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Thierens NDE, Verdonk RC, Löhr JM, van Santvoort HC, Bouwense SA, van Hooft JE. Chronic pancreatitis. Lancet 2025; 404:2605-2618. [PMID: 39647500 DOI: 10.1016/s0140-6736(24)02187-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 09/20/2024] [Accepted: 10/01/2024] [Indexed: 12/10/2024]
Abstract
Chronic pancreatitis is a progressive fibroinflammatory disease primarily caused by a complex interplay of environmental and genetic risk factors. It might result in pancreatic exocrine and endocrine insufficiency, chronic pain, reduced quality of life, and increased mortality. The diagnosis is based on the presence of typical symptoms and multiple morphological manifestations of the pancreas, including pancreatic duct stones and strictures, parenchymal calcifications, and pseudocysts. Management of chronic pancreatitis consists of prevention and treatment of complications, requiring a multidisciplinary approach focusing on lifestyle modifications, exocrine insufficiency, nutritional status, bone health, endocrine insufficiency, pain management, and psychological care. To optimise clinical outcomes, screening for complications and evaluation of treatment efficacy are indicated in all patients with chronic pancreatitis.
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Affiliation(s)
- Naomi DE Thierens
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Research and Development, St Antonius Hospital, Nieuwegein, Netherlands.
| | - Robert C Verdonk
- Department of Gastroenterology and Hepatology, St Antonius Hospital, Nieuwegein, Netherlands
| | - J Matthias Löhr
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Hjalmar C van Santvoort
- Department of Surgery, St Antonius Hospital, Nieuwegein, Netherlands; Department of Surgery, University Medical Center Utrecht, Utrecht, Netherlands
| | - Stefan Aw Bouwense
- Department of Surgery, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
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2
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van Veldhuisen CL, Leseman CA, De Rijk FEM, Marques-Antunes J, Ausania F, Belyaev O, Berrevoet F, Boermeester MA, Boggi U, Bouwense SA, Bruno MJ, Busch OR, Conlon KC, Dokmak S, Falconi M, Ghorbani P, Gryspeerdt F, Haen R, Ibrahimli A, Izbicki JR, Krikke C, Kokkola A, Marique L, Mieog JSD, Nappo G, Pavulans J, Plaudis H, Roeyen G, Scognamiglio P, Tamburrino D, Tholfsen T, Toschka M, Uzunoglu FG, van Dieren S, Van Eijck CHJ, van Hooft JE, van Santvoort HC, Verdonk RC, Voermans RP, Waage A, Besselink MG. Surgery for chronic pancreatitis across Europe (ESCOPA): prospective multicentre study. Br J Surg 2025; 112:znaf068. [PMID: 40296656 PMCID: PMC12038157 DOI: 10.1093/bjs/znaf068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/27/2025] [Accepted: 03/07/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND Randomized trials have demonstrated the superiority of surgery over endoscopy in patients with symptomatic chronic pancreatitis. However, large international studies quantifying the impact of surgery on chronic pancreatitis are lacking. The aim of this study was to evaluate current practice across Europe regarding indications, surgical techniques, and outcomes of surgery for chronic pancreatitis. METHODS A prospective multicentre study of consecutive patients undergoing surgery for symptomatic chronic pancreatitis from 22 centres in 13 countries from 1 June 2021 to 30 November 2022 was conducted. The outcome of interest in patients with pain as an indication was the Izbicki pain score at 6-month follow-up, with complete pain relief defined as an Izbicki pain score ≤10 and partial pain relief defined as an Izbicki pain score >10, but with a >50% decrease compared with the baseline score. Quality of life was assessed using Pancreatitis Quality of Life Instrument (PANQOLI) and 12-Item Short-Form (SF-12) surveys. Predictors of pain relief were analysed using multivariable analysis. RESULTS Overall, 207 patients underwent surgery (24.6% underwent surgical drainage procedures, 29.5% underwent duodenum-preserving head resections, and 45.9% underwent formal pancreatic resections). Before surgery, 48.8% used opioids and 51.2% had undergone prior endoscopic treatment. Major morbidity occurred in 14.0% and the 90-day mortality rate was 1.4%. Among 113 patients operated on for pain, the median Izbicki pain score decreased from 61.3 to 19.0 at 6 months (P < 0.001). Pain relief was achieved in 72.6% (43 patients reported complete pain relief and 39 patients reported partial pain relief). PANQOLI and SF-12 Physical Component Summary scores improved significantly (P < 0.001). Longer symptom duration (OR 0.95 (95% c.i. 0.90 to 1.00), P = 0.045) and use of opioids before surgery (OR 3.16 (95% c.i. 1.04 to 9.64), P = 0.043) predicted less pain relief. CONCLUSION Surgery for chronic pancreatitis across Europe was performed with low morbidity. Patients reported good pain relief and improvements in quality-of-life scores. Multidisciplinary consultation is recommended for all patients with chronic pancreatitis before undergoing any intervention.
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Affiliation(s)
- Charlotte L van Veldhuisen
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Research and Development, St Antonius Hospital, Nieuwegein, The Netherlands
| | - Charlotte A Leseman
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Fleur E M De Rijk
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | | | - Fabio Ausania
- Department of Hepatic, Pancreatic, Biliary, and Transplant Surgery, Clinic Hospital, University of Barcelona, IDIBAPS, Barcelona, Spain
| | - Orlin Belyaev
- Department of Surgery, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Frederik Berrevoet
- General and HPB Surgery and Liver Transplantations, Ghent University Hospital, Ghent, Belgium
| | - Marja A Boermeester
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Ugo Boggi
- Division of General and Transplant Surgery, University of Pisa, Pisa, Italy
| | - Stefan A Bouwense
- Department of Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Olivier R Busch
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Kevin C Conlon
- Department of Surgery, Trinity College Dublin, Tallaght Hospital, Dublin, Ireland
| | - Safi Dokmak
- Department of HPB Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, University of Paris Cité, Centre de Recherche sur l'Inflammation, INSERM Unité Mixte de Recherche 1149, Clichy, France
| | - Massimo Falconi
- Pancreas Translational and Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Università Vita-Salute, Milan, Italy
| | - Poya Ghorbani
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Filip Gryspeerdt
- General and HPB Surgery and Liver Transplantations, Ghent University Hospital, Ghent, Belgium
| | - Roel Haen
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | | | - Jakob R Izbicki
- Department for General, Visceral and Thoracic Surgery, University Hospital Hamburg Eppendorf, Hamburg, Germany
| | - Christina Krikke
- Department of Surgery, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Arto Kokkola
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Lancelot Marique
- Department of HPB Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, University of Paris Cité, Centre de Recherche sur l'Inflammation, INSERM Unité Mixte de Recherche 1149, Clichy, France
| | - J Sven D Mieog
- Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands
| | - Gennaro Nappo
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Pancreatic Surgery Unit, Humanitas Clinical and Research Centre, IRCCS, Milan, Italy
| | - Janis Pavulans
- Department of Surgery, Riga East Clinical University Hospital, Riga, Latvia
| | - Haralds Plaudis
- Department of Surgery, Riga East Clinical University Hospital, Riga, Latvia
| | - Geert Roeyen
- Department of Hepatobiliary Transplantation and Endocrine Surgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium
| | - Pasquale Scognamiglio
- Department for General, Visceral and Thoracic Surgery, University Hospital Hamburg Eppendorf, Hamburg, Germany
| | - Domenico Tamburrino
- Pancreas Translational and Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Università Vita-Salute, Milan, Italy
| | - Tore Tholfsen
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Marie Toschka
- Department of Surgery, St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Faik G Uzunoglu
- Department for General, Visceral and Thoracic Surgery, University Hospital Hamburg Eppendorf, Hamburg, Germany
| | - Susan van Dieren
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Hjalmar C van Santvoort
- Department of Surgery, St Antonius Hospital, Nieuwegein, The Netherlands
