Browsing by Author "Guda, Nalini M."

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    Constant-Severe Pain in Chronic Pancreatitis is Associated with Genetic Loci for Major Depression in the NAPS2 Cohort
    (Springer, 2020) Dunbar, Ellyn; Greer, Phil J.; Melhem, Nadine; Alkaade, Samer; Amann, Stephen T.; Brand, Randall; Coté, Gregory A.; Forsmark, Christopher E.; Gardner, Timothy B.; Gelrud, Andres; Guda, Nalini M.; LaRusch, Jessica; Lewis, Michele D.; Machicado, Jorge D.; Muniraj, Thiruvengadam; Papachristou, Georgios I.; Romagnuolo, Joseph; Sandhu, Bimaljit S.; Sherman, Stuart; Wilcox, Charles M.; Singh, Vikesh K.; Yadav, Dhiraj; Whitcomb, David C.; NAPS2 study group; Medicine, School of Medicine
    Background: Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constant-severe pain experience in RAP/CP patients. Study: A retrospective study was done using North American Pancreatitis Study II (NAPS2) genotyped RAP and CP patients with completed case report forms (n = 1,357). Subjects were divided based on pattern of pain and pain severity as constant-severe pain (n = 787) versus not constant-severe pain (n = 570) to conduct a nested genome-wide association study. The association between reported antidepressant medication use and depression gene loci was tested. Results: Constant-severe pain was reported in 58% (n = 787) of pancreatitis patients. No differences in sex or alcohol consumption were found based on pain severity. Antidepressant use was reported in 28% (n = 223), and they had lower SF-12 mental quality of life (MCS, p < 2.2 × 10- 16). Fifteen loci associated with constant-severe pain (p < 0.00001) were found to be in or near depression-associated genes including ROBO2, CTNND2, SGCZ, CNTN5 and BAIAP2. Three of these genes respond to antidepressant use (SGCZ, ROBO2, and CTNND2). Conclusion: Depression is a major co-factor in the pain experience. This genetic predisposition to depression may have utility in counseling patients and in instituting early antidepressant therapy for pain management of pancreatitis patients. Prospective randomized trials are warranted.
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    Pain Experience in Pancreatitis: Strong Association of Genetic Risk Loci for Anxiety and PTSD in Patients With Severe, Constant, and Constant-Severe Pain
    (Wolters Kluwer, 2021) Dunbar, Ellyn K.; Greer, Phil J.; Amann, Stephen T.; Alkaade, Samer; Banks, Peter; Brand, Randall; Conwell, Darwin L.; Forsmark, Christopher E.; Gardner, Timothy B.; Guda, Nalini M.; Lewis, Michele D.; Machicado, Jorge D.; Muniraj, Thiruvengadam; Papachristou, Georgios I.; Romagnuolo, Joseph; Sandhu, Bimaljit S.; Sherman, Stuart; Slivka, Adam; Wilcox, C. Mel; Yadav, Dhiraj; Whitcomb, David C.; NAPS2 Consortium; Medicine, School of Medicine
    Introduction: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects. Methods: The study cohort included phenotyped and genotyped RAP and CP patients from the North American Pancreatitis Study II of European Ancestry. Candidate genetic association studies were based on the absence of pain vs pain that is constant, constant-severe, or severe. Twenty-eight candidate genetic loci for anxiety and PTSD risk were identified in the literature and were the focus of this study. Results: We identified 24 significant pain-associated single nucleotide polymorphisms within 13 loci across the 3 pain patterns in CP and RAP + CP (P < 0.002). Thirteen anxiety or PTSD genes were within these pain loci indicating nonrandom associations (P < 4.885 × 10-23). CTNND2 was associated with all pain categories and all pancreatitis etiologies. Implicated systems include neuronal signaling (HTR2A, DRD3, NPY, and BDNF), hypothalamic-pituitary-adrenal axis (NR3C1 and FKBP5), and cell-cell interaction (CTNND2 and THBS2). Discussion: A component of constant and severe pain in patients with RAP and CP is associated with genetic predisposition to anxiety and PTSD. Identification of patients at risk eligible for trials of targeted treatment as a component of a multidisciplinary pain management strategy should be formally evaluated.
