Clinical Gastroenterology and Hepatology 2015;13:552–560

PANCREAS, BILIARY TRACT, AND LIVER Chronic Pancreatitis Pain Pattern and Severity Are Independent of Abdominal Imaging Findings C. Mel Wilcox,* Dhiraj Yadav,‡ Tian Ye,§ Timothy B. Gardner,k Andres Gelrud,¶ Bimaljit S. Sandhu,# Michele D. Lewis,** Samer Al-Kaade,‡‡ Gregory A. Cote,§§ Christopher E. Forsmark,kk Nalini M. Guda,¶¶ Darwin L. Conwell,## Peter A. Banks,## Thiruvengadam Muniraj,*** Joseph Romagnuolo,‡‡‡ Randall E. Brand,‡ Adam Slivka,‡ Stuart Sherman,§§ Stephen R. Wisniewski,§ David C. Whitcomb,‡ and Michelle A. Anderson§§§ *University of Alabama at Birmingham, Birmingham, Alabama; ‡University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; § Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania; kDartmouthHitchcock Medical Center, Lebanon, New Hampshire; ¶University of Chicago School of Medicine, Chicago, Illinois; #Virginia Commonwealth University School of Medicine, Richmond, Virginia; **Mayo Clinic, Jacksonville, Florida; ‡‡Saint Louis University School of Medicine, St. Louis, Missouri; §§Indiana University School of Medicine, Indianapolis, Indiana; kkUniversity of Florida College of Medicine, Gainesville, Florida; ¶¶University of Wisconsin School of Medicine, Milwaukee, Wisconsin; ##Brigham and Women’s Hospital, Boston, Massachusetts; ***Griffin Hospital, Derby, Connecticut; ‡‡‡Medical University of South Carolina, Charleston, South Carolina; §§§University of Michigan School of Medicine, Ann Arbor, Michigan This article has an accompanying continuing medical education activity on page e29. Learning Objective–Upon completion of this activity, successful learners will be able to understand the poor correlation between imaging studies and pain patterns in patients with chronic pancreatitis.

BACKGROUND & AIMS:

Chronic pancreatitis is characterized by inflammation, atrophy, fibrosis with progressive ductal changes, and functional changes that include variable exocrine and endocrine insufficiency and multiple patterns of pain. We investigated whether abdominal imaging features accurately predict patterns of pain.

METHODS:

We collected data from participants in the North American Pancreatitis Study 2 Continuation and Validation, a prospective multicenter study of patients with chronic pancreatitis performed at 13 expert centers in the United States from July 2008 through March 2012. Chronic pancreatitis was defined based on the detection of characteristic changes by cross-sectional abdominal imaging, endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, or histology analyses. Patients were asked by a physician or trained clinical research coordinator if they had any abdominal pain during the year before enrollment, those who responded “yes” were asked to select from a list of 5 pain patterns. By using these patterns, we classified patients’ pain based on timing and severity. Abnormal pancreatitis-associated features on abdominal imaging were recorded using standardized case report forms.

RESULTS:

Data were collected from 518 patients (mean age, 52 – 14.6 y; 55% male; and 87.6% white). The most common physician-identified etiologies were alcohol (45.8%) and idiopathic (24.3%); 15.6% of patients reported no abdominal pain in the year before enrollment. The most common individual pain pattern was described as constant mild pain with episodes of severe pain and was reported in 45% of patients. The most common imaging findings included pancreatic ductal dilatation (68%), atrophy (57%), and calcifications (55%). Imaging findings were categorized as obstructive for 20% and as inflammatory for 25% of cases. The distribution of individual imaging findings was similar among patients with different patterns of pain. The distribution of pain patterns did not differ among clinically relevant groups of imaging findings.

CONCLUSIONS:

Mechanisms that determine patterns and severity of pain in patients with chronic pancreatitis are largely independent of structural variants observed by abdominal imaging techniques. Pancreasrelevant quantitative and qualitative pain measures should be included in the evaluation of patients with chronic pancreatitis to assess pain severity independently of imaging findings.

