Saloman, Jami L

INTRODUCTION: Chronic pancreatitis (CP) is a disease associated with chronic inflammation, fibrosis, and pain. There is a lack of tools available that facilitate early diagnosis, when intervention could prevent irreversible damage. Pilot data suggested prostaglandin E2 (PGE2) as a candidate biomarker for early CP. PGE2 activates signaling pathways that promote inflammation, pain, and fibrosis. METHODS: We assessed PGE2, metabolites, and downstream targets in pancreatic fluid collected endoscopically 0–10 (n = 110) and 10–20 (n = 111) minutes after intravenous secretin administration. PGE2 and metabolites were measured in plasma (n = 75) and urine (n = 71) from the same subjects. Subjects were enrolled in the PROCEED study and classified symptomatic controls, acute/recurrent acute pancreatitis (AP/RAP), or CP. RESULTS: A significant main effect was detected in 10–20 minutes pancreas fluid ( P = 0.027) and plasma ( P = 0.046); post hoc testing showed PGE2 was lower in the AP/RAP group compared with symptomatic controls. There was also trend toward lower PGE2 in urine ( P = 0.062). To elucidate the active downstream pathways, calcitonin gene-related peptide, substance P, and matrix metalloproteinases (MMPs) 1, 2, 3, 7, 9, and 13 were measured in pancreas fluid. A significant difference between the 3 groups was detected for both MMP7 and MMP9. MMP7 was elevated in individuals with CP vs AP/RAP ( P = 0.012) for samples collected early but both time points for MMP9 ( P = 0.027, P = 0.002). DISCUSSION: While PGE2 is detectable in pancreas fluid, these data suggest that it may not be sensitive enough to distinguish between AP/RAP and CP. However, MMPs may distinguish between stages of pancreatitis and require further testing as potential diagnostic biomarkers.

INTRODUCTION: Chronic pancreatitis (CP) remains difficult to manage with few treatment options. Prior studies have implicated prostaglandin E 2 (PGE 2 ) in mediating chronic inflammation in the pancreas. Therefore, we aimed to evaluate whether indomethacin, a cyclooxygenase-2 enzyme inhibitor, would reduce PGE 2 levels in CP. METHODS: In this pilot multicenter randomized controlled trial, participants with CP received oral indomethacin (50 mg) or placebo twice daily for 28 days. Measurement of PGE 2 levels in pancreatic fluid collected endoscopically after secretin administration at baseline and posttreatment (day 28) was performed. Quality of life and pain were also assessed at baseline and posttreatment. RESULTS: A total of 27 participants were randomized (indomethacin = 13, placebo = 14). Although PGE 2 levels decreased after treatment in pancreas fluid, plasma, and saliva in the indomethacin group, there was no significant difference in mean change in pancreas fluid PGE 2 levels between the indomethacin and placebo groups (−457.7 pg/mL vs −840.4 pg/mL, P = 0.25). There was also no significant change in pain severity composite score (−1.3 indomethacin vs −0.5 placebo, P = 0.33), but the improvement in pain interference score (−2.9 indomethacin vs −0.4, P = 0.058) trended toward significance. There was no difference in adverse events between the 2 groups. DISCUSSION: In this phase 1/2 study, oral indomethacin was safe and well tolerated by patients with CP. Although there was no significant difference in change in PGE 2 levels, further studies are needed to determine the effect of indomethacin on the inflammatory pathway of CP and patient-centered outcomes.

INTRODUCTION: Opioids are used to treat pain in chronic pancreatitis (CP), but little is known about current use patterns. The aim of this study was to characterize the utilization of opioids and associations with clinical characteristics in adult patients with CP. METHODS: This cross-sectional analysis used baseline data from participants with definite CP enrolled in a cohort study in the United States (PROspective Evaluation of CP for EpidEmiologic and Translational StuDies). Data on demographics, pain medication use, healthcare utilization, disability, and pain patterns were systematically collected in case report forms while quality of life was assessed with patient-reported outcome instruments. Opioid use was classified according to strength (weak or strong) and frequency (scheduled or as-needed). RESULTS: A total of 681 participants (n = 364, 53% male) were included: 299 (44%) were current opioid users (22% only weak opioids and 22% at least 1 strong opioid). Increasing frequency and severity of pain was associated with increase of weak, strong, as-needed, or scheduled opioids. Neuromodulators were used by ∼40% of participants; increasing use was associated with increasing frequency and severity of pain. On multivariate analysis, independent predictors associated with strength and frequency of current opioid use were pain patterns (odds ratios [ORs] 1.84–8.32 and ORs 1.92–8.52, respectively, P < 0.001) and prior celiac plexus block (OR 3.54, 95% confidence intervals 1.82–6.87 and OR 3.42, 95% confidence intervals 1.76–6.64, respectively). Participants using opioids had higher prevalence of disability, healthcare utilization, and poorer quality of life. DISCUSSION: Opioid use in CP is common and associated with increased pain severity and constancy. These data provide foundational estimates for future trials that can elucidate the complex interactions between patient factors, pain, and interventions.