- Department of Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Robert C Verdonk
- Department of Gastroenterology and Hepatology, St Antonius Hospital, Nieuwegein, The Netherlands
| | - Rogier P Voermans
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Anne Waage
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Marc G Besselink
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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3
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Olesen SS, Phillips AE, Faghih M, Kuhlmann L, Steinkohl E, Frøkjær JB, Bick BL, Ramsey ML, Hart PA, Garg PK, Singh VK, Yadav D, Drewes AM. Overlap and cumulative effects of pancreatic duct obstruction, abnormal pain processing and psychological distress on patient-reported outcomes in chronic pancreatitis. Gut 2022; 71:2518-2525. [PMID: 34675068 DOI: 10.1136/gutjnl-2021-325855] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/07/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Several factors have been suggested to mediate pain in patients with chronic pancreatitis. However, it is unknown whether these factors are overlapping and if they have cumulative effects on patient-reported outcomes (PROs). DESIGN We performed a multicentre cross-sectional study of 201 prospectively enrolled subjects with definitive chronic pancreatitis. All subjects underwent evaluation for pancreatic duct obstruction, abnormalities in pain processing using quantitative sensory testing, and screening for psychological distress (anxiety, depression and pain catastrophising) based on validated questionnaires. Abnormality was defined by normal reference values. PROs included pain symptom severity (Brief Pain Inventory short form) and quality of life (EORTC-QLQ-C30 questionnaire). Associations between pain-related factors and PROs were investigated by linear trend analyses, multiple regression models and mediation analyses. RESULTS Clinical evaluation suggestive of pancreatic duct obstruction was observed in 29%, abnormal pain processing in 23%, anxiety in 47%, depression in 39% and pain catastrophising in 28%; each of these factors was associated with severity of at least one PRO. Two or more factors were present in 51% of subjects. With an increasing number of factors, there was an increase in pain severity scores (p<0.001) and pain interference scores (p<0.001), and a reduction in quality of life (p<0.001). All factors had independent and direct effects on PROs, with the strongest effect size observed for psychological distress. CONCLUSION Pain-related factors in chronic pancreatitis are often present in an overlapping manner and have a cumulative detrimental effect on PROs. These findings support a multidisciplinary strategy for pain management. TRIAL REGISTRATION NUMBER The study was registered with ClinicalTrials.gov (NCT03434392).
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Affiliation(s)
- Søren S Olesen
- Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark .,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Anna E Phillips
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mahya Faghih
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Louise Kuhlmann
- Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Emily Steinkohl
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Jens B Frøkjær
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Benjamin L Bick
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Mitchell L Ramsey
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Pramod K Garg
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Vikesh K Singh
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Dhiraj Yadav
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Asbjørn M Drewes
- Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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Phillips AE, Bick BL, Faghih M, Yadav D, Drewes AM, Singh VK, Olesen SS. Pain Sensitivity and Psychiatric Comorbidities in Chronic Pancreatitis Patients With and Without Pain: Past Experience Matters. GASTRO HEP ADVANCES 2022; 1:796-802. [PMID: 39131846 PMCID: PMC11307602 DOI: 10.1016/j.gastha.2022.04.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 04/15/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Pain is the primary symptom of chronic pancreatitis (CP) and has been associated with abnormal pain processing and psychologic distress. Little is known about these phenomena in patients with painless disease. The aim of this study was to characterize patterns of pain processing and psychologic distress in patients with primary painless vs painful CP. Methods This was a cross-sectional multicenter study of 235 patients with definitive CP. Patients were categorized based on current and past pain history; current pain (79%), no current (but prior) pain (11%), and painless CP (10%). Demographic information and clinical data including symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale were collected. All patients underwent quantitative sensory testing to assess patterns of pain processing. Results A total of 235 patients (57% males, mean age 53.9 ± 14.0 years, 41% alcohol etiology) were included. Compared to patients with painless CP, enhanced pain sensitivity was observed in both patients with current pain (odds ratio [OR] 3.29; 95% confidence interval [CI] [1.11-9.77], P = .032) and no current pain (OR 4.07; 95% CI [1.10-15.03], P = .035). Patients with current pain also had increased depression prevalence compared to patients with painless CP (OR 6.15; 95% CI [1.28-29.41], P = .023), while no difference was seen for patients with no current pain (OR 1.24; 95% CI [0.19-8.26], P = .824). Conclusion Total absence of pain in CP is associated with normal pain processing and low prevalence of psychologic distress, whereas patients with prior pain experience appear to have persistent and enhanced pain sensitivity even in the absence of clinical pain and psychologic distress.
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Affiliation(s)
- Anna E. Phillips
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Benjamin L. Bick
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Mahya Faghih
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Asbjørn M. Drewes
- Department of Gastroenterology and Hepatology, Centre for Pancreatic Diseases and Mech-Sense, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Vikesh K. Singh
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Søren S. Olesen
- Department of Gastroenterology and Hepatology, Centre for Pancreatic Diseases and Mech-Sense, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Pancreatic Quantitative Sensory Testing (P-QST) Consortium
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Gastroenterology and Hepatology, Centre for Pancreatic Diseases and Mech-Sense, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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Phillips AE, Faghih M, Singh VK, Olesen SS, Kuhlmann L, Novovic S, Bick B, Hart PA, Ramsey ML, Talukdar R, Garg PK, Yadav D, Drewes AM. Rationale for and Development of the Pancreatic Quantitative Sensory Testing Consortium to Study Pain in Chronic Pancreatitis. Pancreas 2021; 50:1298-1304. [PMID: 34860815 DOI: 10.1097/mpa.0000000000001912] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVES Abdominal pain is the primary symptom of chronic pancreatitis (CP), but pain is difficult to assess, and objective methods for pain assessment are lacking. The characterization of the sensory component of pain as a surrogate for nociception can be achieved by sensory testing using standardized stimuli. Herein, we describe the rationale for and development of an international consortium to better understand and characterize CP pain. METHODS A collaboration was initially formed between the University of Aalborg, Johns Hopkins University, and the University of Pittsburgh. This group refined the protocol for pancreatic quantitative sensory testing (P-QST) and then expanded the collaboration with plans for incorporating P-QST into prospective studies. RESULTS The collaboration has successfully developed a P-QST nomogram. Chronic pancreatitis patients identified with P-QST as having widespread hyperalgesia had higher pain intensity scores, higher prevalence of constant pain, and decreased quality of life. Psychiatric comorbidities were independent of pain phenotypes. Multiple studies are underway to validate these findings and evaluate their utility in clinical trials. CONCLUSIONS Development of the P-QST Consortium will facilitate collaborative efforts to use P-QST as a means for evaluation and characterization of pain in CP patients, and optimize methods to guide individualized pain management approaches.
