|
1
|
Göltl P, Merz P, Schneider A, Ebert MP, Hirth M, Magerl W. Somatosensory profiling to differentiate distinct painful diseases of the pancreas-a quantitative sensory testing case-control study. Pain 2025:00006396-990000000-00871. [PMID: 40198788 DOI: 10.1097/j.pain.0000000000003601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 02/21/2025] [Indexed: 04/10/2025]
Abstract
ABSTRACT Mechanisms of pancreatic pain are insufficiently understood, and quantitative sensory testing (QST) may help to identify the underlying mechanisms. Accordingly, this study assessed comprehensive somatosensory profiles encompassing nociceptive and nonnociceptive parameters in 70 patients with distinct pancreatic diseases, namely acute (n = 23), chronic (n = 20), or autoimmune pancreatitis (n = 10) and pancreatic cancer (n = 17) and compared it with 30 healthy control subjects by standardized QST (protocol of the German research network on neuropathic pain). Patients with pancreatic diseases presented significant somatosensory deficits in all thermal and tactile detection and pain thresholds in the pancreatic viscerotome (Th10), when compared with a remote control area (dermatome C5) or reference data of matched healthy controls (P < 0.05-P < 0.0001). Unaltered vibration detection emphasizes the strictly regional character of losses. Loss of sensitivity paralleled the occurrence of paradoxical heat sensation (Th10 vs C5; P < 0.05), an indicator of thermal integration deficit. Punctate hyperalgesia or pain to light touch, the hallmark signs of spinal central sensitization were mostly absent and pain summation remained unchanged (P > 0.05). Stratification of patients revealed that somatosensory deficits were significantly more pronounced in acute compared with chronic pancreatitis (eg, cold and warm detection thresholds: -2.19 ± 1.42 vs -1.10 ± 1.23 and -1.30 ± 1.68 vs -0.11 ± 1.80 z-values; P < 0.05 each). Notably, blunt pressure hyperalgesia, the only somatosensory parameter exhibiting significant gain compared with the patients' remote C5 segment, was a frequent finding only in acute, but not in chronic pancreatitis. The somatosensory phenotype of patients with distinct pancreatic disorders was characterized by a wide array of sensory losses being most severe in acute pancreatitis.
Collapse
Affiliation(s)
- Philipp Göltl
- Department of Medicine II, Medical Faculty at Mannheim, University of Heidelberg, Mannheim, Germany
| | - Paul Merz
- Department of Neurophysiology, Mannheim Center for Translational Neurosciences (MCTN), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Alexander Schneider
- Department of Medicine II, Medical Faculty at Mannheim, University of Heidelberg, Mannheim, Germany
- Department of Gastroenterology and Hepatology, Medical Center Bad Hersfeld, Bad Hersfeld, Germany
| | - Matthias P Ebert
- Department of Medicine II, Medical Faculty at Mannheim, University of Heidelberg, Mannheim, Germany
| | - Michael Hirth
- Department of Medicine II, Medical Faculty at Mannheim, University of Heidelberg, Mannheim, Germany
| | - Walter Magerl
- Department of Neurophysiology, Mannheim Center for Translational Neurosciences (MCTN), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| |
Collapse
|
|
2
|
Trentini F, Agnetti V, Manini M, Giovannetti E, Garajová I. NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes. Front Pharmacol 2024; 15:1499414. [PMID: 39723256 PMCID: PMC11668609 DOI: 10.3389/fphar.2024.1499414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 11/21/2024] [Indexed: 12/28/2024] Open
Abstract
Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.
Collapse
Affiliation(s)
| | - Virginia Agnetti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Martina Manini
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Lab of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, Netherlands
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Pisa, Italy
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Cancer Pharmacology Iacome Department, San Giuliano Terme, Italy
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| |
Collapse
|
|
3
|
Lee SY, Lee J, Cho JH, Lee DK, Seong Y, Jang SI. Oral high-carbohydrate solution as an alternative dietary modality in patients with acute pancreatitis. Pancreatology 2024; 24:1003-1011. [PMID: 39353844 DOI: 10.1016/j.pan.2024.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 07/07/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND/OBJECTIVES Early enteral feeding is crucial in acute pancreatitis (AP) to preserve the intestinal mucosa, prevent bacterial overgrowth, and prevent progression to pancreatic necrosis, multi-organ failure, and death. However, the optimal early diet remains unclear. This study compared an oral carbohydrate solution (OCS) diet versus a conventional diet (CD) in patients with AP. METHODS We retrospectively enrolled 538 patients diagnosed with AP in 2018-2022: 346 received a CD and 192 received an OCS diet. Because of differences in AP severity between groups, we performed 1:1 propensity score matching to obtain comparable groups (n = 182 in each). The CD group progressed from a liquid diet to soft foods and finally solid foods. The OCS group followed the same progression but received OCS instead of a liquid diet. Primary outcomes were the rate of recurrent postprandial pain after initiating the dietary intervention and hospital length of stay (LOS). Secondary outcomes included intensive care unit admission, mortality, 28-day hospital readmission, and AP-related complications. RESULTS After propensity score matching, baseline characteristics of the OCS and CD groups were comparable. The rate of recurrent pain was significantly higher in the CD group than in the OCS group (13.2 % vs. 3.8 %, p < 0.001), but hospital LOS was similar between groups (CD vs. OCS: 9.2 days vs. 8.7 days, p = 0.533). There were no significant differences in secondary outcomes between groups. CONCLUSIONS In patients with AP, OCS diet was associated with a lower rate of recurrent postprandial pain compared to a CD. Thus, OCS appears to be a beneficial dietary alternative for initial management of AP.
Collapse
Affiliation(s)
- See Young Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jaein Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Hee Cho
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Ki Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yeseul Seong
- Department of Internal Medicine and Statistics, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Ill Jang
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
4
|
Liu L, Liu H, Zhao M, Wen J, Liu J, Lv G, Xiao Z, Wang W, Zu S, Sun W, Zhang X, Gong L. Functional Upregulation of TRPM3 Channels Contributes to Acute Pancreatitis-associated Pain and Inflammation. Inflammation 2024:10.1007/s10753-024-02138-8. [PMID: 39259394 DOI: 10.1007/s10753-024-02138-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/11/2024] [Accepted: 08/27/2024] [Indexed: 09/13/2024]
Abstract
Transient receptor potential melastatin M3 (TRPM3) channels have been recognized as a pain transducer in dorsal root ganglion (DRG) neurons in recent years. TRPM3 activation initiates neurogenic inflammation and is required for the development of inflammatory hyperalgesia. We aimed to evaluate the role of TRPM3 in pancreas sensory afferents in pancreatic nociception, neurogenic inflammation, and acute pancreatitis (AP)-associated pain. AP was induced by intraperitoneal (i.p.) injection of L-arginine in rats. TRPM3 expression in pancreatic DRG neurons, spontaneous or mechanical-stimulation-evoked pain behaviors, and the extent of inflammation were evaluated. We found that TRPM3 channels were expressed on pancreatic primary afferent nerve terminals containing calcitonin gene-related peptide (CGRP). Activation of TRPM3 in the pancreas by injection of its specific agonist CIM0216 (10 μM) induced pain, CGRP and substance P release, and neurogenic inflammation, as evidenced by edema, plasma extravasation, and inflammatory cell accumulation in the pancreas. Increased TRPM3 functional expression was detected in pancreatic DRG neurons from AP rats, and blocking TRPM3 activity with its antagonist (Primidone, 5 mg/kg, i.p.) attenuated AP-associated pain behaviors and pancreatic inflammation. Pre-incubation of pancreatic DRG neurons with nerve growth factor (NGF) enhanced the increase in intracellular Ca2+ induced by the TRPM3 agonist (CIM0216, 1 μM). Our findings indicate that, in addition to TRPV1 and TRPA1 channels, TRPM3 is another pain channel that has a critical role in pancreatic nociception, neurogenic inflammation, and AP-associated pain behaviors. TRPM3 may be a promising pharmaceutical target for AP pain treatment.
