamine administration did not differ. Isometric lengthtension diagrams in terms of tension-strain relations were computed. In both groups the total and passive tension increased exponentially as function of strain or normalized volume. The passive tension curve was translated to the left for the old subjects when compared with the young subjects. The active tension increased until a maximum (L ma) at a strain of 0.96+/-0.13 in the young group and 0.64+/-0.07 in the old group was achieved. L[max] in the old group was significantly lower than that of the young group (P<0.05). Active tension decreased after the maximum was reached in both groups. The pain threshold appeared approximately at a normalized volume of 0.88 in the young group and of 0.77 in the old group. In conclusion, aging resulted in increased passive stiffness of the human duodenum in vivo, whereas the muscle function was preserved. The pain threshold to a controlled mechanical load differed between the two groups, a finding that may be explained by resetting of the intestinal mechanoreceptors. The increased sensation to mechanical stimuli may explain why diseases characterized by pain related to the gut are prevalent in old age groups. [ABSTRACT FROM AUTHOR]

Objectives: The interaction between sleep and pain is important in patients suffering from rheumatic illness. Not only can pain disturb sleep, but alterations in the deeper sleep stages induced by the disease process may have the potential to decrease the pain threshold. Previous studies however, have shown diverging results. In the current experiment we studied the effects of deep sleep deprivation using a standardized, computer-assisted system on subjective symptoms and pain elicited by different experimental modalities. Methods: Ten healthy males, mean age 22.7 years, were subjected to deprivation of the deeper sleep stages for three nights. Following a baseline recording, sleep was analyzed in 2 s segments with on-line frequency analysis. If any 30 s epoch contained more than seven 2 s segments dominated by low frequency content corresponding to deep sleep, the sleep was disturbed by an acoustic stimulus. The amount of delta power was computed in sleep stages non-rapid-eye-movement [NREM]2-4. Subjects rated different questions regarding their feeling of pain, discomfort and psychological complaints twice a day during the experiment. Experimental pain was assessed with thermal [heat and cold pressor] and electrical stimuli as well as pressure pain thresholds in different areas of the body. Results: The first night of deep sleep deprivation resulted in a reduction in delta power to 39.3 and 10.5% of the baseline in stages NREM3 and 4, respectively [P = 0.005, P = 0.015]. In five subjects the delta power deprivation in stages NREM3 + 4 was 62.2% of baseline in the second deprivation night [P = 0.043]. No consistent changes however, were found for the subjective ratings or the experimental pain assessments following the first deprivation night. For the five subjects who were sufficiently deprived for deep sleep in two nights, the same findings as above were seen following both nights. Conclusion: Controlled delta power deprivation during sleep did not result in pain in healthy, young males. Although sleep disturbances may interact with pain and other daytime symptoms, we believe that other factors such as premorbid genetic constitution, age, sex, and several external factors are necessary before sleep disturbances per se are able to induce musculoskeletal symptoms. [ABSTRACT FROM AUTHOR]

Sleep complaints are frequent in patients with rheumatoid arthritis (RA) and sleep disturbances may contribute to pain and other daytime complaints. The aims of the current study were to compare ambulatory sleep recordings from consecutively selected patients with RA to those obtained in healthy controls, and to study the relationships between sleep structure and clinical symptoms. Sleep recordings were obtained from 41 out-patients with RA and 19 matched controls. All had clinical examinations and completed different questionnaires. Recordings were scored traditionally and, moreover, the electroencephalography (EEG) was subjected to frequency analysis. For the study of sleep-wake interactions in the patients, a graphical chain model was used. The patients had many sleep-related complaints. An increase in the number of periodic movements of the legs (PML) during sleep was seen in comparison with controls, but otherwise only minor differences were observed in classical sleep stages. Data from frequency analysis showed an increase in alpha (8-12 Hz)-EEG activity in sleep stages non-rapid eye movement (NREM) 2-4 in most sleep cycles. The statistical model demonstrated a complex but independent correlation between morning stiffness, pain and joint tenderness on the one hand, and awakenings, stage NREM2, slow-wave sleep and stage REM on the other, probably reflecting a relationship between sleep patterns and pain in RA. In conclusion, only the increase in PML and alpha-EEG activity distinguished the sleep in RA patients from that of healthy controls. However, the demonstrated interaction between daytime complaints and sleep patterns may increase the understanding and treatment of the disease. In future research, graphical chain models may improve our understanding of complex relationships between multiple variables. [ABSTRACT FROM PUBLISHER]

Background: Normal upper endoscopy may be a marker of ischemic heart disease in patients with unexplained chest/epigastric pain.Methods: We examined the 10-year risk of ischemic heart disease and mortality in a cohort of 386 Danish patients with chest/epigastric pain, normal upper endoscopy, and no prior hospital discharge diagnosis of ischemic heart disease (defined as patients with unexplained chest/epigastric pain), compared with 3,793 population controls matched by age, gender, and residence. Outcome data were obtained from population-based health registries. Cox regression analysis was used to estimate the relative risk of hospitalization for ischemic heart disease and the adjusted mortality rate ratio (MRR).Results: The 10-year relative risk of hospitalization for ischemic heart disease following a normal upper endoscopy among patients with unexplained chest/epigastric pain was 1.6 (95% CI, 1.1-2.2), compared with controls. The 10-year MRR was 1.1 (95% CI, 0.9-1.5). Within the first year after the upper endoscopy the MRR was 2.4 (95% CI, 1.3-4.5). The cause-specific MRR among patients with unexplained chest/epigastric pain compared with controls was up to threefold higher for deaths related to alcohol dependence, pneumonia, and lung cancer.Conclusion: Unexplained chest/epigastric pain in patients with normal endoscopy is a strong marker for ischemic heart disease and increased mortality. [ABSTRACT FROM AUTHOR]

Objectives: This scoping review aims to provide evidence synthesis of continuous glucose monitoring (CGM) and insulin pump use after undergone total pancreatectomy (TP) with or without islet autotransplantation (TPIAT)., Methods: The review was conducted adhering to PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) checklist., Results: Fifteen studies including 147 patients (adult n = 71/pediatric n = 76) reported on CGM use post-TP (n = 42) and TPIAT (n = 105). Four were randomized controlled trials and 10 observational studies. Six studies evaluated CGM use in the perioperative and 6 in the immediate postoperative period (n = 8) with variable follow-up (14 hours to 20 months). CGM was used as a stand-alone device (8 studies), which allowed assessment of glycemic variability (n=5) and detection of hypoglycemia (n = 1), resulting in lower glucose levels (n = 1). Six studies evaluated insulin pump with CGM with reduction in postoperative mean glucose (n = 4) and hypoglycemic episodes (n = 2). No patient-reported outcome measures (PROMs) or quality of life (QoL) measures were reported., Conclusions: CGM can be used following TP for glucose monitoring and/or linked with insulin pump device in the perioperative period with improved glycemic control. However, the data are limited by short follow-up and lack of PROMs and QoL measures., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Chronic pancreatitis (CP) is a fibroinflammatory disease, with pain as its most prominent symptom. This article provides a comprehensive review of the pathophysiology, assessment methodologies, and management strategies pertaining to pain in CP. Pathophysiological mechanisms include inflammatory and neuropathic components, including peripheral and central sensitization. Pain assessment can include unidimensional and multidimensional pain assessment scales, neurophysiological assessments, and advanced imaging techniques. Management strategies include a spectrum from lifestyle modifications, pharmacologic interventions, and interventional procedures to neuromodulatory techniques and other experimental treatments., Competing Interests: Disclosure None declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)