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Affiliation(s)
- Anna Evans Phillips
- From the Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Mahya Faghih
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Vikesh K Singh
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | | | - Srdan Novovic
- Pancreatitis Centre Copenhagen, Gastrounit, Hvidovre Hospital, Copenhagen, Denmark
| | - Benjamin Bick
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Philip A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Mitchell L Ramsey
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Rupjyoti Talukdar
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad
| | - Pramod K Garg
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Dhiraj Yadav
- From the Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Yadav D, Palermo TM, Phillips AE, Bellin MD, Conwell DL. Painful chronic pancreatitis - new approaches for evaluation and management. Curr Opin Gastroenterol 2021; 37:504-511. [PMID: 34172622 PMCID: PMC8826115 DOI: 10.1097/mog.0000000000000769] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW Management of abdominal pain in patients with chronic pancreatitis is often suboptimal. We review recent data on the epidemiology and new approaches for managing pain in chronic pancreatitis. RECENT FINDINGS Chronic pancreatitis duration does not appear to affect the pain experience. Pain pattern in chronic pancreatitis patients frequently changes and is not related to traditional patient and disease-related factors. Psychologic comorbidities, i.e. anxiety and depression, are frequent in patients with chronic pancreatitis, and are associated with more severe pain and pain interference. Adjunctive treatments, such as cognitive behavioral therapy, may positively influence pain management in chronic pancreatitis. Total pancreatectomy with islet autotransplantation (TPIAT) is an increasingly adopted treatment option in painful chronic pancreatitis. Ongoing multicenter studies will help define optimal candidates, predictors of successful pain remission and diabetes outcomes after TPIAT. Pancreatic quantitative sensory testing, a promising technique to interrogate nociception and sensory response, holds promise to identify patients with central sensitization. Initial studies show feasibility to stratify patients into defined pain profiles, and future studies will explore if these can help in prognostication of pain therapy. SUMMARY Several lines of investigations currently under evaluation are likely to have a positive impact on the management of pain in chronic pancreatitis.
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Affiliation(s)
- Dhiraj Yadav
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Tonya M. Palermo
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA
| | - Anna E. Phillips
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Melena D. Bellin
- Division of Endocrinology and Metabolism, University of Minnesota Medical Center, Minneapolis, MN
| | - Darwin L. Conwell
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
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7
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Nociceptor-localized cGMP-dependent protein kinase I is a critical generator for central sensitization and neuropathic pain. Pain 2021; 162:135-151. [PMID: 32773598 DOI: 10.1097/j.pain.0000000000002013] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Patients with neuropathic pain often experience exaggerated pain and anxiety. Central sensitization has been linked with the maintenance of neuropathic pain and may become an autonomous pain generator. Conversely, emerging evidence accumulated that central sensitization is initiated and maintained by ongoing nociceptive primary afferent inputs. However, it remains elusive what mechanisms underlie this phenomenon and which peripheral candidate contributes to central sensitization that accounts for pain hypersensitivity and pain-related anxiety. Previous studies have implicated peripherally localized cGMP-dependent protein kinase I (PKG-I) in plasticity of nociceptors and spinal synaptic transmission as well as inflammatory hyperalgesia. However, whether peripheral PKG-I contributes to cortical plasticity and hence maintains nerve injury-induced pain hypersensitivity and anxiety is unknown. Here, we demonstrated significant upregulation of PKG-I in ipsilateral L3 dorsal root ganglia (DRG), no change in L4 DRG, and downregulation in L5 DRG upon spared nerve injury. Genetic ablation of PKG-I specifically in nociceptors or post-treatment with intervertebral foramen injection of PKG-I antagonist, KT5823, attenuated the development and maintenance of spared nerve injury-induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in the anterior cingulate cortex upon peripheral neuropathy through presynaptic mechanisms involving brain-derived neurotropic factor signaling. Our results revealed that PKG-I expressed in nociceptors is a key determinant for cingulate synaptic plasticity after nerve injury, which contributes to the maintenance of pain hypersensitivity and anxiety. Thereby, this study presents a strong basis for opening up a novel therapeutic target, PKG-I, in nociceptors for treatment of comorbidity of neuropathic pain and anxiety with least side effects.
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Schneider A, Hirth M. Pain Management in Chronic Pancreatitis: Summary of Clinical Practice, Current Challenges and Potential Contribution of the M-ANNHEIM Classification. Drugs 2021; 81:533-546. [PMID: 33587287 DOI: 10.1007/s40265-021-01472-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2021] [Indexed: 01/06/2023]
Abstract
Abdominal pain, diarrhea with weight loss, and endocrine insufficiency represent the dominant symptoms of chronic pancreatitis (CP). High intensity of pain and constant pain have been shown to reduce quality of life in CP and may result in disability and increased health resource utilization. Various basic challenges and unanswered questions still exist regarding the treatment of pain in CP. Recently, limited evidence has been gained that early surgery for painful disease might be associated with better treatment results. Thus, timing of pancreatic surgery in painful disease represents a major issue that needs to be clarified in future studies. In this context, surveillance of patients is necessary in clinical practice. It appears that a generally accepted classification of the disease represents a major requirement for inter-institutional comparison of data with future progress in clinical research. Among recently proposed classification systems, the M-ANNHEIM classification system of CP with its recently presented M-ANNHEIM Surgery Score might be a useful tool to picture the course of the disease and to monitor treatment results. Future research is required to clarify the possible role of this system in the management of pain in CP. In the present article, we provide an overview of current status, challenges, and unanswered questions in the treatment of pain in CP, and we demonstrate the potential benefits of the M-ANNHEIM classification system in the management of painful CP.
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Affiliation(s)
- Alexander Schneider
- Department of Gastroenterology and Hepatology, Medical Center Bad Hersfeld-Rotenburg, Bad Hersfeld, Germany. .,Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Ratnayake CBB, Kamarajah SK, Loveday BPT, Nayar M, Oppong K, White S, French JJ, Windsor JA, Pandanaboyana S. A Network Meta-analysis of Surgery for Chronic Pancreatitis: Impact on Pain and Quality of Life. J Gastrointest Surg 2020; 24:2865-2873. [PMID: 32705610 DOI: 10.1007/s11605-020-04718-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 06/27/2020] [Indexed: 01/31/2023]
Abstract
BACKGROUND The surgical operation associated with improved pain and quality of life (QoL) in patients with chronic pancreatitis (CP) is unknown. METHOD The Scopus, EMBASE, Medline and Cochrane databases were systematically searched until May 2019, and all randomised trials (RCTs) comparing surgical operations for CP pain were included in a network meta-analysis (NMA). RESULTS Four surgical operations for treating CP were directly compared in eight RCTs including 597 patients. Patients were mainly male (79%, 474/597) with alcoholic CP (85%, 382/452). Surgical operations included were pancreatoduodenectomy (224, 38%), Berne procedure (168, 28%), Beger procedure (133, 22%) and Frey procedure (72, 12%). The NMA revealed that the Beger procedure ranked best for pain relief, whilst the Frey procedure ranked best for postoperative QoL, postoperative pancreatic fistula rate and postoperative exocrine insufficiency rate during a median follow-up of 26 months (reported range 6-58 months). Overall the Frey procedure ranked best for the combination of primary outcome measures based on surface under cumulative ranking curve scores. CONCLUSIONS Overall the Frey procedure may perform the best for both pain relief and postoperative QoL in patients with CP. Further trials are warranted in defining the role of surgery in relation to endotherapy.