Collapse
Affiliation(s)
- Lei Liu
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Hanwen Liu
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Mengmeng Zhao
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Jiliang Wen
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Jiaxin Liu
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Guangda Lv
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Zhiying Xiao
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Wenzhen Wang
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Shulu Zu
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Wendong Sun
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Xiulin Zhang
- Department of Urology, The Second Hospital of Shandong University, Shandong, PR, China
| | - Liping Gong
- Department of Academic Research, The Second Hospital of Shandong University, Shandong, PR, China.
| |
Collapse
|
|
5
|
On W, Ahmed W, Everett S, Huggett M, Paranandi B. Utility of interventional endoscopic ultrasound in pancreatic cancer. Front Oncol 2023; 13:1252824. [PMID: 37781196 PMCID: PMC10540845 DOI: 10.3389/fonc.2023.1252824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 08/30/2023] [Indexed: 10/03/2023] Open
Abstract
Endoscopic ultrasound (EUS) has an important role in the management algorithm of patients with pancreatic ductal adenocarcinoma (PDAC), typically for its diagnostic utilities. The past two decades have seen a rapid expansion of the therapeutic capabilities of EUS. Interventional EUS is now one of the more exciting developments within the field of endoscopy. The local effects of PDAC tend to be in anatomical areas which are difficult to target and endoscopy has cemented itself as a key role in managing the clinical sequelae of PDAC. Interventional EUS is increasingly utilized in situations whereby conventional endoscopy is either impossible to perform or unsuccessful. It also adds a different dimension to the host of oncological and surgical treatments for patients with PDAC. In this review, we aim to summarize the various ways in which interventional EUS could benefit patients with PDAC and aim to provide a balanced commentary on the current evidence of interventional EUS in the literature.
Collapse
Affiliation(s)
- Wei On
- Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | | | | | | | | |
Collapse
|
|
6
|
Barreto SG, Kaambwa B, Venkatesh K, Sasson SC, Andersen C, Delaney A, Bihari S, Pilcher D. Mortality and costs related to severe acute pancreatitis in the intensive care units of Australia and New Zealand (ANZ), 2003-2020. Pancreatology 2023; 23:341-349. [PMID: 37121877 DOI: 10.1016/j.pan.2023.04.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/21/2023] [Accepted: 04/17/2023] [Indexed: 05/02/2023]
Abstract
BACKGROUND AND OBJECTIVE Comprehensive data on the burden of severe acute pancreatitis (SAP) in global intensive care units (ICUs) and trends over time are lacking. Our objective was to compare trends in hospital and ICU mortality, in-hospital and ICU length of stay, and costs related to ICU admission in Australia and New Zealand (ANZ) for SAP. METHODS We performed a retrospective, observational, cohort study of ICU admissions reported to the ANZ Intensive Care Society Adult Patient Database over three consecutive six-year time periods from 2003 to 2020. RESULTS 12,635 patients with SAP from 189 ICUs in ANZ were analysed. No difference in adjusted hospital mortality (11.4% vs 11.5% vs 11.0%, p = 0.85) and ICU mortality rates (7.5% vs 8.0% vs 8.1%, p = 0.73) were noted over the study period. Median length of hospital admission reduced over time (13.9 days in 2003-08, 13.1 days in 2009-14 and 12.5 days in 2015-20; p < 0.01). No difference in length of ICU stay was noted over the study period (p = 0.13). The cost of managing SAP in ANZ ICUs remained constant over the three time periods. CONCLUSIONS In critically-ill SAP patients in ANZ, no change in mortality has been noted over nearly two decades. There was a slight reduction in hospital stay (1 day), while the length of ICU stay remained unchanged. Given the significant costs related to care of patients with SAP in ICU, these findings highlight the need to prioritise resource allocation for healthcare delivery and targeted clinical research to identify treatments aimed at reducing mortality.
Collapse
Affiliation(s)
- Savio George Barreto
- Division of Surgery and Perioperative Medicine, Flinders Medical Center, Bedford Park, Adelaide, South Australia, Australia; College of Medicine and Public Health, Flinders University, South Australia, Australia.
| | - Billingsley Kaambwa
- College of Medicine and Public Health, Flinders University, South Australia, Australia
| | - Karthik Venkatesh
- Malcolm Fisher Department of Intensive Care, The Royal North Shore Hospital, St Leonards, NSW, 2065, Australia; The Kirby Institute, UNSW, Sydney, Australia
| | - Sarah C Sasson
- The Kirby Institute, UNSW, Sydney, Australia; NSW Health Pathology I.C.P.M.R, Westmead Hospital, Sydney, Australia
| | - Christopher Andersen
- Malcolm Fisher Department of Intensive Care, The Royal North Shore Hospital, St Leonards, NSW, 2065, Australia; The Kirby Institute, UNSW, Sydney, Australia; Northern Clinical School, University of Sydney, Sydney, NSW, Australia; The George Institute for Global Health, King Street, Newtown, NSW, 2042, Australia
| | - Anthony Delaney
- Malcolm Fisher Department of Intensive Care, The Royal North Shore Hospital, St Leonards, NSW, 2065, Australia; Northern Clinical School, University of Sydney, Sydney, NSW, Australia
| | - Shailesh Bihari
- College of Medicine and Public Health, Flinders University, South Australia, Australia; Department of ICCU, Flinders Medical Centre, Bedford Park, South Australia, 5042, Australia
| | - David Pilcher
- Department of Intensive Care, The Alfred Hospital, Commercial Road, Prahran, Melbourne, Victoria, 3004, Australia; The Australian and New Zealand Intensive Care-Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, 3004, Australia; The Australian and New Zealand Intensive Care Society (ANZICS), Centre for Outcome and Resource Evaluation (CORE), 277 Camberwell Road, Camberwell, Victoria, 3124, Australia
| |
Collapse
|
|
7
|
Gould Rothberg BE, Quest TE, Yeung SCJ, Pelosof LC, Gerber DE, Seltzer JA, Bischof JJ, Thomas CR, Akhter N, Mamtani M, Stutman RE, Baugh CW, Anantharaman V, Pettit NR, Klotz AD, Gibbs MA, Kyriacou DN. Oncologic emergencies and urgencies: A comprehensive review. CA Cancer J Clin 2022; 72:570-593. [PMID: 35653456 DOI: 10.3322/caac.21727] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/15/2022] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Patients with advanced cancer generate 4 million visits annually to emergency departments (EDs) and other dedicated, high-acuity oncology urgent care centers. Because of both the increasing complexity of systemic treatments overall and the higher rates of active therapy in the geriatric population, many patients experiencing acute decompensations are frail and acutely ill. This article comprehensively reviews the spectrum of oncologic emergencies and urgencies typically encountered in acute care settings. Presentation, underlying etiology, and up-to-date clinical pathways are discussed. Criteria for either a safe discharge to home or a transition of care to the inpatient oncology hospitalist team are emphasized. This review extends beyond familiar conditions such as febrile neutropenia, hypercalcemia, tumor lysis syndrome, malignant spinal cord compression, mechanical bowel obstruction, and breakthrough pain crises to include a broader spectrum of topics encompassing the syndrome of inappropriate antidiuretic hormone secretion, venous thromboembolism and malignant effusions, as well as chemotherapy-induced mucositis, cardiomyopathy, nausea, vomiting, and diarrhea. Emergent and urgent complications associated with targeted therapeutics, including small molecules, naked and drug-conjugated monoclonal antibodies, as well as immune checkpoint inhibitors and chimeric antigen receptor T-cells, are summarized. Finally, strategies for facilitating same-day direct admission to hospice from the ED are discussed. This article not only can serve as a point-of-care reference for the ED physician but also can assist outpatient oncologists as well as inpatient hospitalists in coordinating care around the ED visit.
