No Effect of Methylnaltrexone on Acute Pancreatitis Severity: A Multicenter Randomized Controlled Trial.

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.

Opioid analgesia and severity of acute pancreatitis: An international multicentre cohort study on pain management in acute pancreatitis.

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.

Spinal Excitability in Patients with Painful Chronic Pancreatitis.

Purpose: 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.

Effects of a peripherally acting µ-opioid receptor antagonist for the prevention of recurrent acute pancreatitis: study protocol for an investigator-initiated, randomized, placebo-controlled, double-blind clinical trial (PAMORA-RAP trial).

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.

Opioids in the Treatment of Chronic Idiopathic Diarrhea in Humans-A Systematic Review and Treatment Guideline.

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.

Effects of opium tincture on the enteric and central nervous systems: A randomized controlled trial.

Opioids change gut motility, and opium tincture has been used for treatment of chronic diarrhoea for centuries. However, the effects have never been documented in controlled trials. We aimed to investigate the effects of opium tincture on gastrointestinal transit and motility, frequency of bowel movements, stool consistency, gastrointestinal symptoms and sedation. Twenty healthy subjects were included in this randomized controlled trial. Opium tincture or placebo was each applied for 9 days. Gastrointestinal transit and motility were investigated with the 3D-transit system. Bowel movements and gastrointestinal symptoms were recorded daily. General cognition, reaction time, memory and electroencephalography were used to assess effects on the central nervous system. Opium tincture doubled colonic transit (49 vs. 23 h, p < 0.001), decreased antegrade colonic movements (p < 0.05), reduced daily bowel movements (0.7 vs. 1.2, p < 0.001) and increased stool consistency (Type 3 vs. Type 4, p < 0.001). No changes in general cognition, reaction time or memory were observed, and minor changes of power observed by electroencephalography did not indicate sedation. This study is the first to show that opium tincture has anti-propulsive properties in the healthy gut, while no sedative effects were seen. This indicates that opium tincture is a relevant and safe treatment option in chronic diarrhoea.

Effects of the peripherally acting µ-opioid receptor antagonist methylnaltrexone on acute pancreatitis severity: study protocol for a multicentre double-blind randomised placebo-controlled interventional trial, the PAMORA-AP trial.

BACKGROUND: Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting µ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP. METHODS: PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer's lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method. DISCUSSION: This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04743570 . Registered on 28 January 2021. EudraCT 2020-002313-18.

Psychosocial factors associated with bulimia nervosa during pregnancy: An internal validation study.

OBJECTIVE: The aim of this paper was to internally validate previously reported relations (Knoph Berg et al., Aust N Z J Psychiatry, 42, 396-404, 2008) between psychosocial factors and bulimia nervosa (BN) outcomes during pregnancy. METHOD: This study is based on the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. Participants were women enrolled during pregnancy (N = 69,030). Internal validity was evaluated by way of bootstrapped parameter estimates using the overall sample and a split sample calibration approach. RESULTS: Bootstrap bias estimates were below the problematic threshold, and extend earlier findings (Knoph Berg et al., Aust N Z J Psychiatry, 42, 396-404, 2008) by providing support for the validity of the models at the population level of all pregnant women in Norway. Bootstrap risk ratios indicated that prevalence, incidence, and remission of BN during pregnancy were significantly associated with psychosocial factors. The split sample procedure showed that the models developed on the training sample did not predict risks in the validation sample. DISCUSSION: This study characterizes associations between psychosocial exposures and BN outcomes among pregnant women in Norway. Women with lifetime and current self-reported psychosocial adversities were at a much higher risk for BN during pregnancy. Psychosocial factors were associated with BN remission during pregnancy, inviting the prospect of enhancing therapeutic interventions. We consider the findings in the context of reproducibility in science.

The influence of women's preferences and actual mode of delivery on post-traumatic stress symptoms following childbirth: a population-based, longitudinal study.