Keywords: NAPS2-CV; Chronic Pancreatitis; Abdominal Pain; Abdominal Imaging.

Abbreviations used in this paper: ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; MRI, magnetic resonance imaging; NAPS2-CV, North American Pancreatitis Study 2: Continuation and Validation Study.

© 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.10.015

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bdominal pain remains one of the most distressing symptoms of chronic pancreatitis. The character of abdominal pain in these patients is highly variable, with some patients having severe daily pain whereas others have fleeting discomfort or are asymptomatic.1 The pathogenesis of abdominal pain in chronic pancreatitis is poorly understood, likely owing to multiple mechanisms, and variable mechanisms may be operative at different time points.2 Imaging studies are important to confirm the diagnosis as well as to assess disease severity and complications. Cross-sectional abdominal imaging remains the mainstay for evaluation of abdominal pain in chronic pancreatitis in anticipation of identifying structural abnormalities that can be treated with endoscopic or surgical approaches. In most patients, radiographic findings coupled with the patient’s complaints help dictate subsequent management. A number of prior studies using cross-sectional abdominal imaging, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasonography (EUS) have correlated ductal changes and morphologic abnormalities, suggesting a poor correlation between these changes and abdominal pain.3–9 However, these studies typically evaluated pain severity, rather than pain pattern, which correlates poorly with pancreatitisassociated quality of life and disability.1 By using data from a prospective study evaluating patients with chronic pancreatitis, which included details on pain patterns and imaging findings, we were able to assess the relationship between such radiographic abnormalities and the patient’s complaints.

A

Patients and Methods North American Pancreatitis Study 2: Continuation and Validation Study The North American Pancreatitis Study 2: Continuation and Validation Study (NAPS2-CV) is a multicenter study that prospectively enrolled patients with chronic pancreatitis from 13 US centers with specific interest in pancreatic disease from July 2008 to March 2012. The NAPS2-CV study is part of the NAPS2 Program, which has an overall goal to better understand the role of environmental and genetic factors in the susceptibility and progression of pancreatitis, and was developed to ascertain a genetic replication cohort for the NAPS2 cohort.10 The study was approved by the Institutional Review Boards of individual participating centers and all study subjects signed an informed consent form before enrollment. The current article focuses only on patients with chronic pancreatitis (n ¼ 521) enrolled in the NAPS2-CV study. Chronic pancreatitis was defined by the presence of characteristic changes on abdominal imaging studies (computerized tomography scan, magnetic resonance imaging [MRI]/magnetic resonance cholangiopancreatography, ERCP [Cambridge classification], or EUS

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[presence of 5 findings or presence of calcifications]) or histology. The number of patients fulfilling the entry criteria on one or more individual studies was as follows: computerized tomography scan (n ¼ 323), ERCP (n ¼ 176), MRI/magnetic resonance cholangiopancreatography (n ¼ 194), EUS (n ¼ 132), and histology (n ¼ 25).

Patient and Physician Questionnaires Information was collected from each patient and the enrolling physician using 2 sets of questionnaires. Patient questionnaires were administered by a physician or trained clinical research coordinator to collect detailed information on demographics, personal and family history, alcohol consumption, smoking, symptoms (including pain, see later), hospitalizations and emergency room visits, medication use, and quality of life (Short Form-12 v2). Physicians answered questions relating to disease phenotype (history of acute pancreatitis, age at first acute pancreatitis attack, history of recurrent acute pancreatitis and number of acute pancreatitis attacks patients, age at onset of symptoms and diagnosis of chronic pancreatitis, presence and pattern of pain [see later], exocrine and endocrine insufficiency presence, age of diagnosis, method of diagnosis, and treatment), imaging findings (see later), histology, toxicmetabolic; idiopathic; genetic; autoimmune; recurrent and severe acute pancreatitis; obstructive risk factors,11 etiology, treatments tried, and their perceived effectiveness.