Collapse
Affiliation(s)
- Bonnie E Gould Rothberg
- Yale Cancer Center Innovations Laboratory, Yale Comprehensive Cancer Center, New Haven, Connecticut
| | - Tammie E Quest
- Department of Emergency Medicine, Emory University, Atlanta, Georgia
| | - Sai-Ching J Yeung
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lorraine C Pelosof
- Office of Oncologic Diseases, US Food and Drug Administration, Silver Spring, Maryland
| | - David E Gerber
- Division of Hematology-Oncology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical School, Dallas, Texas
| | - Justin A Seltzer
- Department of Emergency Medicine, University of California San Diego, San Diego, California
| | - Jason J Bischof
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Charles R Thomas
- Department of Radiation Oncology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, New Hampshire
| | - Nausheen Akhter
- Department of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Mira Mamtani
- Department of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Robin E Stutman
- Department of Medicine, Division of Urgent Care Services, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Christopher W Baugh
- Department of Emergency Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Venkataraman Anantharaman
- Department of Emergency Medicine, Singapore General Hospital, SingHealth Duke-National University of Singapore Academic Medical Center, Singapore, Singapore
| | - Nicholas R Pettit
- Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Adam D Klotz
- Department of Medicine, Division of Urgent Care Services, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael A Gibbs
- Department of Emergency Medicine, Atrium Health-Carolinas Medical Center, Charlotte, North Carolina
| | - Demetrios N Kyriacou
- Department of Emergency Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| |
Collapse
|
|
8
|
Földi M, Gede N, Kiss S, Vincze Á, Bajor J, Szabó I, Szepes Z, Izbéki F, Gervain J, Hamvas J, Vitális Z, Fehér E, Crai S, Sallinen V, Ramirez‐Maldonado E, Meczker Á, Varjú P, Poropat G, Stimac D, Faluhelyi N, Miseta A, Nagy T, Márton Z, Vereczkei A, Jenő Hegyi P, Párniczky A, Hegyi P, Szentesi A, the Hungarian Pancreatic Study Group. The characteristics and prognostic role of acute abdominal on-admission pain in acute pancreatitis: A prospective cohort analysis of 1432 cases. Eur J Pain 2022; 26:610-623. [PMID: 34758174 PMCID: PMC9299627 DOI: 10.1002/ejp.1885] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/17/2021] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Pain is the most common symptom in acute pancreatitis (AP) and is among the diagnostic criteria. Therefore, we aimed to characterize acute abdominal pain in AP. METHODS The Hungarian Pancreatic Study Group prospectively collected multicentre clinical data on 1435 adult AP patients between 2012 and 2017. Pain was characterized by its intensity (mild or intense), duration prior to admission (hours), localization (nine regions of the abdomen) and type (sharp, dull or cramping). RESULTS 97.3% of patients (n = 1394) had pain on admission. Of the initial population with acute abdominal pain, 727 patients answered questions about pain intensity, 1148 about pain type, 1134 about pain localization and 1202 about pain duration. Pain was mostly intense (70%, n = 511/727), characterized by cramping (61%, n = 705/1148), mostly starting less than 24 h prior to admission (56.7%, n = 682/1202). Interestingly, 50.9% of the patients (n = 577/1134) had atypical pain, which means pain other than epigastric or belt-like upper abdominal pain. We observed a higher proportion of peripancreatic fluid collection (19.5% vs. 11.0%; p = 0.009) and oedematous pancreas (8.4% vs. 3.1%; p = 0.016) with intense pain. Sharp pain was associated with AP severity (OR = 2.481 95% CI: 1.550-3.969) and increased mortality (OR = 2.263, 95% CI: 1.199-4.059) compared to other types. Longstanding pain (>72 h) on admission was not associated with outcomes. Pain characteristics showed little association with the patient's baseline characteristics. CONCLUSION A comprehensive patient interview should include questions about pain characteristics, including pain type. Patients with sharp and intense pain might need special monitoring and tailored pain management. SIGNIFICANCE Acute abdominal pain is the leading presenting symptom in acute pancreatitis; however, we currently lack specific guidelines for pain assessment and management. In our cohort analysis, intense and sharp pain on admission was associated with higher odds for severe AP and several systemic and local complications. Therefore, a comprehensive patient interview should include questions about pain characteristics and patients with intense and sharp pain might need closer monitoring.