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Affiliation(s)
- Chathura B B Ratnayake
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Surgery, Auckland District Health Board, Auckland, New Zealand
| | - Sivesh K Kamarajah
- Department of Hepatobiliary, Pancreatic and Transplant Surgery, Department of Surgery,, Freeman Hospital, Newcastle upon Tyne, UK
| | - Benjamin P T Loveday
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Surgery, The Royal Melbourne Hospital, Melbourne, Australia
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Manu Nayar
- Department of Gastroenterology, Freeman Hospital, Newcastle upon Tyne, UK
| | - Kofi Oppong
- Department of Gastroenterology, Freeman Hospital, Newcastle upon Tyne, UK
| | - Steve White
- Department of Hepatobiliary, Pancreatic and Transplant Surgery, Department of Surgery,, Freeman Hospital, Newcastle upon Tyne, UK
| | - Jeremy J French
- Department of Hepatobiliary, Pancreatic and Transplant Surgery, Department of Surgery,, Freeman Hospital, Newcastle upon Tyne, UK
| | - John A Windsor
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Surgery, Auckland District Health Board, Auckland, New Zealand
| | - Sanjay Pandanaboyana
- Department of Hepatobiliary, Pancreatic and Transplant Surgery, Department of Surgery,, Freeman Hospital, Newcastle upon Tyne, UK.
- Population Health Sciences Institute, Newcastle University, Newcastle, UK.
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Patient and Disease Characteristics Associate With Sensory Testing Results in Chronic Pancreatitis. Clin J Pain 2020; 35:786-793. [PMID: 31268890 PMCID: PMC6693925 DOI: 10.1097/ajp.0000000000000740] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Abdominal pain is the most common symptom in chronic pancreatitis (CP) and has an extensive impact on patients' lives. Quantitative sensory testing (QST) provides information on sensitivity to pain and mechanisms that can help quantify pain and guide treatment. The aims of this study were (1) to explore sensitivity to pain in patients with CP using QST and (2) to associate patient and disease characteristics with QST results. METHODS Ninety-one patients with painful CP and 28 healthy control participants completed a QST paradigm using static tests (muscle pressure stimulation and electrical skin stimulations) to unravel segmental and widespread hyperalgesia as a consequence of visceral pain. A dynamic conditioned pain modulation (CPM) paradigm was used as a proxy of pain modulation from the brainstem to inhibit incoming nociceptive barrage, and questionnaires were used to gather information on pain experience and quality of life. RESULTS Patients had impaired CPM compared with controls (18.0±29.3% vs. 30.9±29.3%, P=0.04) and were hypersensitive to pressure stimulation, specifically in the pancreatic (Th10) dermatome (P<0.001). The capacity of CPM was associated with clinical pain intensity (P=0.01) and (in the univariate analysis only) the use of opioids was associated with hyperalgesia to pressure stimulation (P<0.05). CONCLUSIONS Sensitivity to pain in CP patients can be characterized by a simple bedside QST. Severe clinical pain in CP was associated with reduced CPM function and should be targeted in management.
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11
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Olesen SS, Drewes AM, Gaud R, Tandan M, Lakhtakia S, Ramchandani M, Rao GV, Reddy DN, Talukdar R. Combined extracorporeal shock wave lithotripsy and endoscopic treatment for pain in chronic pancreatitis (SCHOKE trial): study protocol for a randomized, sham-controlled trial. Trials 2020; 21:338. [PMID: 32299454 PMCID: PMC7164272 DOI: 10.1186/s13063-020-04296-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 03/30/2020] [Indexed: 02/08/2023] Open
Abstract
Background Pain is the primary symptom of chronic pancreatitis (CP) and remains a considerable therapeutic challenge. In patients with obstruction of the pancreatic duct, including stones and strictures, endoscopic treatment with or without preceding extracorporeal shock wave lithotripsy (ESWL) has been used for pancreatic duct decompression. The rationale for these procedures is based on the assumption that obstruction of the pancreatic duct leads to ductal hypertension and pain. However, clinical pain symptoms correlate poorly with pancreatic duct morphology, and the evidence for pancreatic duct decompression as an effective treatment for pain is based on case series and comparison between different procedures. No randomized, prospective, sham-controlled trials are currently available. The SCHOKE (Extracorporeal Shock Wave Lithotripsy and Endotherapy for Pain in Chronic Pancreatitis) trial is a randomized, sham-controlled trial designed to determine if pancreatic duct decompression is an effective treatment for pain in patients with CP. Methods The SCHOKE trial is a randomized, single-blind, parallel-group, sham-controlled trial designed to evaluate the effect of combined ESWL and endoscopic treatment for pain in patients with CP. In total, 106 adult patients with painful CP and pancreatic duct obstruction will be randomized to combined ESWL and subsequent endoscopic treatment or corresponding sham procedures. The primary outcome is pain relief during the 3-month postrandomization period as documented in a pain diary. Secondary outcomes include quality of life and functional scores, patient global impression of change, change in use of analgesics, frequency of hospitalization, and complications. Standard follow-up is at 3 and 6 months after randomization. In an experimental substudy, quantitative sensory testing obtained before and after intervention will be used to obtain information on central pain processing and to develop models for prediction of treatment outcome. Discussion The SCHOKE trial investigates if pancreatic duct decompression, obtained by combined ESWL and endoscopic treatment, is effective for pain treatment in patients with CP. Trial registration ClinicalTrials.gov, NCT03966781. Registered on May 25, 2019. Protocol date and version identifier: March 1, 2020; version 3.0. Sponsor: Rupjyoti Talukdar, Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India.
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Affiliation(s)
- Søren S Olesen
- Department of Gastroenterology and Hepatology, Centre for Pancreatic Diseases, Aalborg University Hospital, Aalborg, Denmark.
| | - Asbjørn M Drewes
- Department of Gastroenterology and Hepatology, Centre for Pancreatic Diseases, Aalborg University Hospital, Aalborg, Denmark
| | - Rajesh Gaud
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Manu Tandan
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Sundeep Lakhtakia
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Mohan Ramchandani
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - G V Rao
- Department of Surgical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - D Nageshwar Reddy
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Rupjyoti Talukdar
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India.,Pancreas Research Group, Wellcome DBT Labs, Asian Healthcare Foundation, Hyderabad, Telangana, India
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12
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Cleland T, Jain NB, Chae J, Hansen KM, Hisel TZ, Gunzler DD, Whitehair VC, Kim CH, Wilson RD. The protocol for a multisite, double blind, randomized, placebo-controlled trial of axillary nerve stimulation for chronic shoulder pain. Trials 2020; 21:248. [PMID: 32143732 PMCID: PMC7059286 DOI: 10.1186/s13063-020-4174-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 02/17/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Shoulder impingement syndrome is one of the most common causes of shoulder pain, accounting for approximately 30% of all shoulder pain. Approximately 35% of patients with shoulder impingement syndrome are refractory to conservative treatment. For patients who fail conservative treatment, there is no established treatment to successfully treat their chronic pain. Prior randomized control trials have demonstrated efficacy for the use of a single lead intramuscular peripheral nerve stimulation of the axillary nerve at the motor points of the deltoid muscle for treatment of hemiplegic shoulder pain. This is the first controlled trial to utilize the same novel technology to treat shoulder impingement syndrome outside of the stroke population. METHODS This is a dual-site, placebo-controlled, double-blinded, randomized control trial. Participants will be randomized to two treatment groups. The intervention group will be treated with active peripheral nerve stimulation of the axillary nerve of the affected shoulder and the control group will be treated with sham peripheral nerve stimulation of the axillary nerve of the affected shoulder. Both groups will receive a standardized exercise therapy program directed by a licensed therapist. DISCUSSION This study protocol will allow the investigators to determine if this novel, non-pharmacologic treatment of shoulder pain can demonstrate the same benefit in musculoskeletal patients which has been previously demonstrated in the stroke population. TRIAL REGISTRATION Clinicaltrials.gov, NCT03752619. Registered on 26 November 2018.
