Neural Sensitisation and Neuropsychological Alterations in Painful Chronic Pancreatitis

Official title

EVALUATION OF THE RELATIONSHIP BETWEEN NEURAL SENSITISATION AND NEUROPSYCHOLOGICAL ALTERATIONS IN PATIENTS WITH PAINFUL CHRONIC PANCREATITIS

Overview

Chronic pancreatitis (CP) is a progressive inflammatory disease in which chronic abdominal pain affects up to 80% of patients and remains difficult to manage despite treatment of pancreatic pathology. Increasing evidence suggests that persistent pain is not solely driven by peripheral pancreatic abnormalities but also by central sensitization, involving maladaptive changes in central nervous system pain-processing pathways. While altered brain connectivity and neurochemical changes have been demonstrated in other chronic pain disorders, these mechanisms remain poorly characterized in CP. This study aims to integrate clinical phenotyping with blood-based metabolite profiling and advanced neuroimaging, including resting-state functional MRI and magnetic resonance spectroscopy, to investigate the relationship between central sensitization, brain dysfunction, and neuropsychological alterations. The findings may identify objective neurobiological markers of pain and facilitate the development of mechanism-based, personalized treatment strategies for patients with chronic pancreatitis.

Detailed description

Chronic pancreatitis (CP) is a progressive inflammatory disorder affecting 50-100 per 100,000 adults globally, with 50-80% of patients experiencing debilitating abdominal pain. Despite advances in understanding pancreatic pathology, pain management remains inadequate, leading to high rates of opioid dependence (40%) and reduced quality of life. Traditional models attribute CP pain to peripheral mechanisms (e.g., ductal hypertension, inflammation), yet many patients report persistent pain even after surgical or endoscopic interventions. This paradox highlights the critical role for central mechanisms, including central sensitization.

Central sensitization refers to increased responsiveness of nociceptive neurons in the central nervous system (CNS) to normal or subthreshold afferent input. In CP, prolonged peripheral inflammation may induce long-lasting changes in the brain's pain processing pathways. Emerging literature in other chronic pain conditions (e.g., fibromyalgia, irritable bowel syndrome) supports the notion that central sensitization is associated with altered brain connectivity and neurochemical imbalances. However, few studies have explored this in CP, and none have integrated central sensitization with neuropsychological dysfunction, which frequently co-occurs in chronic pain states.

Understanding these CNS mechanisms is essential for redefining pain management in CP. By combining clinical phenotyping, advanced neuroimaging (resting-state fMRI and MR spectroscopy), our study aims to offer a comprehensive picture of how altered brain function contributes to the pain experience. Identifying neurobiological markers of pain will also support the development of mechanism-based therapies and allow better stratification of patients who may benefit from central neuromodulatory interventions.

This prospective observational study will enroll 200 participants (120 with painful CP, 30 with painless CP, and 50 healthy controls) over one year. Participants will undergo clinical assessments, pain detection questionnaires (Izbicki, painDetect), and evaluations for quality of life (EORTC QLQ-C30 + PAN28), mental state (HADS), and sleep quality (PSQI). The primary assessments include Pancreatic Quantitative Sensory Testing (P-QST) to evaluate sensitization, resting-state fMRI to assess brain connectivity, and MR Spectroscopy to evaluate brain metabolites. Blood samples will be collected from all participants to quantify blood-based metabolites for exploratory biomarker analysis to identify potential correlates with pain phenotypes in chronic pancreatitis.

Interventions

• Diagnostic test Comprehensive Neuropsychological Assessment
  A comprehensive set of clinical and neurological tests to be performed on all participants. This includes validated mental state and sleep evaluations (HADS, PSQI), quality-of-life assessments (EORTC QLQ-C30 + PAN28),and quantitative sensory testing (P-QST)
• Diagnostic test Resting-State Functional MRI (fMRI)
  An advanced neuroimaging scan performed on all participants to assess resting-state functional connectivity within key pain-processing networks.
• Diagnostic test Magnetic Resonance Spectroscopy (MRS)
  A neuroimaging technique performed on all participants to quantify brain metabolites in key brain regions.
• Diagnostic test Blood-Based Metabolite Profiling
  Blood samples will be collected from all participants to quantify metabolomic signatures and to identify potential correlates with pain phenotypes in chronic pancreatitis.