Collapse
Affiliation(s)
- Mária Földi
- Centre for Translational MedicineDepartment of MedicineUniversity of SzegedSzegedHungary
- Institute for Translational MedicineMedical SchoolUniversity of PécsPécsHungary
- Doctoral School of Clinical MedicineUniversity of SzegedSzegedHungary
| | - Noémi Gede
- Institute for Translational MedicineMedical SchoolUniversity of PécsPécsHungary
| | - Szabolcs Kiss
- Centre for Translational MedicineDepartment of MedicineUniversity of SzegedSzegedHungary
- Institute for Translational MedicineMedical SchoolUniversity of PécsPécsHungary
- Doctoral School of Clinical MedicineUniversity of SzegedSzegedHungary
| | - Áron Vincze
- Division of GastroenterologyFirst Department of MedicineMedical SchoolUniversity of PécsPécsHungary
| | - Judit Bajor
- Division of GastroenterologyFirst Department of MedicineMedical SchoolUniversity of PécsPécsHungary
| | - Imre Szabó
- Division of GastroenterologyFirst Department of MedicineMedical SchoolUniversity of PécsPécsHungary
| | - Zoltán Szepes
- Department of MedicineUniversity of SzegedSzegedHungary
| | - Ferenc Izbéki
- Szent György University Teaching Hospital of Fejér CountySzékesfehérvárHungary
| | - Judit Gervain
- Szent György University Teaching Hospital of Fejér CountySzékesfehérvárHungary
| | | | - Zsuzsanna Vitális
- Division of GastroenterologyDepartment of Internal MedicineUniversity of DebrecenDebrecenHungary
| | - Eszter Fehér
- Division of GastroenterologyDepartment of Internal MedicineUniversity of DebrecenDebrecenHungary
| | - Stefan Crai
- Pándy Kálmán Hospital of Békés CountyGyulaHungary
| | - Ville Sallinen
- Department of Transplantation and Liver SurgeryHelsinki University Hospital and University of HelsinkiHelsinkiFinland
| | | | - Ágnes Meczker
- Institute for Translational MedicineMedical SchoolUniversity of PécsPécsHungary
| | - Péter Varjú
- Institute for Translational MedicineMedical SchoolUniversity of PécsPécsHungary
| | | | | | - Nándor Faluhelyi
- Department of Medical ImagingMedical SchoolUniversity of PécsPécsHungary
| | - Attila Miseta
- Department of Laboratory MedicineMedical SchoolUniversity of PécsPécsHungary
| | - Tamás Nagy
- Department of Laboratory MedicineMedical SchoolUniversity of PécsPécsHungary
| | - Zsolt Márton
- First Department of MedicineMedical SchoolUniversity of PécsPécsHungary
| | - András Vereczkei
- Department of SurgeryMedical SchoolUniversity of PécsPécsHungary
| | - Péter Jenő Hegyi
- Institute for Translational MedicineMedical SchoolUniversity of PécsPécsHungary
- Center for Translational MedicineSemmelweis UniversityBudapestHungary
| | - Andrea Párniczky
- Centre for Translational MedicineDepartment of MedicineUniversity of SzegedSzegedHungary
- Center for Translational MedicineSemmelweis UniversityBudapestHungary
- Heim Pál National Pediatric InstituteBudapestHungary
| | - Péter Hegyi
- Institute for Translational MedicineMedical SchoolUniversity of PécsPécsHungary
- Center for Translational MedicineSemmelweis UniversityBudapestHungary
- Division of Pancreatic Diseases, Heart and Vascular CenterSemmelweis UniversityBudapestHungary
| | - Andrea Szentesi
- Centre for Translational MedicineDepartment of MedicineUniversity of SzegedSzegedHungary
- Institute for Translational MedicineMedical SchoolUniversity of PécsPécsHungary
- Center for Translational MedicineSemmelweis UniversityBudapestHungary
| | | |
Collapse
|
|
9
|
Lkhagvasuren B, Mee-Inta O, Zhao ZW, Hiramoto T, Boldbaatar D, Kuo YM. Pancreas-Brain Crosstalk. Front Neuroanat 2021; 15:691777. [PMID: 34354571 PMCID: PMC8329585 DOI: 10.3389/fnana.2021.691777] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/30/2021] [Indexed: 12/19/2022] Open
Abstract
The neural regulation of glucose homeostasis in normal and challenged conditions involves the modulation of pancreatic islet-cell function. Compromising the pancreas innervation causes islet autoimmunity in type 1 diabetes and islet cell dysfunction in type 2 diabetes. However, despite the richly innervated nature of the pancreas, islet innervation remains ill-defined. Here, we review the neuroanatomical and humoral basis of the cross-talk between the endocrine pancreas and autonomic and sensory neurons. Identifying the neurocircuitry and neurochemistry of the neuro-insular network would provide clues to neuromodulation-based approaches for the prevention and treatment of diabetes and obesity.
Collapse
Affiliation(s)
- Battuvshin Lkhagvasuren
- Brain Science Institute, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Onanong Mee-Inta
- Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Zi-Wei Zhao
- Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Tetsuya Hiramoto
- Department of Psychosomatic Medicine, Fukuoka Hospital, National Hospital Organization, Fukuoka, Japan
| | - Damdindorj Boldbaatar
- Brain Science Institute, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Yu-Min Kuo
- Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan.,Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, Tainan, Taiwan
| |
Collapse
|
|
10
|
Coveler AL, Mizrahi J, Eastman B, Apisarnthanarax SJ, Dalal S, McNearney T, Pant S. Pancreas Cancer-Associated Pain Management. Oncologist 2021; 26:e971-e982. [PMID: 33885205 PMCID: PMC8176967 DOI: 10.1002/onco.13796] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 04/02/2021] [Indexed: 12/12/2022] Open
Abstract
Pain is highly prevalent in patients with pancreas cancer and contributes to the morbidity of the disease. Pain may be due to pancreatic enzyme insufficiency, obstruction, and/or a direct mass effect on nerves in the celiac plexus. Proper supportive care to decrease pain is an important aspect of the overall management of these patients. There are limited data specific to the management of pain caused by pancreatic cancer. Here we review the literature and offer recommendations regarding multiple modalities available to treat pain in these patients. The dissemination and adoption of these best supportive care practices can improve quantity and quality of life for patients with pancreatic cancer. IMPLICATIONS FOR PRACTICE: Pain management is important to improve the quality of life and survival of a patient with cancer. The pathophysiology of pain in pancreas cancer is complex and multifactorial. Despite tumor response to chemotherapy, a sizeable percentage of patients are at risk for ongoing cancer-related pain and its comorbid consequences. Accordingly, the management of pain in patients with pancreas cancer can be challenging and often requires a multifaceted approach.
Collapse
Affiliation(s)
- Andrew L Coveler
- Department of Medical Oncology, University of Washington, Seattle, Washington, USA
| | - Jonathan Mizrahi
- Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Bory Eastman
- Department of Radiation Oncology, University of Washington, Seattle, Washington, USA
| | | | - Shalini Dalal
- Department of Palliative, Rehabilitation and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Shubham Pant
- Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | |
Collapse
|
|
11
|
Dai J, Teng L, Zhao L, Zou H. The combined analgesic effect of pregabalin and morphine in the treatment of pancreatic cancer pain, a retrospective study. Cancer Med 2021; 10:1738-1744. [PMID: 33594813 PMCID: PMC7940217 DOI: 10.1002/cam4.3779] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Pregabalin is commonly used to relieve neuropathic pain. However, data are lacking on its efficacy for the treatment of chronic cancer pain. The purpose of this study was to determine the analgesic efficacy of pregabalin combined with morphine in the management of pancreatic cancer pain. METHODS This study reviewed patients who were prescribed morphine and 150 mg/d pregabalin between 1 January 2017 and 10 November 2018 in our institute. The primary outcomes of this study were the average pain score and dose of morphine. Secondary outcomes included characters of breakthrough cancer pain, functional interference related to pain, anxiety/depression status, and incidence of treatment-related adverse events during the study. RESULTS A total of 240 patients with pain related to pancreatic cancer were included in the study. The results showed that patients of both combination therapy group (pregabalin+morphine) and monotherapy group (morphine) achieved similar analgesic efficacy, demonstrated by NRS (2.4 ± 0.9 vs. 2.6 ± 0.9; combination vs. monotherapy) at the end of the study. Mean daily dose of morphine used in the combination group was significant lower compared to monotherapy group (39.5 ± 16.0 mg vs. 61.5 ± 19.3 mg, net difference 23.5, 95% CI: 18.4-28.6, p < 0.001). The change of functional interference score related to pain was significantly different between combination and monotherapy group (12.0 ± 0.4 vs. 9.8 ± 4.9; net difference, 2.3; 95% CI: 1.1-3.3; p < 0.001). Patients in combination therapy group had experienced shorter duration of breakthrough cancer pain than those in monotherapy group (X2 p < 0.001, Cramer's V:0.36). The incidence of somnolence, dizziness, and cognitive dysfunction were significantly higher in the combination group compared to monotherapy group. No serious treatment-related side effects were observed. CONCLUSIONS The findings of this study supported the use of pregabalin with morphine to relieve pain in patients of pancreatic cancer.
