Unraveling the Mysteries of Pain in Chronic Pancreatitis

Anna Evans Phillips, MD, MS, is a clinician-researcher in the Division of Gastroenterology, Hepatology and Nutrition. Dr. Phillips attended the University of Pittsburgh School of Medicine after graduating from Harvard University. Her medical training included a residency at Yale New Haven Hospital, followed by gastroenterology training at New York Presbyterian/Columbia Hospital and the University of Pittsburgh School of Medicine. She is currently completing a medical pancreatology fellowship at the University of Pittsburgh School of Medicine under the mentorship of Dhiraj Yadav, MD, MPH, and David C. Whitcomb MD, PhD. In 2018, Dr. Phillips received an American Pancreatic Association Young Investigator Career Development Award to continue her explorations of the nature and role of pain in chronic pancreatitis.

In addition to the study of pain in chronic pancreatitis, Dr. Phillips’ research interests include understanding the underlying mech - anisms in acute and chronic pancre atitis, fatty acid and lipotoxicity in severe acute pancreatitis, and nutrition and nutritional support in patients with pancreatitis.

Origins of Pain in Chronic Pancreatitis

Chronic pancreatitis (CP) is often the result of repeated episodes of acute pancreatitis (AP). Some patients experience recurrent episodes of acute pancreatitis that even-tually result in a scarred, fibrotic pancreas. These patients develop diabetes from an inability to make enough insulin and may have difficulty absorbing nutrients since their pancreas can no longer supply adequate digestive juices. Furthermore, they may have pain from damage to their pancreatic nerves, and if the pain has gone on extensively, then they may have remodeling of peripheral nerves that results in more systemic symptoms.

“Abdominal pain affects more than 90 percent of chronic pancreatitis patients.  Chronic, daily pain significantly impacts patients’ quality-of-life and functioning, as was seen in the North American Pancreatitis Study 2 (NAPS2) led by the University of Pittsburgh,” says Dr. Phillips.

One of Dr. Phillips’ ongoing research investigations seeks to create a protocol that will phenotype patients with chronic pain from chronic pancreatitis. “The underlying purpose of this research is to identify specific patterns of pain that may predict the potential for responses to available therapy.”

In the current understanding of CP, scarring to the organ often occurs early in the central, or main, pancreatic duct. It is theorized that this leads to an elevated level of pressure — either from the scarring or blockage or, perhaps, from the formation of calcified stones that cause a blockage.

“Current invasive therapy often involves endotherapy, where we insert a stent in the pancreatic duct to alleviate a blockage or stricture, or we try and remove stones from the pancreatic duct to relieve resultant elevated pressures. Invasive surgical therapies are targeted to remove diseased portions of the gland, or in extreme cases the whole gland. In some cases, neither endotherapy nor surgery is appropriate, and we focus efforts on using medications to dull or decrease the neural response to stimulation from the pancreatic nerves. We currently rely on extensive clinical expertise to make the decision about which therapy to recommend. We do not know, however, which patients will respond to therapy.

It would greatly strengthen our decision-making to have a tool that would allow us to predict how likely a patient is to experience pain reduction as part of their response. This would allow us to forego unnecessary or high-risk procedures for those patients in favor of conservative measures that could have a more long-lasting impact,” says Dr. Phillips.

Of particular interest in CP is the under-standing that a patient’s pain does not correlate with imaging findings of disease. This finding was part of the NAPS2 cohort study and was published several years ago by colleagues from the Division.

“Similar studies have confirmed these original findings. For example, some patients who have evidence of parenchymal calcifications, dilated ducts, or large pan creatic duct stones on CT or MRI may have no pain; in the opposite manner, someone else could experience chronic daily debilitating pain and have a pancreas that looks very mildly affected. Pain does not correlate with disease activity, at least related to the physical appearance of the pancreas on cross-sectional imaging.

This tells us, frankly, that pain associated with CP is a highly complex and hetero-geneous process,” says Dr. Phillips.

Quantitative Sensory Testing (QST) and Patient Phenotyping

Previous animal model studies have shown that patients with chronic pain undergo remodeling of their central nervous system, which can change their perception of pain over time. This process may alter patients’ sensitivity to pain on a systemic level. Early work in CP has suggested that this phenomenon may similarly be present in these patients.

To study this phenomenon and to pheno-type patients, Dr. Phillips is using a process called quantitative sensory testing (QST). Researchers at the Aalborg University in Denmark have pioneered the methodology, and Dr. Phillips is collaborating with this institution as she investigates a modified QST protocol for patient testing.