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Affiliation(s)
- Travis Cleland
- MetroHealth Rehabilitation Institute, MetroHealth System, 4229 Pearl Rd, N5-27, Cleveland, OH 44109 USA
| | - Nitin B. Jain
- Vanderbilt University Medical Center, 3319 West End Ave, Nashville, TN 37203 USA
| | - John Chae
- MetroHealth Rehabilitation Institute, MetroHealth System, 4229 Pearl Rd, N5-27, Cleveland, OH 44109 USA
| | - Kristine M. Hansen
- MetroHealth Rehabilitation Institute, MetroHealth System, 4229 Pearl Rd, N5-27, Cleveland, OH 44109 USA
| | - Terri Z. Hisel
- MetroHealth Rehabilitation Institute, MetroHealth System, 4229 Pearl Rd, N5-27, Cleveland, OH 44109 USA
| | - Douglas D. Gunzler
- Center for Healthcare Research and Policy, MetroHealth System, 2500 MetroHealth Dr., Cleveland, OH 44109 USA
| | - Victoria C. Whitehair
- MetroHealth Rehabilitation Institute, MetroHealth System, 4229 Pearl Rd, N5-27, Cleveland, OH 44109 USA
| | - Chong H. Kim
- MetroHealth Rehabilitation Institute, MetroHealth System, 4229 Pearl Rd, N5-27, Cleveland, OH 44109 USA
| | - Richard D. Wilson
- MetroHealth Rehabilitation Institute, MetroHealth System, 4229 Pearl Rd, N5-27, Cleveland, OH 44109 USA
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13
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A clinically feasible method for the assessment and characterization of pain in patients with chronic pancreatitis. Pancreatology 2020; 20:25-34. [PMID: 31787527 DOI: 10.1016/j.pan.2019.11.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/14/2019] [Accepted: 11/18/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Pain is the primary symptom of chronic pancreatitis (CP), but methods for sensory testing and pain characterization have not previously been validated for clinical use. We present a clinically feasible method for the assessment and characterization of pain mechanisms in patients with CP based on quantitative sensory testing (QST). METHODS This was a cross-sectional, multicenter study of 122 control subjects without pancreatic disease and another 60 patients with painful CP. All subjects underwent standardized QST assessments including a cold pressor test, a conditioned pain modulation paradigm, repetitive pin-prick stimuli (temporal summation) and pressure stimulation of the upper abdominal (pancreatic) and control dermatomes. The effects of age and gender on QST assessment parameters were investigated and normative reference values based on quartile regression were derived and implemented in algorithms to categorize patients according to their patterns of central pain processing (normal vs. segmental sensitization vs. widespread sensitization). RESULTS Absolute pressure thresholds were subject to clinically relevant gender effects (all p < 0.001), while the remainder of QST parameters were unaffected by age and gender. The algorithm with the best discriminatory capacity showed good separation between patients and controls (p < 0.001); 50% of patients had normal central pain processing, 23% had evidence of segmental sensitization and 27% had evidence of widespread sensitization. CONCLUSION We show normative reference values for a clinically feasible method for assessment and characterization of pain mechanisms in patients with CP. Application of this method streamlines the evaluation of pancreatic pain and may be used to inform treatment. CLINICALTRIALS. GOV ID NCT03434392.
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14
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Drewes AM, Kempeneers MA, Andersen DK, Arendt-Nielsen L, Besselink MG, Boermeester MA, Bouwense S, Bruno M, Freeman M, Gress TM, van Hooft JE, Morlion B, Olesen SS, van Santvoort H, Singh V, Windsor J. Controversies on the endoscopic and surgical management of pain in patients with chronic pancreatitis: pros and cons! Gut 2019; 68:1343-1351. [PMID: 31129569 PMCID: PMC6691929 DOI: 10.1136/gutjnl-2019-318742] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/01/2019] [Accepted: 05/07/2019] [Indexed: 01/09/2023]
Affiliation(s)
- Asbjørn Mohr Drewes
- Centre for Pancreatic Diseases, Department of Gastroenterology, Aalborg University Hospital & Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Marinus A Kempeneers
- Department of Surgery, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Lars Arendt-Nielsen
- Center for Sensory-Motor Interactions (SMI), Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - Marc G Besselink
- Department of Surgery, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Marja A Boermeester
- Department of Surgery, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Stefan Bouwense
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marco Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Martin Freeman
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnessota Medical School, Minneapolis, Minnesota, USA
| | - Thomas M Gress
- Department of Gastroenterology, Philipps University & University Hospital of Marburg, Marburg, Germany
| | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Bart Morlion
- The Leuven Centre for Algology & Pain Management, University Hospitals Leuven, Leuven, Belgium
| | - Søren Schou Olesen
- Centre for Pancreatic Diseases, Department of Gastroenterology, Aalborg University Hospital & Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Hjalmar van Santvoort
- Department of Surgery, St Antonius Hospital, Nieuwegein, The Netherlands,Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Vikesh Singh
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - John Windsor
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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15
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Towards a neurobiological understanding of pain in chronic pancreatitis: mechanisms and implications for treatment. Pain Rep 2017; 2:e625. [PMID: 29392239 PMCID: PMC5741325 DOI: 10.1097/pr9.0000000000000625] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 08/30/2017] [Accepted: 09/08/2017] [Indexed: 12/19/2022] Open
Abstract
We summarize the evidence for a neurobiological understanding of pain in patients with chronic pancreatitis and discuss its potential impact on prevention and treatment. Introduction: Chronic pancreatitis (CP) is a disease characterized by inflammation of the pancreas resulting in replacement of the normal functioning parenchyma by fibrotic connective tissue. This process leads to progressively impairment of exocrine and endocrine function and many patients develop a chronic pain syndrome. Objectives: We aimed to characterize the neurobiological signature of pain associated with CP and to discuss its implications for treatment strategies. Methods: Relevant basic and clinical articles were selected for review following an extensive search of the literature. Results: Pathophysiological changes in the peripheral (pancreatic gland) and central nervous system characterize the pain syndrome associated with CP; involved mechanisms can be broken down to 3 main branches: (1) peripheral sensitization, (2) pancreatic neuropathy, and (3) neuroplastic changes in the central pain pathways. Disease flares (recurrent pancreatitis) may accelerate the pathophysiological process and further sensitize the pain system, which ultimately results in an autonomous and self-perpetuating pain state that may become independent of the peripheral nociceptive drive. These findings share many similarities with those observed in neuropathic pain disorders and have important implications for treatment; adjuvant analgesics are effective in a subset of patients, and neuromodulation and neuropsychological interventions may prove useful in the future. Conclusion: Chronic pancreatitis is associated with abnormal processing of pain at the peripheral and central level of the pain system. This neurobiological understanding of pain has important clinical implications for treatment and prevention of pain chronification.