Collapse
Affiliation(s)
- Junzhu Dai
- Department of Pain Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lei Teng
- Department of Pain Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Liuyuan Zhao
- Department of Pain Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Huichao Zou
- Department of Pain Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| |
Collapse
|
|
12
|
Choe JW, Hyun JJ. [Relief of Cancer Pain in Patients with Pancreatic Cancer]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 74:81-86. [PMID: 31438659 DOI: 10.4166/kjg.2019.74.2.81] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 07/23/2019] [Accepted: 07/23/2019] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is a dismal disease with a poor prognosis and is one of the most painful malignancies. Therefore, adequate pain control is essential to improving the patient's quality of life. Pain in pancreatic cancer has complex pathophysiologic mechanisms and different characteristics. The choice of pain management modalities should be individualized depending on the pain characteristics using a multidisciplinary approach. The treatment options available include medical treatment, chemotherapy, celiac plexus/ganglion neurolysis, radiotherapy, and endoscopic technique. This review discusses the medical and interventional options, leading to optimal pain management in patients with pancreatic cancer.
Collapse
Affiliation(s)
- Jung Wan Choe
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea
| | - Jong Jin Hyun
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea
| |
Collapse
|
|
13
|
Bouwense SAW, Kempeneers MA, van Santvoort HC, Boermeester MA, van Goor H, Besselink MG. Surgery in Chronic Pancreatitis: Indication, Timing and Procedures. Visc Med 2019; 35:110-118. [PMID: 31192244 DOI: 10.1159/000499612] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 03/14/2019] [Indexed: 12/21/2022] Open
Abstract
Chronic pancreatitis is a chronic inflammation of the pancreas with pain as its severest symptom and often an impaired quality of life. Surgical intervention plays an important role in the management of pain but is generally kept as a last resort when conservative measures and endoscopy have failed. However, in the last few years multiple studies suggested the superiority of (early) surgical treatment in chronic pancreatitis for multiple end points, including pain relief. In this paper we highlight the most recent high-quality evidence on surgical therapy in chronic pancreatitis and the rationale for early (surgical) intervention.
Collapse
Affiliation(s)
- Stefan A W Bouwense
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marinus A Kempeneers
- Department of Surgery, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Hjalmar C van Santvoort
- Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.,Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marja A Boermeester
- Department of Surgery, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Harry van Goor
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marc G Besselink
- Department of Surgery, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
14
|
Molnár I, Hegyi G, Zsom L, Saahs C, Vagedes J, Kapócs G, Kovács Z, Sterner MG, Szőke H. Celiac plexus block increases quality of life in patients with pancreatic cancer. J Pain Res 2019; 12:307-315. [PMID: 30679920 PMCID: PMC6338112 DOI: 10.2147/jpr.s186659] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Background Pancreatic cancer is a malignant disease with a high mortality rate and severe pain that is challenging to manage. To reduce the excruciating abdominal pain, opioids and adjuvant agents are conventionally used. Objectives PRNCPB is a treatment of neural therapy. The number of studies assessing the effect on patients' QoL is limited and inconsistent. With this study, we intended to address this issue. Study design A prospective nonrandomized study with a series of cases of unresectable pancreatic cancer was conducted. Setting The study was performed at our pain clinic under real life conditions. Materials and methods A total number of 16 patients with severe abdominal pain were enrolled in the study all of whom had responded to combined systemic analgesic therapy inadequately and had intolerable side effects contraindicating further increase in dose. The efficacy of this invasive, palliative analgesic procedure was evaluated 35 days after PRNCPB was performed. Primary outcomes were changed in pain intensity using the VAS questionnaire. Secondary outcomes were improved in QoL using the SF-36 questionnaire. Changes in pain medications and adverse reactions were monitored. Results After PRNCPB patients experienced a significant decrease (P=0.002) in pain intensity as shown by the VAS score, and a decreased opiate demand. Their QoL scores considering effect sizes also improved (P<0.001). No complications attributable to PRNCPB were observed during the study period. Additionally, no adverse drug reactions were observed. Limitations Detection, observation, and reporting bias can be estimated as moderate. Selection bias was not detected. Conclusion Our results give preliminary evidence that PRNCPB might be helpful as an additional treatment to conventional pain management in end-stage pancreatic cancer patients. PRNCPB seems to improve QoL in these patients in a time frame of at least 5 weeks after intervention.
Collapse
Affiliation(s)
- István Molnár
- Doctoral School of Health Sciences, Faculty of Health Sciences, University of Pécs, Pécs, Hungary,
| | - Gabriella Hegyi
- Doctoral School of Health Sciences, Faculty of Health Sciences, University of Pécs, Pécs, Hungary, .,Department of CAM, Faculty of Health Sciences, University of Pécs, Pécs, Hungary,
| | - Lajos Zsom
- Department of Nephrology, Fresenius Medical Care, Cegléd, Hungary
| | - Christine Saahs
- Department of Pediatrics, University of Vienna, Vienna, Austria.,Pediatric Outpatient Department, Krems, Austria
| | - Jan Vagedes
- University Children's Hospital, University of Tuebingen, Tuebingen, Germany.,Department of Complementary and Integrative Medicine, ARCIM Institute (Academic Research in Complementary and Integrative Medicine), Filderstadt, Germany
| | - Gábor Kapócs
- Department of Psychiatry and Psychiatric Rehabilitation, Saint John Hospital, Budapest, Hungary
| | - Zoltán Kovács
- Doctoral School of Health Sciences, Faculty of Health Sciences, University of Pécs, Pécs, Hungary,
| | | | - Henrik Szőke
- Doctoral School of Health Sciences, Faculty of Health Sciences, University of Pécs, Pécs, Hungary, .,Department of CAM, Faculty of Health Sciences, University of Pécs, Pécs, Hungary,
| |
Collapse
|
|
15
|
Abstract
Mast cells are best recognized for their role in allergy and anaphylaxis, but increasing evidence supports their role in neurogenic inflammation leading to pain and itch. Mast cells act as a "power house" by releasing algogenic and pruritogenic mediators, which initiate a reciprocal communication with specific nociceptors on sensory nerve fibers. Consequently, nerve fibers release inflammatory and vasoactive neuropeptides, which in turn activate mast cells in a feedback mechanism, thus promoting a vicious cycle of mast cell and nociceptor activation leading to neurogenic inflammation and pain/pruritus. Mechanisms underlying mast cell differentiation, activation, and intercellular interactions with inflammatory, vascular, and neural systems are deeply influenced by their microenvironment, imparting enormous heterogeneity and complexity in understanding their contribution to pain and pruritus. Neurogenic inflammation is central to both pain and pruritus, but specific mediators released by mast cells to promote this process may vary depending upon their location, stimuli, underlying pathology, gender, and species. Therefore, in this review, we present the contribution of mast cells in pathological conditions, including distressing pruritus exacerbated by psychologic stress and experienced by the majority of patients with psoriasis and atopic dermatitis and in different pain syndromes due to mastocytosis, sickle cell disease, and cancer.