Presence of Pain and Pain Patterns Patients were asked if they had any abdominal pain from chronic pancreatitis during the year before enrollment. Patients who responded “yes” to this question were asked to choose the pattern of pain that best described their pain experience from a list of 5 pain patterns (Table 1).1 Patient responses were used to determine the temporal nature (intermittent vs constant) and severity (mild-moderate vs severe) of their pain experience. Patients were asked to provide the frequency and duration of their pain attacks, to rate their pain experience (McGill pain questionnaire,12,13 patient reported outcome measurement information system pain impact), and to specify their use of pain medications. Physicians also were asked to provide their interpretation of the patient’s pain symptoms using the 5 categories of pain patterns, pain frequency and duration, and pain medication use. Because the focus of this article is the correlation of pain experience from the patient’s perspective with their findings on imaging studies, the case report form containing the physician’s interpretation of the patient’s pain experience was not used for analyses.

Imaging Studies and Classification of Findings The enrolling physician was asked to indicate the study that established the diagnosis (imaging study,

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Table 1. Definitions and Distribution of Pain Patterns, Temporal Nature, and Severity of Pain and Classification of Imaging Findings Into Hierarchical Categories in 518 Patients With Chronic Pancreatitis in the NAPS2-CV Study Pain patterna (n ¼ 81; 15.6%) A (n ¼ 67; 12.9%) B (n ¼ 23; 4.6%) C (n ¼ 98; 18.9%) D (n ¼ 229; 44.2%) E (n ¼ 19; 3.7%) Temporal nature of paina Intermittent (n ¼ 165; 31.9%) Constant (n ¼ 272; 52.5%) Pain severitya Mild-moderate (n ¼ 91; 17.6%) Severe (n ¼ 346; 66.8%) Imaging categoriesb Obstructive (n ¼ 103; 19.9%) Inflammation (n ¼ 130; 25.1%) Pseudocyst (n ¼ 52; 10.0%) All others (n ¼ 233; 45.0%)

Description No pain Usually pain free, but episodes of mild to moderate pain Constant mild to moderate pain Usually free of abdominal pain, but episodes of severe pain Constant mild to moderate pain plus episodes of severe pain Constant severe pain Pain pattern A or C Pain pattern B, D, or E Pain pattern A or B Pain pattern C, D, or E Presence of pancreatic duct obstruction/stricture irrespective of the presence of any additional imaging finding Presence of inflammation or inflammatory mass irrespective of the presence of any additional imaging finding Presence of pseudocyst(s) irrespective of the presence of any additional imaging finding All remaining patients

a

Based on patient description of pain experience in the year before study enrollment. Patients were assigned to an imaging category using a hierarchical model based on physician responses to the presence of individual imaging findings on the most recent studies. The categories were mutually exclusive. The hierarchical model starts with the obstructive category and assigns each subsequent category only to the remaining patients. A patient in a higher category can have findings from a subsequent category but not vice versa.

b

histology) and the finding used to diagnose chronic pancreatitis (eg, calcifications, atrophy, and so forth). Physicians provided information regarding the date and findings of the most recent imaging studies. In the initial half of the patient enrollment period, findings from individual studies were recorded; in the later half, the presence of individual findings on any of the most recent images was recorded. Data were collected for the following imaging findings: calcifications (yes/no, location, severity), pancreatic atrophy (yes/no, severity), pancreatic duct dilatation (yes/no, degree of dilatation), pancreatic duct stricture/obstruction (yes/no), pancreatic duct irregularities (yes/no, degree), side branch dilatation (yes/no), pancreatic/peripancreatic inflammatory changes (yes/no), pseudocyst (yes/no, number, size of largest pseudocyst), pancreatic mass (yes/no, location), common bile duct stricture (yes/no), common bile duct dilatation (yes/no), liver-related findings (findings for cirrhosis, portal hypertension, splenomegaly, splenic vein thrombosis, ascites, hepatomegaly, and so forth) (yes/no). The choice of treatment for pain in chronic pancreatitis may be determined by a combinations of findings on imaging studies. For example, a patient with pain who has a pancreatic duct stricture with or without pancreatic duct stones is a candidate for attempting endoscopic therapy with or without lithotripsy. We therefore used a hierarchical algorithm based on physician responses to individual imaging findings on the most recent imaging studies to create the following 4 categories of imaging

