Effects of Peripherally Acting µ-opioid Receptor Antagonists on Acute Pancreatitis

Asbjørn Mohr Drewes105 enrolled

Overview

This study will investigate the effect of peripheral acting opioid antagonist (PAMORA) on the disease course of patients with acute inflammation of the pancreas (acute pancreatitis). The study will be conducted by treating hospitalized patients with acute pancreatitis with a PAMORA (methylnaltrexone).

In this study, the effects of peripheral acting µ-opioid receptor antagonists (PAMORA) on disease development and progression in patients with acute pancreatitis (AP) will be investigated. Patients with AP will be administered Methylnaltrexone (Relistor®) intravenously. This medication is defined as the investigational product. Relistor® is approved and sold on the Danish marked for treatment of opioid-induced constipation. This PAMORA have not previously been investigated in patients with pancreatitis. The dose regimes for this study will be according to label. It has previously been shown, in patients with opioid-induced obstipation and healthy subjects, that opioid antagonism incl. PAMORA treatment increases gut motility, relaxes gastrointestinal sphincters, increases the intestinal water content and improves the immune response, without affecting analgesia. The affinity of PAMORAs to the µ-opioid receptors is much stronger than opioid analgesics. Therefore, they as antagonists have the potential to counteract the harmful effects of opioids on the gut mucosa, bacterial translocation and inflammation despite the high levels of exogenous opioids present in patients with pancreatitis. PAMORAs do not cross the blood-brain barrier and consequently do not interfere with analgesia or other central effects of opioids. We hypothesize that treatment with the PAMORA methylnaltrexone will antagonize the harmful effects of opioids without reducing analgesia in patients with AP and hence reduce disease severity and improve clinical outcomes. If successful, this sub-study will for the first time document the effects of a targeted pharmacotherapy in AP with the potential benefit of improved patient outcomes.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

105

Conditions

Acute Pancreatitis

Interventions

Placebo treatmentDRUG

Active drug/placebo is given for the first 5 days of admission.

Methylnaltrexone treatmentDRUG

Active drug/placebo is given for the first 5 days of admission.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 85 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Signed informed consent before any study specific procedures * Able to read and understand Danish * Male or female age between 18 and 80 years * The researcher believes that the participant understands what the study entails, is capable of following instructions, can attend when needed, and is expected to complete the study * The investigator will ensure that fertile female participants have a negative pregnancy test before treatment initiation and use contraception during the study period. The following methods of contraception, if properly used, are generally considered reliable: oral contraceptives, patch contraceptives, injection contraceptives, vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation), vasectomized partner, double barrier (condom and pessary), or sexual abstinence. Methods of contraception will be documented in the source documents * At least two of the following criteria need to be fulfilled to establish a diagnosis of AP (according to the revised Atlanta criteria (16)): i) abdominal pain consistent with AP (acute onset of a persistent, severe, epigastric pain often radiating to the back); ii) serum amylase activity at least three times greater than the upper limit of normal; and iii) characteristic findings of AP on diagnostic imaging * Predicted moderate or severe AP based on 2 or more systemic inflammatory response syndrome criteria upon admission Exclusion Criteria: * Definitive chronic pancreatitis according to the M-ANNHEIM criteria * Known allergy towards study medication * Known or suspected major stenosis or perforation of the intestines * Known or suspected abdominal cancer (incl. intestine, pancreas and the biliary tree) * Pre-existing renal insufficiency (defined as habitual estimated glomerular filtration rate below 45) * Severe pre-existing comorbidities (assessed by investigator upon inclusion) * Severe non-pancreaticobiliary infections or sepsis caused by non-pancreaticobiliary disease * Child-Pugh class B or C liver cirrhosis * Females that are currently lactating

Locations (4)

Mech-Sense, Department of Medical Gastroenterology, Aalborg University Hospital

Aalborg, Jutland, Denmark

Digestive Disease Center K, Bispebjerg University Hospital

Bispebjerg, Denmark

Gastrounit, Hvidovre University Hospital

Hvidovre, Denmark

Odense Pancreas Center

Svendborg, Denmark

Outcomes

Primary Outcomes

Pancreatitis activity scoring system

Difference in Pancreatitis activity scoring system (PASS) score between the methylnaltrexone group and the placebo group. The PASS-score is a weighted score of presence of organ failure, number of criterias of Systemic Inflammatory Response Syndrome fulfilled, abdominal pain (0-10), morphine equivalent dose (mg) and tolerance to solid food. Minimum value is 0 and higher score is equal to higher disease activity. Documentation for the PASS can be found on the following link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519418/

Time frame: 48 hours after randomization

Secondary Outcomes

Pancreatitis activity scoring system

Difference PASS scores between subgroups

Time frame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit

Difference in assessments of circulating proinflammatory marker

C-Reactive Protein (mg/L)

Time frame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit

Difference in assessments of circulating pro- and anti-inflammatory markers

Interleukin-6, Interleukin-8, Interleukin-18, Tumor necrosis factor alpha, Cluster of Differentiation 163 (serum) (all measured in pg/mL)

Time frame: 24 hours after randomization and every 24 hours untill end of study at day 5 (after 120 hours) and again at the day 14 follow-up visit

Intestinal permeability

Difference in intestinal permeability between subgroups using the oral polyethylene glycol 400/4000 test

Time frame: From 48 to 72 hours after randomization

Intestinal motility

Data from ClinicalTrials.gov

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