Collapse
Affiliation(s)
- Kalpna Gupta
- Vascular Biology Center, Division of Hematology/Oncology/Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Ilkka T Harvima
- Department of Dermatology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| |
Collapse
|
|
16
|
da Silva-Leite KES, Girão DKFB, de Freitas Pires A, Assreuy AMS, de Moraes PAF, Cunha AP, Ricardo NMPS, Criddle DN, de Souza MHLP, Pereira MG, Soares PMG. Ximenia americana heteropolysaccharides ameliorate inflammation and visceral hypernociception in murine caerulein-induced acute pancreatitis: Involvement of CB2 receptors. Biomed Pharmacother 2018; 106:1317-1324. [DOI: 10.1016/j.biopha.2018.07.067] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 07/10/2018] [Accepted: 07/13/2018] [Indexed: 01/12/2023] Open
|
|
17
|
Minaga K, Takenaka M, Kamata K, Yoshikawa T, Nakai A, Omoto S, Miyata T, Yamao K, Imai H, Sakamoto H, Kitano M, Kudo M. Alleviating Pancreatic Cancer-Associated Pain Using Endoscopic Ultrasound-Guided Neurolysis. Cancers (Basel) 2018; 10:50. [PMID: 29462851 PMCID: PMC5836082 DOI: 10.3390/cancers10020050] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 02/09/2018] [Accepted: 02/12/2018] [Indexed: 12/17/2022] Open
Abstract
The most common symptom in patients with advanced pancreatic cancer is abdominal pain. This has traditionally been treated with nonsteroidal anti-inflammatory drugs and opioid analgesics. However, these treatments result in inadequate pain control or drug-related adverse effects in some patients. An alternative pain-relief modality is celiac plexus neurolysis, in which the celiac plexus is chemically ablated. This procedure was performed percutaneously or intraoperatively until 1996, when endoscopic ultrasound (EUS)-guided celiac plexus neurolysis was first described. In this transgastric anterior approach, a neurolytic agent is injected around the celiac trunk under EUS guidance. The procedure gained popularity as a minimally invasive approach and is currently widely used to treat pancreatic cancer-associated pain. We focus on two relatively new techniques of EUS-guided neurolysis: EUS-guided celiac ganglia neurolysis and EUS-guided broad plexus neurolysis, which have been developed to improve efficacy. Although the techniques are safe and effective in general, some serious adverse events including ischemic and infectious complications have been reported as the procedure has gained widespread popularity. We summarize reported clinical outcomes of EUS-guided neurolysis in pancreatic cancer (from the PubMed and Embase databases) with a goal of providing information useful in developing strategies for pancreatic cancer-associated pain alleviation.
Collapse
Affiliation(s)
- Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| | - Mamoru Takenaka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| | - Tomoe Yoshikawa
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| | - Atsushi Nakai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| | - Shunsuke Omoto
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| | - Takeshi Miyata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| | - Kentaro Yamao
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| | - Hajime Imai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| | - Hiroki Sakamoto
- Department of Gastroenterology, Katsuragi Hospital, Kishiwada 596-0825, Japan.
| | - Masayuki Kitano
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
| |
Collapse
|
|
18
|
Pain in Patients with Pancreatic Cancer: Prevalence, Mechanisms, Management and Future Developments. Dig Dis Sci 2017; 62:861-870. [PMID: 28229252 DOI: 10.1007/s10620-017-4488-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 02/01/2017] [Indexed: 12/18/2022]
Abstract
Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patients' quality of life and survival.
Collapse
|
|
19
|
Roles of prefrontal cortex and paraventricular thalamus in affective and mechanical components of visceral nociception. Pain 2016; 156:2479-2491. [PMID: 26262826 DOI: 10.1097/j.pain.0000000000000318] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Visceral pain represents a major clinical challenge in the management of many gastrointestinal disorders, eg, pancreatitis. However, cerebral neurobiological mechanisms underlying visceral nociception are poorly understood. As a representative model of visceral nociception, we applied cerulein hyperstimulation in C57BL6 mice to induce acute pancreatitis and performed a behavioral test battery and c-Fos staining of brains. We observed a specific pain phenotype and a significant increase in c-Fos immunoreactivity in the paraventricular nucleus of the thalamus (PVT), the periaqueductal gray, and the medial prefrontal cortex (mPFC). Using neuronal tracing, we observed projections of the PVT to cortical layers of the mPFC with contacts to inhibitory GABAergic neurons. These inhibitory neurons showed more activation after cerulein treatment suggesting thalamocortical "feedforward inhibition" in visceral nociception. The activity of neurons in pancreatitis-related pain centers was pharmacogenetically modulated by designer receptors exclusively activated by designer drugs, selectively and cell type specifically expressed in target neurons using adeno-associated virus-mediated gene transfer. Pharmacogenetic inhibition of PVT but not periaqueductal gray neurons attenuated visceral pain and induced an activation of the descending inhibitory pain pathway. Activation of glutamatergic principle neurons in the mPFC, but not inhibitory neurons, also reversed visceral nociception. These data reveal novel insights into central pain processing that underlies visceral nociception and may trigger the development of novel, potent centrally acting analgesic drugs.
Collapse
|
|
20
|
Oz HS. Multiorgan chronic inflammatory hepatobiliary pancreatic murine model deficient in tumor necrosis factor receptors 1 and 2. World J Gastroenterol 2016; 22:4988-4998. [PMID: 27275091 PMCID: PMC4886374 DOI: 10.3748/wjg.v22.i21.4988] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues.
METHODS: Tumor necrosis factor receptors 1 and 2 (TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride (DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and naïve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining.
RESULTS: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls (P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2 (severe) in DBTC-treated animals vs score 0 (normal) in sham-treated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of inflammatory cells, degeneration, vacuolization, and necrosis of acinar cells and distention of pancreatic ducts. Extent of pancreatic damage and pancreatitis were scored 3.6 ± 0.4 (severe) for DBTC-treated in contrast to score 0 (normal) in sham-treated animals. The gall bladder became expanded with ductal distention, and occasional bile stones were detected along with microscopic hepatic lesions. DBTC-treated animals developed splenic hypertrophy with increased weight and length (P < 0.01) along with thymic atrophy (P < 0.001). Finally, colitic lesions and colitis were prominent in DBTC-treated animals and scored 3.4 ± 0.3 (moderately severe) vs 0 (normal) for the sham-treated animals.
CONCLUSION: This is the first report of chronic inflammatory multiorgan hepatobiliary pancreatitis, along with fibrosis and calculi formation induced reliably utilizing oral DBTC administration in TNFR1/R2 deficient mice.