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16
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Drewes AM, Bouwense SAW, Campbell CM, Ceyhan GO, Delhaye M, Demir IE, Garg PK, van Goor H, Halloran C, Isaji S, Neoptolemos JP, Olesen SS, Palermo T, Pasricha PJ, Sheel A, Shimosegawa T, Szigethy E, Whitcomb DC, Yadav D. Guidelines for the understanding and management of pain in chronic pancreatitis. Pancreatology 2017; 17:720-731. [PMID: 28734722 DOI: 10.1016/j.pan.2017.07.006] [Citation(s) in RCA: 187] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 06/26/2017] [Accepted: 07/11/2017] [Indexed: 12/11/2022]
Abstract
Abdominal pain is the foremost complication of chronic pancreatitis (CP). Pain can be related to recurrent or chronic inflammation, local complications or neurogenic mechanisms with corresponding changes in the nervous systems. Both pain intensity and the frequency of pain attacks have been shown to reduce quality of life in patients with CP. Assessment of pain follows the guidelines for other types of chronic pain, where the multidimensional nature of symptom presentation is taken into consideration. Quantitative sensory testing may be used to characterize pain, but is currently used in a research setting in advanced laboratories. For pain relief, current guidelines recommend a simple stepwise escalation of analgesic drugs with increasing potency until pain relief is obtained. Abstinence from alcohol and smoking should be strongly advised. Pancreatic enzyme therapy and antioxidants may be helpful as initial treatment. Endoscopic treatment can be used in patients with evidence of ductal obstruction and may be combined with extracorporeal shock wave lithothripsy. The best candidates are those with distal obstruction of the main pancreatic duct and in early stage of disease. Behavioral interventions should be part of the multidisciplinary approach to chronic pain management particularly when psychological impact is experienced. Surgery should be considered early and after a maximum of five endoscopic interventions. The type of surgery depends on morphological changes of the pancreas. Long-term effects are variable, but high success rates have been reported in open studies and when compared with endoscopic treatment. Finally, neurolytical interventions and neuromodulation can be considered in difficult patients.
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Affiliation(s)
- Asbjørn M Drewes
- Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark.
| | - Stefan A W Bouwense
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Claudia M Campbell
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Güralp O Ceyhan
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Myriam Delhaye
- Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Pramod K Garg
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Harry van Goor
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Shuiji Isaji
- Department of Surgery, Mie University Graduate School of Medicine, Japan
| | - John P Neoptolemos
- Institute of Translational Medicine, University of Liverpool, United Kingdom
| | - Søren S Olesen
- Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark
| | - Tonya Palermo
- Seattle Children's Hospital Research Institute, Washington School of Medicine, USA
| | - Pankaj Jay Pasricha
- Center for Neurogastroenterology, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Andrea Sheel
- Institute of Translational Medicine, University of Liverpool, United Kingdom
| | - Tooru Shimosegawa
- Department of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Eva Szigethy
- Visceral Inflammation and Pain Center, Division of Gastroenterology, University of Pittsburgh and UPMC, Pittsburgh, PA, USA
| | - David C Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, PA, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, PA, USA
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van Rijckevorsel DC, Boelens OB, Roumen RM, Wilder-Smith OH, van Goor H. Treatment response and central pain processing in Anterior Cutaneous Nerve Entrapment Syndrome: An explorative study. Scand J Pain 2017; 14:53-59. [PMID: 28850430 DOI: 10.1016/j.sjpain.2016.09.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 08/21/2016] [Accepted: 09/30/2016] [Indexed: 12/28/2022]
Abstract
BACKGROUND 10-30% of chronic abdominal pain originates in the abdominal wall. A common cause for chronic abdominal wall pain is the Anterior Cutaneous Nerve Entrapment Syndrome (ACNES), in which an intercostal nerve branch is entrapped in the abdominal rectus sheath. Treatment consists of local anaesthetics and neurectomy, and is ineffective in 25% of cases for yet unknown reasons. In some conditions, chronic pain is the result of altered pain processing. This so-called sensitization can manifest as segmental or even generalized hyperalgesia, and is generally difficult to treat. OBJECTIVE The aim of this study was to assess pain processing in ACNES patients responsive and refractory to treatment by using Quantitative Sensory Testing, in order to explore whether signs of altered central pain processing are present in ACNES and are a possible explanation for poor treatment outcomes. METHODS 50 patients treated for ACNES with locally orientated treatment were included. They were allocated to a responsive or refractory group based on their response to treatment. Patients showing an improvement of the Visual Analogue Scale (VAS) pain score combined with a current absolute VAS of <40mm were scored as responsive. Sensation and pain thresholds to pressure and electric skin stimulation were determined in the paravertebral bilateral ACNES dermatomes and at four control areas on the non-dominant side of the body, i.e. the musculus trapezius pars medialis, musculus rectus femoris, musculus abductor hallucis and the thenar. The ACNES dermatomes were chosen to signal segmental hyperalgesia and the sum of the control areas together as a reflection of generalized hyperalgesia. Lower thresholds were interpreted as signs of sensitized pain processing. To test for alterations in endogenous pain inhibition, a conditioned pain modulation (CPM) response to a cold pressor task was determined. Also, patients filled in three pain-related questionnaires, to evaluate possible influence of psychological characteristics on the experienced pain. RESULTS Patients refractory to treatment showed significantly lower pressure pain thresholds in the ACNES dermatomes and for the sum of as well as in two individual control areas. No differences were found between groups for electric thresholds or CPM response. Duration of complaints before diagnosis and treatment was significantly longer in the refractory compared to the responsive group, and refractory patients scored higher on the pain-related psychological surveys. CONCLUSION AND IMPLICATIONS In this hypothesis-generating exploratory study, ACNES patients refractory to treatment showed more signs of sensitized segmental and central pain processing. A longer duration of complaints before diagnosis and treatment may be related to these alterations in pain processing, and both findings could be associated with less effective locally orientated treatment. In order to validate these hypotheses further research is needed. REGISTRATION NUMBER NCT01920880 (Clinical Trials Register; http://www.clinicaltrials.gov).