Background and Aims: This investigation examined the association of pancreatitis and pancreatitis-related pain with serum levels of two endocannabinoid molecules such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and two paracannabinoid molecules such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Methods: A case–control study was conducted within the Prospective Evaluation of Chronic Pancreatitis for Epidemiological and Translational Studies, including participants with no pancreas disease ( N = 56), chronic abdominal pain of suspected pancreatic origin or indeterminate chronic pancreatitis (CP) ( N = 22), acute pancreatitis ( N = 33), recurrent acute pancreatitis ( N = 57), and definite CP ( N = 63). Results: Circulating AEA concentrations were higher in women than in men ( p = 0.0499), and PEA concentrations were higher in obese participants than those who were underweight/normal or overweight ( p = 0.003). Asymptomatic controls with no pancreatic disease had significantly ( p = 0.03) lower concentrations of AEA compared with all disease groups combined. The highest concentrations of AEA were observed in participants with acute pancreatitis, followed by those with recurrent acute pancreatitis, chronic abdominal pain/indeterminant CP, and definite CP. Participants with pancreatitis reporting abdominal pain in the past year had significantly ( p = 0.04) higher concentrations of AEA compared with asymptomatic controls. Levels of 2-AG were significantly lower ( p = 0.02) among participants reporting abdominal pain in the past week, and pain intensity was inversely associated with concentrations of 2-AG and OEA. Conclusions: Endocannabinoid levels may be associated with stage of pancreatitis, perhaps through activation of the CB1 receptor. Validation of our findings would support the investigation of novel therapeutics, including cannabinoid receptor-1 antagonists, in this patient population.

INTRODUCTION: Chronic Pancreatitis Prognosis Score (COPPS) was developed to discriminate disease severity and predict risk for future hospitalizations. In this cohort study, we evaluated if COPPS predicts the likelihood of hospitalization(s) in an American cohort. METHODS: The Chronic Pancreatitis, Diabetes, and Pancreatic Cancer consortium provided data and serum from subjects with chronic pancreatitis (N = 279). COPPS was calculated with baseline data and stratified by severity (low, moderate, and high). Primary endpoints included number and duration of hospitalizations during 12-month follow-up. RESULTS: The mean ± SD COPPS was 8.4 ± 1.6. COPPS correlated with all primary outcomes: hospitalizations for any reason (number: r = 0.15, P = 0.01; duration: r = 0.16, P = 0.01) and pancreas-related hospitalizations (number: r = 0.15, P = 0.02; duration: r = 0.13, P = 0.04). The severity distribution was 13.3% low, 66.0% moderate, and 20.8% high. 37.6% of subjects had ≥1 hospitalization(s) for any reason; 32.2% had ≥1 pancreas-related hospitalizations. All primary outcomes were significantly different between severity groups: hospitalizations for any reason (number, P = 0.004; duration, P = 0.007) and pancreas-related hospitalizations (number, P = 0.02; duration, P = 0.04). The prevalence of continued drinking at follow-up ( P = 0.04) was higher in the low and moderate groups. The prevalence of anxiety at enrollment ( P = 0.02) and follow-up ( P < 0.05) was higher in the moderate and high groups. DISCUSSION: Statistically, COPPS significantly correlated with hospitalization outcomes, but the correlations were weaker than in previous studies, which may be related to the outpatient nature of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies cohort and lower prevalence of high severity disease. Studies in other prospective cohorts are needed to understand the full utility of COPPS as a potential tool for clinical risk assessment and intervention.

Abstract Pain is common in chronic pancreatitis (CP) and profoundly reduces quality of life (QoL). Multiple underlying mechanisms contribute to a heterogenous pain experience and reduce efficacy of pain management. This study was designed to characterize the distribution of mechanism-based pain phenotypes in painful CP. The data analyzed were collected as part of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, an NCI/NIDDK-funded longitudinal study of the natural history of CP. The PROspective Evaluation of Chronic pancreatitis for EpidEmiologic and translational stuDies includes patient-reported outcome (PRO) measures of pain, medication use, global health, and QoL. Of subjects (N = 681) with CP, 80% experienced abdominal pain within the year before enrollment. Subjects who experienced pain in the week before enrollment (N = 391) completed PROMIS Neuropathic and Nociceptive Pain Quality instruments which were then used to classify them by pain type: 40% had nociceptive, 5% had neuropathic-like, and 32% had both types of pain. The prevalence of having both types of pain was higher among women and subjects with diabetes mellitus, whereas nociceptive-only pain was more prevalent among men and those with pancreatic duct stricture. Other factors, including pain medication use and healthcare utilization, did not differ between groups based on pain type. Subjects in the Both group had significantly worse health and QoL scores relative to those with nociceptive-only pain, suggesting that using psychosocial pain surveys may be useful for understanding pain subtypes in patients with CP. Additional research is needed to identify biochemical and biophysical signatures that may associate with and predict responses to mechanism-specific interventions.