Collapse
MESH Headings
- Abdominal Pain/chemically induced
- Abdominal Pain/genetics
- Abdominal Pain/metabolism
- Animals
- Behavior, Animal
- Bile Ducts/metabolism
- Bile Ducts/pathology
- Chemical and Drug Induced Liver Injury/etiology
- Chemical and Drug Induced Liver Injury/genetics
- Chemical and Drug Induced Liver Injury/metabolism
- Chemical and Drug Induced Liver Injury/psychology
- Cholangitis/chemically induced
- Cholangitis/genetics
- Cholangitis/metabolism
- Cholangitis/psychology
- Colitis/chemically induced
- Colitis/genetics
- Colitis/metabolism
- Exploratory Behavior
- Genetic Predisposition to Disease
- Grooming
- Hepatic Stellate Cells/metabolism
- Hepatic Stellate Cells/pathology
- Hyperalgesia/chemically induced
- Hyperalgesia/genetics
- Hyperalgesia/metabolism
- Lithiasis/chemically induced
- Lithiasis/genetics
- Lithiasis/metabolism
- Lithiasis/psychology
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Experimental/chemically induced
- Liver Cirrhosis, Experimental/genetics
- Liver Cirrhosis, Experimental/metabolism
- Liver Cirrhosis, Experimental/psychology
- Mice, Knockout
- Organotin Compounds
- Pain Perception
- Pancreas/metabolism
- Pancreas/pathology
- Pancreatic Stellate Cells/metabolism
- Pancreatic Stellate Cells/pathology
- Pancreatitis/genetics
- Pancreatitis/metabolism
- Pancreatitis/psychology
- Phenotype
- Receptors, Tumor Necrosis Factor, Type I/deficiency
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type II/deficiency
- Receptors, Tumor Necrosis Factor, Type II/genetics
- Spleen/metabolism
- Spleen/pathology
- Weight Loss
Collapse
|
|
21
|
Dobosz Ł, Kaczor M, Stefaniak TJ. Pain in pancreatic cancer: review of medical and surgical remedies. ANZ J Surg 2016; 86:756-761. [DOI: 10.1111/ans.13609] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2016] [Indexed: 12/27/2022]
Affiliation(s)
- Łukasz Dobosz
- Department of General, Endocrine and Transplant Surgery; Medical University of Gdansk; Gdansk Poland
| | - Maciej Kaczor
- Department of General, Endocrine and Transplant Surgery; Medical University of Gdansk; Gdansk Poland
| | - Tomasz J. Stefaniak
- Department of General, Endocrine and Transplant Surgery; Medical University of Gdansk; Gdansk Poland
| |
Collapse
|
|
22
|
Atsawarungruangkit A, Pongprasobchai S. Current understanding of the neuropathophysiology of pain in chronic pancreatitis. World J Gastrointest Pathophysiol 2015; 6:193-202. [PMID: 26600977 PMCID: PMC4644883 DOI: 10.4291/wjgp.v6.i4.193] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 07/22/2015] [Accepted: 09/16/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis (CP) is a chronic inflammatory disease of the pancreas. The main symptom of patients with CP is chronic and severe abdominal pain. However, the pathophysiology of pain in CP remains obscure. Traditionally, researchers believed that the pain was caused by anatomical changes in pancreatic structure. However, treatment outcomes based on such beliefs are considered unsatisfactory. The emerging explanations of pain in CP are trending toward neurobiological theories. This article aims to review current evidence regarding the neuropathophysiology of pain in CP and its potential implications for the development of new treatments for pain in CP.
Collapse
|
|
23
|
Abstract
Pancreatic nerves undergo prominent alterations during the evolution and progression of human chronic pancreatitis and pancreatic cancer. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibres (neural remodelling) is switched, and are infiltrated by perineural inflammatory cells (pancreatic neuritis) or invaded by pancreatic cancer cells (neural invasion). These neuropathic alterations also correlate with neuropathic pain. Instead of being mere histopathological manifestations of disease progression, pancreatic neural plasticity synergizes with the enhanced excitability of sensory neurons, with Schwann cell recruitment toward cancer and with central nervous system alterations. These alterations maintain a bidirectional interaction between nerves and non-neural pancreatic cells, as demonstrated by tissue and neural damage inducing neuropathic pain, and activated neurons releasing mediators that modulate inflammation and cancer growth. Owing to the prognostic effects of pain and neural invasion in pancreatic cancer, dissecting the mechanism of pancreatic neuroplasticity holds major translational relevance. However, current in vivo models of pancreatic cancer and chronic pancreatitis contain many discrepancies from human disease that overshadow their translational value. The present Review discusses novel possibilities for mechanistically uncovering the role of the nervous system in pancreatic disease progression.
Collapse
Affiliation(s)
- Ihsan Ekin Demir
- Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Strasse 22, D-81675 Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Strasse 22, D-81675 Munich, Germany
| | - Güralp O Ceyhan
- Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Strasse 22, D-81675 Munich, Germany
| |
Collapse
|
|
24
|
Wang S, Zhu HY, Jin Y, Zhou Y, Hu S, Liu T, Jiang X, Xu GY. Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2015; 308:G710-9. [PMID: 25634810 DOI: 10.1152/ajpgi.00395.2014] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 01/24/2015] [Indexed: 02/08/2023]
Abstract
The mechanism of pain in chronic pancreatitis (CP) is poorly understood. The aim of this study was designed to investigate roles of norepinephrine (NE) and P2X receptor (P2XR) signaling pathway in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Mechanical hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. P2XR-mediated responses of pancreatic dorsal root ganglion (DRG) neurons were measured utilizing calcium imaging and whole cell patch-clamp-recording techniques. Western blot analysis and immunofluorescence were performed to examine protein expression. TNBS injection produced a significant upregulation of P2X3R expression and an increase in ATP-evoked responses of pancreatic DRG neurons. The sensitization of P2X3Rs was reversed by administration of β-adrenergic receptor antagonist propranolol. Incubation of DRG neurons with NE significantly enhanced ATP-induced intracellular calcium signals, which were abolished by propranolol, and partially blocked by protein kinase A inhibitor H-89. Interestingly, TNBS injection led to a significant elevation of NE concentration in DRGs and the pancreas, an upregulation of β2-adrenergic receptor expression in DRGs, and amplification of the NE-induced potentiation of ATP responses. Importantly, pancreatic hyperalgesia was markedly attenuated by administration of purinergic receptor antagonist suramin or A317491 or β2-adrenergic receptor antagonist butoxamine. Sensitization of P2X3Rs, which was likely mediated by adrenergic signaling in primary sensory neurons, contributes to pancreatic pain, thus identifying a potential target for treating pancreatic pain caused by inflammation.
Collapse
Affiliation(s)
- Shusheng Wang
- The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Hong-Yan Zhu
- The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Yi Jin
- Department of Anesthesiology, Nanjing Jinling Hospital, Nanjing, China
| | - Youlang Zhou
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Shufen Hu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Tong Liu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Xinghong Jiang
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Guang-Yin Xu
- The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China;
| |
Collapse
|
|
25
|
Bouwense SAW, de Vries M, Schreuder LTW, Olesen SS, Frøkjær JB, Drewes AM, van Goor H, Wilder-Smith OHG. Systematic mechanism-orientated approach to chronic pancreatitis pain. World J Gastroenterol 2015; 21:47-59. [PMID: 25574079 PMCID: PMC4284360 DOI: 10.3748/wjg.v21.i1.47] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 08/23/2014] [Accepted: 11/19/2014] [Indexed: 02/07/2023] Open
Abstract
Pain in chronic pancreatitis (CP) shows similarities with other visceral pain syndromes (i.e., inflammatory bowel disease and esophagitis), which should thus be managed in a similar fashion. Typical causes of CP pain include increased intrapancreatic pressure, pancreatic inflammation and pancreatic/extrapancreatic complications. Unfortunately, CP pain continues to be a major clinical challenge. It is recognized that ongoing pain may induce altered central pain processing, e.g., central sensitization or pro-nociceptive pain modulation. When this is present conventional pain treatment targeting the nociceptive focus, e.g., opioid analgesia or surgical/endoscopic intervention, often fails even if technically successful. If central nervous system pain processing is altered, specific treatment targeting these changes should be instituted (e.g., gabapentinoids, ketamine or tricyclic antidepressants). Suitable tools are now available to make altered central processing visible, including quantitative sensory testing, electroencephalograpy and (functional) magnetic resonance imaging. These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes. The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved. Future research should address the circumstances under which central nervous system pain processing changes in CP, and how this is influenced by ongoing nociceptive input and therapies. Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy, leading to improved treatment of chronic pain in CP and other visceral pain disorders.