Primary outcome measures

• Role of Central Sensitization [Time frame: At the time of the single study visit]

Secondary outcome measures (3)

• Brain Connectivity [Time frame: At the time of the single study visit.]
• Brain Metabolites [Time frame: At the time of the single study visit.]
• Quantification of Blood-Based Metabolites [Time frame: At the time of the single study visit.]

Eligibility criteria

Inclusion criteria

• Diagnosed with CP confirmed by CECT, MRCP, or EUS based on Cambridge or Rosemont criteria.
• Age 18-60 years.
• Both genders

Exclusion criteria

• Recent episode of acute pancreatitis or ongoing pain (VAS >5).
• Pancreatic cancer and other significant comorbidities.
• Recent use of antidepressants, anxiolytics, high-potency opioids, or neuromodulators.
• Pregnancy and lactation.
• Inability to give informed consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

India · 1 center

• Asian Institute of Gastroenterology — Hyderabad

Publications

• Dimcevski G, Sami SA, Funch-Jensen P, Le Pera D, Valeriani M, Arendt-Nielsen L, Drewes AM. Pain in chronic pancreatitis: the role of reorganization in the central nervous system. Gastroenterology. 2007 Apr;132(4):1546-56. doi: 10.1053/j.gastro.2007.01.037. Epub 2007 Jan 25. PMID 17408654
• Faghih M, Phillips AE, Kuhlmann L, Afghani E, Drewes AM, Yadav D, Singh VK, Olesen SS; Pancreatic Quantitative Sensory Testing (P-QST) Consortium. Pancreatic QST Differentiates Chronic Pancreatitis Patients into Distinct Pain Phenotypes Independent of Psychiatric Comorbidities. Clin Gastroenterol Hepatol. 2022 Jan;20(1):153-161.e2. doi: 10.1016/j.cgh.2020.10.036. Epub 2020 Oct 22. PMID 34108130
• Sarkar S, Sarkar P, M R, Hazarika D, Prasanna A, Pandol SJ, Unnisa M, Jakkampudi A, Bedarkar AP, Dhagudu N, Reddy DN, Talukdar R. Pain, depression, and poor quality of life in chronic pancreatitis: Relationship with altered brain metabolites. Pancreatology. 2022 Sep;22(6):688-697. doi: 10.1016/j.pan.2022.06.007. Epub 2022 Jun 8. PMID 35710761
• Keller CE, Wilcox CM, Gudleski GD, Branham S, Lackner JM. Beyond Abdominal Pain: Pain Beliefs, Pain Affect, and Distress as Determinants of Quality of Life in Patients With Chronic Pancreatitis. J Clin Gastroenterol. 2018 Jul;52(6):563-568. doi: 10.1097/MCG.0000000000000922. PMID 28858939
• Phillips AE, Faghih M, Drewes AM, Singh VK, Yadav D, Olesen SS; Pancreatic Quantitative Sensory Testing (P-QST) Consortium. Psychiatric Comorbidity in Patients With Chronic Pancreatitis Associates With Pain and Reduced Quality of Life. Am J Gastroenterol. 2020 Dec;115(12):2077-2085. doi: 10.14309/ajg.0000000000000782. PMID 32740078
• Talukdar R, Reddy DN. Pain in chronic pancreatitis: managing beyond the pancreatic duct. World J Gastroenterol. 2013 Oct 14;19(38):6319-28. doi: 10.3748/wjg.v19.i38.6319. PMID 24151350

Identifiers

NCT: NCT07707609 · NACP1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