Interventions for Pancreatitis-New Approaches, Knowledge Gaps, and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop

Abstract

There exists no cure for acute, recurrent acute or chronic pancreatitis and treatments to date have been focused on managing symptoms. A recent workshop held by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) focused on interventions that might disrupt or perhaps even reverse the natural course of this heterogenous disease, aiming to identify knowledge gaps and research opportunities that might inform future funding initiatives for NIDDK. The breadth and variety of identified active or planned clinical trials traverses the spectrum of the disease and was conceptually grouped for the workshop into behavioral, nutritional, pharmacologic and biologic, and mechanical interventions. Cognitive and other behavioral therapies are proven interventions for pain and addiction, but barriers exist to their use. Whilst a disease specific instrument quantifying pain is now validated, an equivalent is lacking for nutrition - and both face challenges in ease and frequency of administration. Multiple pharmacologic agents hold promise. Ongoing development of Patient Reported Outcome (PRO) measurements can satisfy Investigative New Drug (IND) regulatory assessments. Despite multiple randomized clinical trials demonstrating benefit, great uncertainty remains regarding patient selection, timing of intervention, and type of mechanical intervention (endoscopic versus surgery). Challenges and opportunities to establish beneficial interventions for patients were identified.

Figure 1:. Cycle of Addiction.

Stages of the Addiction Cycle. During intoxication, drug-induced activation of the brain’s reward regions (blue) is enhanced by conditioned cues in areas of increased sensitization (green). During withdrawal, the activation of brain regions involved in emotions (pink) results in negative mood and enhanced sensitivity to stress. During preoccupation, the decreased function of the prefrontal cortex leads to an inability to balance the strong desire for the drug with the will to abstain, which triggers relapse and reinitiates the cycle of addiction. The compromised neuro-circuitry reflects the disruption of the dopamine and glutamate systems and the stress-control systems of the brain, which are affected by corticotropin-releasing factor and dynorphin. The behaviors during the three stages of addiction change as a person transitions from drug experimentation to addiction as a function of the progressive neuroadaptations that occur in the brain. (Adapted From) and reproduced with permission NEJM 2016 Jan 28;374(4):363-71. doi: 10.1056/NEJMra1511480.

Figure 2.. Preservation of islets following acetic acid-induced pancreatectomy

Morphological and histological changes in mouse pancreas specimens following chemical pancreatectomy. (A) After AcA infusion, gross morphology of the pancreas was abnormally white and edematous at 2 days, translucent with visible islets (arrow) at 2 weeks, and replaced by fatty tissue with visible islets (arrow) at 8 weeks. (B and C) Normal pancreas histology is seen at 2 days after saline infusion (B). Two days after AcA infusion, exocrine tissue necrosis (asterisks) is seen with intact islets (i). Magnification (inset) of the apparently preserved acinar cells revealed cell swelling and cytoplasmic vacuolization (arrows) (C). (D) Histology of the pancreas after AcA infusion. Intact islets are denoted by i. Arrows denote fat cells at 4 weeks. (E) Immunostaining after AcA infusion showed negative amylase staining (arrows denote amylase remnants at 2 days), with normal insulin and glucagon staining. Illustrative histology results from 5 animals per time point are shown. Scale bars: 200 μm. Reproduced (adapted) with permission J Clin Invest. 2021 Feb 1; 131(3): e143301. Published online 2021 Feb 1. doi: 10.1172/JCI143301