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    Rectal Indomethacin Dose Escalation (RIDE) for Prevention of Post-ERCP Pancreatitis in High-Risk Patients: a Randomized Trial
    (Elsevier, 2020-02) Fogel, Evan L.; Lehman, Glen A.; Tarnasky, Paul; Cote, Gregory A.; Schmidt, Suzette E.; Waljee, Akbar K.; Higgins, Peter D. R.; Watkins, James L.; Sherman, Stuart; Kwon, Richard S. Y.; Elta, Grace H.; Easler, Jeffrey J.; Pleskow, Douglas K.; Scheiman, James M.; El Hajj, Ihab I.; Guda, Nalini M.; Gromski, Mark A.; McHenry, Lee, Jr.; Arol, Seena; Korsnes, Sheryl; Suarez, Alejandro L.; Spitzer, Rebecca; Miller, Marilyn; Hofbauer, Maria; Elmunzer, Badih Joseph; Medicine, School of Medicine
    Background Although rectal indometacin 100 mg is effective in reducing the frequency and severity of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients, the optimal dose is unknown, and pancreatitis incidence remains high. The aim of this study was to compare the efficacy of two dose regimens of rectal indometacin on the frequency and severity of pancreatitis after ERCP in high-risk patients. Methods In this randomised, double-blind, comparative effectiveness trial, we enrolled patients from six tertiary medical centres in the USA. Eligible patients were those at high risk for the development of pancreatitis after ERCP. We randomly assigned eligible patients (1:1) immediately after ERCP to receive either two 50 mg indometacin suppositories and a placebo suppository (standard-dose group) or three 50 mg indometacin suppositories (high-dose group). 4 h after the procedure, patients assigned to the high-dose group received an additional 50 mg indometacin suppository, whereas patients in the standard-dose group received an additional placebo suppository. The randomisation schedule, stratified according to study centre and with no other restrictions, was computer generated by an investigator who was uninvolved in the clinical care of any participants, distributed to the sites, and kept by personnel not directly involved with the study. These same personnel were responsible for packaging the drug and placebo in opaque envelopes. Patients, study personnel, and treating physicians were masked to study group assignment. The primary outcome of the study was the development of pancreatitis after ERCP. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01912716, and enrolment is complete. Findings Between July 9, 2013, and March 22, 2018, 1037 eligible patients were enrolled and randomly assigned to receive either standard-dose (n=515) or high-dose indometacin (n=522). Pancreatitis after ERCP occurred in 141 (14%) of 1037 patients—76 (15%) of 515 patients in the standard-dose indometacin group and 65 (12%) of 522 patients in the high-dose indometacin group (risk ratio [RR] 1·19, 95% CI 0·87–1·61; p=0·32). We observed 19 adverse events that were potentially attributable to study drug. Clinically significant bleeding occurred in 14 (1%) of 1037 patients—six (1%) of 515 patients in the standard-dose indometacin group and eight (2%) of 522 patients in the high-dose indometacin group (p=0·79). Three (1%) of 522 patients in the high-dose indometacin group developed acute kidney injury versus none in the standard-dose group (p=0·25). A non-ST elevation myocardial infarction occurred in the standard-dose indometacin group 2 days after ERCP. A transient ischaemic attack occurred in the high-dose indometacin group 5 days after ERCP. All 19 adverse events, in addition to the 141 patients who developed pancreatitis after ERCP, were considered serious as all required admission to hospital. We observed no allergic reactions or deaths at 30 day follow-up. Interpretation Dose escalation to rectal indometacin 200 mg did not confer any advantage compared with the standard 100 mg regimen, with pancreatitis incidence remaining high in high-risk patients. Current practice should continue unchanged. Further research should consider the pharmacokinetics of non-steroidal anti-inflammatory drugs to determine the optimal timing of their administration to prevent pancreatitis after ERCP.