“Our colleagues in Denmark created a simplified QST protocol based on their past work, which is what we are currently using for testing in our subjects. The QST protocol captures a series of surface stimulations on the body from which we elicit a measured response. Subjective and objective measures are collected. We hypothesize that pain phenotypes identified by QST will correlate with specific patient and disease-related characteristics,” says Dr. Phillips.

The basic idea behind QST is that it can map a pain system in the body. The neural pathways can be explored using a standardized stimulation followed by recording the patient’s response. QST has been shown to be able to differentiate pancreatic sensitization from a more central pain sensitization. Dr. Phillips’ research, if successful, may allow for patients to be phenotyped based on QST findings to allow clinicians to better understand and treat pain syndromes occurring in cases of CP, and it may also allow for the prediction of response or pain resolution from endoscopic or surgical interventions.

Burnout Theory and CP

Another aspect of Dr. Phillips’ investigations into pain in CP deals with the phenomenon known as burnout theory. Approximately 15 percent of chronic pancreatitis patients experience a peak in their pancreatitis-related pain at some point relatively early in their disease course. These individuals then enter a stage where they no longer have pain from their chronic pancreatitis.

“The theory is that chronic inflammation has burned out the neural response in the pancreas. Burnout theory affects a minority of patients. However, it will be intriguing to compare those patients to patients who have a similar clinical history but still experience severe pain,” says Dr. Phillips.

References and Further Reading

Past research by Dr. Phillips has examined a number of aspects of pancreatitis in various settings. Below is a sample of published papers for further reading.

Phillips AE, Shah N, Borhani A, Yadav D, Brand R. Prior History of Pancreatitis Accelerates the Development of Pancreatic Adenocarcinoma.  Pancreas. 2018; 47(10): 1262-1266.

Phillips AE, Shah N, Borhani A, Yadav D, Brand R. Known Genetic Susceptibility Factors for Chronic Pancreatitis in Patients of European Ancestry Are Rare in Patients of African Ancestry.  Pancreatology. 2018; May 19, doi: 10.1016/j. pan.2018.05.482.

Bishu S, Koutroumpakis E, Mounzer R, Stello K, Pollock N, Evans A, Whitcomb DC, Papachristou GI. The -251A/T Polymorphism in the IL8 Promoter Is a Risk Factor for Acute Pancreatitis.  Pancreas. 2018 Jan; 47(1): 87-91.

Ooka K, Rustagi T, Evans A, Farrell JJ. Surveillance and Outcomes of Non-Resected Presumed Branch-Duct Intraductal Papillary Mucinous Neoplasms: A Meta-Analysis. Pancreas. 2017 Aug; 46(7): 927-935.

Seaman JB, Evans AC, Sciulli AM, Barnato AE, Sereika SM, Happ MB. Abstracting ICU Nursing Care Quality Data From the Electronic Health Record. West J Nursing Res. 2017 Sep; 39(9): 1271-1288.

Mounzer R, Langmead CJ, Wu BU, Evans AC, Bishehsari F, Muddana V, Singh VK, Slivka A, Whitcomb DC, Yadav D, Banks PA, Papachristou GI. Comparison of Existing Clinical Scoring Systems to Predict Persistent Organ Failure in Patients With Acute Pancreatitis. Gastroenterology. 2012 Jun; 142(7): 1476-82.

Bishehsari F, Sharma A, Stello K, Toth C, O’Connell MR, Evans AC, LaRusch J, Muddana V, Papachristou GI, Whitcomb DC. TNF-Alpha Gene (TNFA) Variants Increase Risk for Multi-Organ Dysfunction Syndrome (MODS) in Acute Pancreatitis. Pancreatology. 2012 Mar-Apr; 12(2): 113-8.

Whitcomb DC, Muddana V, Langmead CJ, Houghton FD Jr, Guenther A, Eagon PK, Mayerle J, Aghdassi AA, Weiss FU, Evans A, Lamb J, Clermont G, Lerch MM, Papachristou GI.   Angiopoietin-2, a Regulator of Vascular Permeability in Inflammation, Is Associated With Persistent Organ Failure in Patients With Acute Pancreatitis From the United States and Germany. Am J Gastroenterology. 2010 Oct; 105(10): 2287-92.

Evans AC, Papachristou GI, Whitcomb DC. Obesity and the Risk of Severe Acute Pancreatitis. Minerva Gastroenterologica e Dietologica. 2010; 56(2): 169-79.