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Affiliation(s)
- Dagmar C van Rijckevorsel
- Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud university medical center, Nijmegen, The Netherlands
| | - Oliver B Boelens
- Pain and Nociception Neuroscience Research Group, Department of Surgery, Maasziekenhuis Pantein, Boxmeer, Boxmeer, The Netherlands
| | - Rudi M Roumen
- Pain and Nociception Neuroscience Research Group, SolviMáx, Center of Excellence for Abdominal Wall and Groin Pain, Department of Surgery, Máxima Medical Centre, Veldhoven, The Netherlands
| | - Oliver H Wilder-Smith
- Pain and Nociception Neuroscience Research Group, Department of Anesthesiology, Pain and Palliative Medicine, Radboud university medical center, Nijmegen, The Netherlands.,Pain and Nociception Neuroscience Research Group, Centre for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark
| | - Harry van Goor
- Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud university medical center, Nijmegen, The Netherlands
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18
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Poulsen JL, Olesen SS, Drewes AM, Ye B, Li WQ, Aghdassi AA, Sendler M, Mayerle J, Lerch MM. The Pathogenesis of Chronic Pancreatitis. CHRONIC PANCREATITIS 2017:29-62. [DOI: 10.1007/978-981-10-4515-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
OBJECTIVES The authors investigated if timing of medical treatment is associated with the analgesic effect of pregabalin or placebo in patients with chronic pancreatitis (CP). METHODS Sixty-four patients received pregabalin (150-300 mg twice a day) or matching placebo for 3 consecutive weeks. Responders to treatment were defined as patients with a reduction in clinical pain scores of 30% or greater. Factors associated with timing of pain treatment (ie, duration of CP and opioid usage) were collected at baseline. In addition, other factors that potentially could influence outcome (eg, clinical pain scores prior to study medication, diabetes, and exocrine pancreatic insufficiency) were also included. Conventional groupwise logistic regression and analysis on the individual patient level with a machine learning technique were used to predict treatment response. RESULTS In the conventional statistical analysis duration of CP (odds ratio, 0.9; 95% confidence interval, 0.8-1.1; P = 0.3) and opioid treatment (odds ratio, 1.0; 95% confidence interval, 0.9-1.1; P = 0.6) were not associated with pain relief. In addition, none of the supplementary factors were associated with treatment response (all P > 0.1). Likewise, in the individual patient-level analysis, none of the included variables reached classification accuracies greater than chance level (all P > 0.1). CONCLUSIONS Pregabalin can be added as adjuvant analgesic at any time point during the disease course of CP.
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20
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Bouwense SA, Olesen SS, Drewes AM, van Goor H, Wilder-Smith OH. Pregabalin and placebo responders show different effects on central pain processing in chronic pancreatitis patients. J Pain Res 2015. [PMID: 26203273 PMCID: PMC4506030 DOI: 10.2147/jpr.s84484] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Pain control in chronic pancreatitis is a major challenge; the mechanisms behind analgesic treatment are poorly understood. This study aims to investigate the differences in pain sensitivity and modulation in chronic pancreatitis patients, based on their clinical response (responders vs nonresponders) to placebo or pregabalin treatment. METHODS This study was part of a randomized, double-blind, placebo-controlled trial evaluating the analgesic effects of pregabalin and placebo in chronic pancreatitis. Post hoc, patients were assigned to one of four groups, ie, responders and nonresponders to pregabalin (n=16; n=15) or placebo (n=12; n=17) treatment. Responders were defined as patients with >30% pain reduction after 3 weeks of treatment. We measured change in pain sensitivity before and after the treatment using electric pain detection thresholds (ePDT) in dermatomes C5 (generalized effects) and Ventral T10 (segmental effects). Descending endogenous pain modulation was quantified via conditioned pain modulation (CPM) paradigm. RESULTS Sixty patients were analyzed in a per-protocol analysis. ePDT change in C5 was significant vs baseline and greater in pregabalin (1.3 mA) vs placebo responders (-0.1 mA; P=0.015). This was not so for ePDT in Ventral T10. CPM increased more in pregabalin (9%) vs placebo responders (-17%; P<0.001). CPM changed significantly vs baseline only for pregabalin responders (P=0.006). CONCLUSION This hypothesis-generating study provides the first evidence that pain relief with pregabalin is associated with anti-hyperalgesic effects and increased endogenous inhibitory modulation. No such effects were observed in patients experiencing pain relief with the placebo treatment. The mechanisms underlying analgesic response to placebo vs drug treatments are different and, together with their interactions, deserve further study.
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Affiliation(s)
- Stefan Aw Bouwense
- Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud university medical center, Nijmegen, The Netherlands
| | - Søren S Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Asbjørn M Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Harry van Goor
- Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud university medical center, Nijmegen, The Netherlands
| | - Oliver Hg Wilder-Smith
- Pain and Nociception Neuroscience Research Group, Department of Anaesthesiology, Pain and Palliative Medicine, Radboud university medical center, Nijmegen, The Netherlands
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Smith AD, Jull GA, Schneider GM, Frizzell B, Hooper RA, Sterling MM. Low Pain Catastrophization and Disability Predict Successful Outcome to Radiofrequency Neurotomy in Individuals with Chronic Whiplash. Pain Pract 2015; 16:311-9. [DOI: 10.1111/papr.12282] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 10/14/2014] [Accepted: 11/02/2014] [Indexed: 10/24/2022]
Affiliation(s)
- Ashley D. Smith
- Division of Physiotherapy; Centre of Clinical Excellence Spinal Pain, Injury and Health; University of Queensland; Brisbane Queensland Australia
| | - Gwendolen A. Jull
- Division of Physiotherapy; Centre of Clinical Excellence Spinal Pain, Injury and Health; University of Queensland; Brisbane Queensland Australia
| | | | | | | | - Michele M. Sterling
- Griffith Health Institute; Centre of National Research on Disability and Rehabilitation Medicine; Griffith University; Gold Coast Queensland Australia
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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.
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23
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Haroutounian S, Nikolajsen L, Bendtsen TF, Finnerup NB, Kristensen AD, Hasselstrøm JB, Jensen TS. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain 2014; 155:1272-1279. [DOI: 10.1016/j.pain.2014.03.022] [Citation(s) in RCA: 149] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 03/21/2014] [Accepted: 03/27/2014] [Indexed: 12/29/2022]
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Bouwense SA, Ahmed Ali U, ten Broek RP, Issa Y, van Eijck CH, Wilder-Smith OH, van Goor H. Altered central pain processing after pancreatic surgery for chronic pancreatitis. Br J Surg 2014; 100:1797-804. [PMID: 24227367 DOI: 10.1002/bjs.9322] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic abdominal pain is common in chronic pancreatitis (CP) and may involve altered central pain processing. This study evaluated the relationship between pain processing and pain outcome after pancreatic duct decompression and/or pancreatic resection in patients with CP. METHODS Patients with CP underwent quantitative sensory testing. Pain processing was measured via electrical pain detection (ePDT) and electrical pain tolerance (ePTT) thresholds in dermatomes C5 and L4. Inhibitory descending pain control mechanisms were assessed using the conditioned pain modulation (CPM) paradigm. Healthy controls and patients with CP were compared, and patients with CP and a poor pain outcome (visual analogue scale (VAS) score greater than 30) were compared with those with a good pain outcome (VAS score 30 or less). RESULTS Forty-eight patients with CP had lower ePDT, ePTT and CPM responses compared with values in 15 healthy controls (P < 0·030). The sum of ePDT values was lower in patients with a poor pain outcome than in those with a good outcome (median 7·1 versus 11·2 mA; P = 0·008). There was a correlation with the VAS score and the sum of ePDT values (rs = -0·45, P = 0·016) and ePTT values (rs = -0·46, P = 0·011), and CPM response (rs = -0·43, P = 0·006) in patients with CP. CONCLUSION After pain-relieving pancreatic surgery, patients with CP exhibit altered central pain processing compared with that in healthy controls. Poor pain outcomes are associated with more central sensitization and more pronociceptive descending pain modulation, and this should be considered when managing persistent pain after pain-relieving surgery for CP.