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    Rectal Indomethacin Dose Escalation (RIDE) for Prevention of Post-ERCP Pancreatitis in High-Risk Patients: a Randomized Trial
    (Elsevier, 2020) Fogel, Evan L.; Lehman, Glen A.; Tarnasky, Paul; Cote, Gregory A.; Schmidt, Suzette E.; Waljee, Akbar K.; Higgins, Peter D. R.; Watkins, James L.; Sherman, Stuart; Kwon, Richard S. Y.; Elta, Grace H.; Easler, Jeffrey J.; Pleskow, Douglas K.; Scheiman, James M.; El Hajj, Ihab I.; Guda, Nalini M.; Gromski, Mark A.; McHenry, Lee, Jr.; Arol, Seena; Korsnes, Sheryl; Suarez, Alejandro L.; Spitzer, Rebecca; Miller, Marilyn; Hofbauer, Maria; Elmunzer, B. Joseph; US Cooperative for Outcomes Research in Endoscopy (USCORE); Medicine, School of Medicine
    Background: Although rectal indometacin 100 mg is effective in reducing the frequency and severity of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients, the optimal dose is unknown, and pancreatitis incidence remains high. The aim of this study was to compare the efficacy of two dose regimens of rectal indometacin on the frequency and severity of pancreatitis after ERCP in high-risk patients. Methods: In this randomised, double-blind, comparative effectiveness trial, we enrolled patients from six tertiary medical centres in the USA. Eligible patients were those at high risk for the development of pancreatitis after ERCP. We randomly assigned eligible patients (1:1) immediately after ERCP to receive either two 50 mg indometacin suppositories and a placebo suppository (standard-dose group) or three 50 mg indometacin suppositories (high-dose group). 4 h after the procedure, patients assigned to the high-dose group received an additional 50 mg indometacin suppository, whereas patients in the standard-dose group received an additional placebo suppository. The randomisation schedule, stratified according to study centre and with no other restrictions, was computer generated by an investigator who was uninvolved in the clinical care of any participants, distributed to the sites, and kept by personnel not directly involved with the study. These same personnel were responsible for packaging the drug and placebo in opaque envelopes. Patients, study personnel, and treating physicians were masked to study group assignment. The primary outcome of the study was the development of pancreatitis after ERCP. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01912716, and enrolment is complete. Findings: Between July 9, 2013, and March 22, 2018, 1037 eligible patients were enrolled and randomly assigned to receive either standard-dose (n=515) or high-dose indometacin (n=522). Pancreatitis after ERCP occurred in 141 (14%) of 1037 patients-76 (15%) of 515 patients in the standard-dose indometacin group and 65 (12%) of 522 patients in the high-dose indometacin group (risk ratio [RR] 1·19, 95% CI 0·87-1·61; p=0·32). We observed 19 adverse events that were potentially attributable to study drug. Clinically significant bleeding occurred in 14 (1%) of 1037 patients-six (1%) of 515 patients in the standard-dose indometacin group and eight (2%) of 522 patients in the high-dose indometacin group (p=0·79). Three (1%) of 522 patients in the high-dose indometacin group developed acute kidney injury versus none in the standard-dose group (p=0·25). A non-ST elevation myocardial infarction occurred in the standard-dose indometacin group 2 days after ERCP. A transient ischaemic attack occurred in the high-dose indometacin group 5 days after ERCP. All 19 adverse events, in addition to the 141 patients who developed pancreatitis after ERCP, were considered serious as all required admission to hospital. We observed no allergic reactions or deaths at 30 day follow-up. Interpretation: Dose escalation to rectal indometacin 200 mg did not confer any advantage compared with the standard 100 mg regimen, with pancreatitis incidence remaining high in high-risk patients. Current practice should continue unchanged. Further research should consider the pharmacokinetics of non-steroidal anti-inflammatory drugs to determine the optimal timing of their administration to prevent pancreatitis after ERCP.