Collapse
|
|
26
|
D’Haese JG, Hartel M, Demir IE, Hinz U, Bergmann F, Büchler MW, Friess H, Ceyhan GO. Pain sensation in pancreatic diseases is not uniform: The different facets of pancreatic pain. World J Gastroenterol 2014; 20:9154-9161. [PMID: 25083089 PMCID: PMC4112857 DOI: 10.3748/wjg.v20.i27.9154] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/13/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To systematically characterize specific pain patterns in the most frequent pancreatic diseases.
METHODS: Pain in patients with chronic pancreatitis (n = 314), pancreatic cancer (n = 469), and other pancreatic tumors (n = 249) including mucinous (n = 20) and serous cystadenoma (n = 31), invasive (n = 37) and non-invasive intraductal papillary mucinous neoplasia (IPMN; n = 48), low stage (n = 18) and high stage neuroendocrine neoplasia (n = 44), and ampullary cancer (n = 51) was registered and correlated with clinicopathological data. Survival times were estimated by the Kaplan-Meier method. Patients alive at the follow-up time were censored. Survival curves were compared statistically using the log-rank test.
RESULTS: Forty-nine point one percent of pancreatic cancer patients revealed no pain, whereas in chronic pancreatitis only 18.3% were pain free. In contrary, moderate/severe pain was registered in 15.1% in pancreatic cancer patients that was increased in chronic pancreatitis with up to 34.2%. Serous cystadenoma was asymptomatic in most cases (58.1%), whereas 78.9% of all mucinous cystadenoma patients suffered pain. In neuroendocrine neoplasia pain was not a key clinical symptom since 64% of low stage neuroendocrine neoplasia and 59% of high stage neuroendocrine neoplasia patients were pain free. Cancer localization in the pancreatic body and patients with malignant pancreatic neoplasms were associated with more severe pain. Tumor grading and stage did not show any impact on pain. Only in pancreatic cancer, pain was directly associated with impaired survival.
CONCLUSION: Pancreatic pain depicts different patterns of abdominal pain sensation according to the respective pancreatic disorder and does not allow a unification of the term pancreatic pain.
Collapse
|
|
27
|
Zhao JB, Liao DH, Nissen TD. Animal models of pancreatitis: Can it be translated to human pain study? World J Gastroenterol 2013; 19:7222-7230. [PMID: 24259952 PMCID: PMC3831203 DOI: 10.3748/wjg.v19.i42.7222] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 08/12/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis affects many individuals around the world, and the study of the underlying mechanisms leading to better treatment possibilities are important tasks. Therefore, animal models are needed to illustrate the basic study of pancreatitis. Recently, animal models of acute and chronic pancreatitis have been thoroughly reviewed, but few reviews address the important aspect on the translation of animal studies to human studies. It is well known that pancreatitis is associated with epigastric pain, but the understanding regarding to mechanisms and appropriate treatment of this pain is still unclear. Using animal models to study pancreatitis associated visceral pain is difficult, however, these types of models are a unique way to reveal the mechanisms behind pancreatitis associated visceral pain. In this review, the animal models of acute, chronic and un-common pancreatitis are briefly outlined and animal models related to pancreatitis associated visceral pain are also addressed.
Collapse
|
|
28
|
Cattaruzza F, Johnson C, Leggit A, Grady E, Schenk AK, Cevikbas F, Cedron W, Bondada S, Kirkwood R, Malone B, Steinhoff M, Bunnett N, Kirkwood KS. Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice. Am J Physiol Gastrointest Liver Physiol 2013; 304:G1002-12. [PMID: 23558009 PMCID: PMC3680686 DOI: 10.1152/ajpgi.00005.2013] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic pancreatitis (CP) is a devastating disease characterized by persistent and uncontrolled abdominal pain. Our lack of understanding is partially due to the lack of experimental models that mimic the human disease and also to the lack of validated behavioral measures of visceral pain. The ligand-gated cation channel transient receptor potential ankyrin 1 (TRPA1) mediates inflammation and pain in early experimental pancreatitis. It is unknown if TRPA1 causes fibrosis and sustained pancreatic pain. We induced CP by injecting the chemical agent trinitrobenzene sulfonic acid (TNBS), which causes severe acute pancreatitis, into the pancreatic duct of C57BL/6 trpa1(+/+) and trpa1(-/-) mice. Chronic inflammatory changes and pain behaviors were assessed after 2-3 wk. TNBS injection caused marked pancreatic fibrosis with increased collagen-staining intensity, atrophy, fatty replacement, monocyte infiltration, and pancreatic stellate cell activation, and these changes were reflected by increased histological damage scores. TNBS-injected animals showed mechanical hypersensitivity during von Frey filament probing of the abdomen, decreased daily voluntary wheel-running activity, and increased immobility scores during open-field testing. Pancreatic TNBS also reduced the threshold to hindpaw withdrawal to von Frey filament probing, suggesting central sensitization. Inflammatory changes and pain indexes were significantly reduced in trpa1(-/-) mice. In conclusion, we have characterized in mice a model of CP that resembles the human condition, with marked histological changes and behavioral measures of pain. We have demonstrated, using novel and objective pain measurements, that TRPA1 mediates inflammation and visceral hypersensitivity in CP and could be a therapeutic target for the treatment of sustained inflammatory abdominal pain.
Collapse
Affiliation(s)
- Fiore Cattaruzza
- 1Department of Surgery, University of California, San Francisco, California;
| | - Cali Johnson
- 1Department of Surgery, University of California, San Francisco, California;
| | - Alan Leggit
- 2Department of Neuroscience, University of California, San Francisco, California;
| | - Eileen Grady
- 1Department of Surgery, University of California, San Francisco, California;
| | - A. Katrin Schenk
- 5Department of Physics, Randolph College, Lynchburg, Virginia; and
| | - Ferda Cevikbas
- 3Department of Dermatology, University of California, San Francisco, California;
| | - Wendy Cedron
- 3Department of Dermatology, University of California, San Francisco, California;
| | - Sandhya Bondada
- 1Department of Surgery, University of California, San Francisco, California;
| | - Rebekah Kirkwood
- 1Department of Surgery, University of California, San Francisco, California;
| | - Brian Malone
- 4Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, California;
| | - Martin Steinhoff
- 1Department of Surgery, University of California, San Francisco, California; ,3Department of Dermatology, University of California, San Francisco, California;
| | - Nigel Bunnett
- 6Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | | |
Collapse
|
|
29
|
Current world literature. Curr Opin Organ Transplant 2013; 18:111-30. [PMID: 23299306 DOI: 10.1097/mot.0b013e32835daf68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|