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Affiliation(s)
- S A Bouwense
- Department of Surgery, Rotterdam, The Netherlands
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Poulsen JL, Olesen SS, Malver LP, Frøkjær JB, Drewes AM. Pain and chronic pancreatitis: A complex interplay of multiple mechanisms. World J Gastroenterol 2013; 19:7282-7291. [PMID: 24259959 PMCID: PMC3831210 DOI: 10.3748/wjg.v19.i42.7282] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 07/22/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Despite multiple theories on the pathogenesis of pain in chronic pancreatitis, no uniform and consistently successful treatment strategy exists and abdominal pain still remains the dominating symptom for most patients and a major challenge for clinicians. Traditional theories focussed on a mechanical cause of pain related to anatomical changes and evidence of increased ductal and interstitial pressures. These observations form the basis for surgical and endoscopic drainage procedures, but the outcome is variable and often unsatisfactory. This underscores the fact that other factors must contribute to pathogenesis of pain, and has shifted the focus towards a more complex neurobiological understanding of pain generation. Amongst other explanations for pain, experimental and human studies have provided evidence that pain perception at the peripheral level and central pain processing of the nociceptive information is altered in patients with chronic pancreatitis, and resembles that seen in neuropathic and chronic pain disorders. However, pain due to e.g., complications to the disease and adverse effects to treatment must not be overlooked as an additional source of pain. This review outlines the current theories on pain generation in chronic pancreatitis which is crucial in order to understand the complexity and limitations of current therapeutic approaches. Furthermore, it may also serve as an inspiration for further research and development of methods that can evaluate the relative contribution and interplay of different pain mechanisms in the individual patients, before they are subjected to more or less empirical treatment.
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Olesen SS, Juel J, Graversen C, Kolesnikov Y, Wilder-Smith OHG, Drewes AM. Pharmacological pain management in chronic pancreatitis. World J Gastroenterol 2013; 19:7292-7301. [PMID: 24259960 PMCID: PMC3831211 DOI: 10.3748/wjg.v19.i42.7292] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Revised: 08/05/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical challenge. Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders. An important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established, the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive drive. Consequently, the management of pain by traditional methods based on nociceptive deafferentation (e.g., surgery and visceral nerve blockade) becomes difficult and often ineffective. This novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic pancreatitis. Modern mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source, which should be reserved for special and carefully selected cases. In this review, we offer an overview of the current available pharmacological options for pain management in chronic pancreatitis. In addition, future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity.
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A comparison of physical and psychological features of responders and non-responders to cervical facet blocks in chronic whiplash. BMC Musculoskelet Disord 2013; 14:313. [PMID: 24188899 PMCID: PMC3819261 DOI: 10.1186/1471-2474-14-313] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 10/11/2013] [Indexed: 11/16/2022] Open
Abstract
Background Cervical facet block (FB) procedures are often used as a diagnostic precursor to radiofrequency neurotomies (RFN) in the management of chronic whiplash associated disorders (WAD). Some individuals will respond to the FB procedures and others will not respond. Such responders and non-responders provided a sample of convenience to question whether there were differences in their physical and psychological features. This information may inform future predictive studies and ultimately the clinical selection of patients for FB procedures. Methods This cross-sectional study involved 58 individuals with chronic WAD who responded to cervical FB procedures (WAD_R); 32 who did not respond (WAD_NR) and 30 Healthy Controls (HC)s. Measures included: quantitative sensory tests (pressure; thermal pain thresholds; brachial plexus provocation test); nociceptive flexion reflex (NFR); motor function (cervical range of movement (ROM); activity of the superficial neck flexors during the cranio-cervical flexion test (CCFT). Self-reported measures were gained from the following questionnaires: neuropathic pain (s-LANSS); psychological distress (General Health Questionnaire-28), post-traumatic stress (PDS) and pain catastrophization (PCS). Individuals with chronic whiplash attended the laboratory once the effects of the blocks had abated and symptoms had returned. Results Following FB procedures, both WAD groups demonstrated generalized hypersensitivity to all sensory tests, decreased neck ROM and increased superficial muscle activity with the CCFT compared to controls (p < 0.05). There were no significant differences between WAD groups (all p > 0.05). Both WAD groups demonstrated psychological distress (GHQ-28; p < 0.05), moderate post-traumatic stress symptoms and pain catastrophization. The WAD_NR group also demonstrated increased medication intake and elevated PCS scores compared to the WAD_R group (p < 0.05). Conclusions Chronic WAD responders and non-responders to FB procedures demonstrate a similar presentation of sensory disturbance, motor dysfunction and psychological distress. Higher levels of pain catastrophization and greater medication intake were the only factors found to differentiate these groups.
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Olesen SS, Graversen C, Bouwense SAW, van Goor H, Wilder-Smith OHG, Drewes AM. Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis. PLoS One 2013. [PMID: 23469256 DOI: 10.1371/journal.pone.005796340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis. METHODS Sixty-four patients with painful chronic pancreatitis received pregabalin (150-300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy. RESULTS The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9-1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5-2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy. CONCLUSIONS The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient's individual sensory profile and thus comprises a significant step towards personalized pain medicine.
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Affiliation(s)
- Søren S Olesen
- Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
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Olesen SS, Graversen C, Bouwense SAW, van Goor H, Wilder-Smith OHG, Drewes AM. Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis. PLoS One 2013; 8:e57963. [PMID: 23469256 PMCID: PMC3585877 DOI: 10.1371/journal.pone.0057963] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Accepted: 01/29/2013] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis. METHODS Sixty-four patients with painful chronic pancreatitis received pregabalin (150-300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy. RESULTS The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9-1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5-2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy. CONCLUSIONS The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient's individual sensory profile and thus comprises a significant step towards personalized pain medicine.
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Affiliation(s)
- Søren S. Olesen
- Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
| | - Carina Graversen
- Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
- Mech-Sense, Department of Radiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
- Department of Neurorehabilitation Engineering, Bernstein Center for Computational Neuroscience, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Stefan A. W. Bouwense
- Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Harry van Goor
- Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - Oliver H. G. Wilder-Smith
- Pain and Nociception Neuroscience Research Group, Department of Anaesthesiology, Pain and Palliative Care, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Asbjørn M. Drewes
- Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
- Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
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Abstract
Chronic pancreatitis is typically a painful condition and it can be associated with a severe burden of disease. The pathogenesis of pain in this disorder is poorly understood and its treatment has been largely empirical, often consisting of surgical or other invasive methods, with an outcome that is variable and frequently unsatisfactory. Human and experimental studies have indicated a critical role for neuronal mechanisms that result in peripheral and central sensitization. The pancreatic nociceptor seems to be significantly affected in this condition, with increased excitability associated with downregulation of potassium currents. Some of the specific molecules implicated in this process include the vanilloid receptor, TRPV1, nerve growth factor, the protease activated receptor 2 and a variety of others that are discussed in this Review. Studies have also indicated novel therapeutic targets for this condition.
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Affiliation(s)
- Pankaj Jay Pasricha
- Stanford University School of Medicine, 300 Pasteur Drive, M211 Alway Building, Stanford, CA 94305, USA.
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