BACKGROUND: This study aimed to examine whether a mismatch between a woman's preferred and actual mode of delivery increases the risk of post-traumatic stress symptoms after childbirth. METHODS: The study sample consisted of 1,700 women scheduled to give birth between 2009 and 2010 at Akershus University Hospital, Norway. Questionnaire data from pregnancy weeks 17 and 32 and from 8 weeks postpartum were used along with data obtained from hospital birth records. Post-traumatic stress symptoms were measured with the Impact of Event Scale. Based on the women's preferred and actual mode of delivery, four groups were established: Match 1 (no preference for cesarean section, no elective cesarean section, N = 1,493); Match 2 (preference for cesarean section, elective cesarean section, N = 53); Mismatch 1 (no preference for cesarean section, elective cesarean section, N = 42); and Mismatch 2 (preference for cesarean section, no elective cesarean section, N = 112). Analysis of variance (ANOVA) and analysis of covariance (ANCOVA) were conducted to examine whether the level of post-traumatic stress symptoms differed significantly among these four groups. RESULTS: Examining differences for all four groups, ANOVA yielded significant overall group differences (F = 11.96, p < 0.001). However, Bonferroni post-hoc tests found significantly higher levels of post-traumatic stress symptoms only in Mismatch 2 compared to Match 1. This difference could be partly explained by a number of risk factors, particularly psychological risk factors such as fear of childbirth, depression, and anxiety. CONCLUSIONS: The results suggest increased post-traumatic stress symptoms in women who preferred delivery by cesarean section but delivered vaginally compared to women who both preferred vaginal delivery and delivered vaginally. In psychologically vulnerable women, such mismatch may threaten their physical integrity and, in turn, result in post-traumatic stress symptoms. These women, who often fear childbirth, may prefer a cesarean section even though vaginal delivery is usually the best option in the absence of medical indications. To avoid potential trauma, fear of childbirth and maternal requests for a cesarean section should be taken seriously and responded to adequately.

The role of labor pain and overall birth experience in the development of posttraumatic stress symptoms: a longitudinal cohort study.

BACKGROUND: The aim of this prospective study was to investigate the role of labor pain and overall birth experience in the development of posttraumatic stress symptoms in a comprehensive framework. METHODS: The study sample (N = 1893) comprised women with a vaginal delivery and was drawn from the Akershus Birth Cohort, which targeted all women scheduled to give birth at Akershus University Hospital in Norway. Questionnaires were given at three different stages: from pregnancy weeks 17 to 32, from the maternity ward, and from 8 weeks postpartum. Data were also obtained from the hospital's birth record. Using structural equation modeling, a prospective mediation model was tested. RESULTS: Posttraumatic stress symptoms were significantly related to both labor pain (r = 0.23) and overall birth experience (r = 0.39). A substantial portion (33%) of the effect of labor pain on posttraumatic stress symptoms was mediated by the overall birth experience. CONCLUSIONS: Although the results of this study showed that both labor pain and overall birth experience played a role in the development of posttraumatic stress symptoms after childbirth, overall birth experience appeared to be the central factor. The women's birth experience was not only related to posttraumatic stress symptoms directly but also mediated a substantial portion of the effect of labor pain on posttraumatic stress symptoms. Future work should address which areas of birth experience confer protective effects on women to improve clinical care.

Eating Disorders, Pregnancy, and the Postpartum Period: Findings from the Norwegian Mother and Child Cohort Study (MoBa).

This review summarizes studies on eating disorders in pregnancy and the postpartum period that have been conducted as part of the broader Norwegian Mother and Child Cohort Study (MoBa). Prior to the 2000s, empirical literature on eating disorders in pregnancy was sparse and consisted mostly of studies in small clinical samples. MoBa has contributed to a new era of research by making population-based and large-sample research possible. To date, MoBa has led to 19 studies on diverse questions including the prevalence, course, and risk correlates of eating disorders during pregnancy and the postpartum. The associations between eating disorder exposure and pregnancy, birth and obstetric outcomes, and maternal and offspring health and well-being, have also been areas of focus. The findings indicate that eating disorders in pregnancy are relatively common and appear to confer health risks to mother and her child related to sleep, birth outcomes, maternal nutrition, and child feeding and eating.

Course and predictors of maternal eating disorders in the postpartum period.

OBJECTIVE: To investigate course and predictors of eating disorders in the postpartum period. METHOD: A total of 77,807 women, participating in the Norwegian Mother and Child Cohort Study (MoBa), completed questionnaires during pregnancy including items covering DSM-IV criteria for prepregnancy anorexia nervosa (AN), bulimia nervosa (BN), eating disorder not otherwise specified (EDNOS-P), and binge eating disorder (BED). Additional questionnaires were completed at 18 and 36 months postpartum. RESULTS: Proportions of women remitting at 18 months and 36 months postpartum were 50% and 59% for AN, 39% and 30% for BN, 46% and 57% for EDNOS-P, and 45% and 42% for BED, respectively. However, disordered eating persisted in a substantial proportion of women meeting criteria for either full or subthreshold eating disorders. BN during pregnancy increased the risk for continuation of BN. BMI and psychological distress were significantly associated with course of BED. DISCUSSION: This is the first large-scale population-based study on course of eating disorders in the postpartum period. The results indicated that disordered eating persists in a substantial proportion of women with prepregnancy eating disorders. Health care professionals working with women in this phase of life need to pay specific attention to eating disorder symptoms and behaviors.