findings: (1) obstructive findings: the presence of pancreatic duct obstruction/stricture irrespective of the presence of any additional imaging finding; (2) inflammatory findings: the presence of inflammation or inflammatory mass irrespective of the presence of any additional imaging finding; (3) pseudocysts: the presence of pseudocyst(s) irrespective of the presence of any additional imaging finding; and (4) all other patients: all remaining patients were assigned to this category. Because pancreatic duct obstruction can be a mechanism for the development of pseudocysts, we also performed a sensitivity analysis by creating 3 categories (obstructive, inflammatory, others) in which the hierarchical model incorporated pseudocysts into the obstructive category.

Comparison Groups and Statistical Analyses Descriptive analyses are presented as proportions for categoric data and as mean  SD or median and interquartile range for continuous data as applicable. We evaluated the prevalence of individual imaging findings in all patients and within subgroups of pain patterns (no pain, pain subtype A–E), temporal nature of pain (intermittent, constant), and severity of pain (mildmoderate, severe), and within each of the imaging classification categories (obstructive, inflammation, pseudocyst, others). We then evaluated the distribution of pain patterns (no pain, pain subtype A–E), the temporal nature of the pain (intermittent, constant), and the severity of pain (mild-moderate, severe) within each of

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Table 2. Distribution of Individual Imaging Findings in Chronic Pancreatitis Patients in Imaging Categories Imaging category Individual imaging findings Calcification Calcificationa Atrophy Atrophya PD dilatation PD dilatationa PD stricture/obstruction PD stricture/obstructiona Pseudocyst Pseudocysta PD irregularity Inflammation Pancreatic mass Abnormal side branches CBD stricture CBD dilatation Liver-related findings

All patients (n ¼ 518) 276 286 281 297 317 350 103 142 137 167 266 176 30 213 61 92 64

(53.3) (55.2) (54.2) (57.3) (61.2) (67.6) (19.9) (27.4) (26.4) (32.2) (51.4) (34.0) (5.8) (41.1) (11.8) (17.8) (12.4)

Obstructive (n ¼ 103) 63 67 61 64 90 94 103 103 25 35 87 46 10 57 21 29 16

(61.2) (65.0) (59.2) (62.1) (87.4) (91.3) (100) (100) (24.3) (34.0) (84.5) (44.7) (9.7) (55.3) (20.4) (28.2) (15.5)

Inflammatory (n ¼ 130) 74 76 54 57 66 73 0 17 60 68 55 130 11 44 17 23 14

(56.9) (58.5) (41.5) (43.8) (50.8) (56.2) (0) (13.1) (46.2) (52.3) (42.3) (100) (8.5) (33.8) (13.1) (17.7) (10.8)

Pseudocysts (n ¼ 52) 25 26 35 36 37 41 0 4 52 52 29 0 0 26 6 9 10

(48.1) (50.0) (67.3) (69.2) (71.2) (78.8) (0) (7.7) (100) (100) (55.8) (0) (0) (50.0) (11.5) (17.3) (19.2)

Others (n ¼ 233) 114 117 131 140 124 142 0 18 0 12 95 0 9 86 17 31 24

(48.9) (50.2) (56.2) (60.1) (53.2) (60.9) (0) (7.7) (0) (5.2) (40.8) (0) (3.9) (36.9) (7.3) (13.3) (10.3)

P value .134 .057 .004 .002

Chronic pancreatitis pain pattern and severity are independent of abdominal imaging findings.

Chronic pancreatitis is characterized by inflammation, atrophy, fibrosis with progressive ductal changes, and functional changes that include variable...
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