Towards a neurobiological understanding of pain in chronic pancreatitis: mechanisms and implications for treatment

Abstract

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.

Keywords: Chronic pancreatitis; Mechanisms; Pain; Treatment.

Figure 1.

During inflammation of the pancreas, neurons respond to chemical agents, such as H+, K+, bradykinin, ATP, prostaglandins, and other inflammatory molecules, that are released following cellular damage. Substance P (SP), calcitonin gene–related peptide (CGRP), and neurokinins are transported antegrade to activate mast cells and platelets. These release serotonin (5-HT), nerve growth factor, and histamine, which again activate the sensory afferents.

Figure 2.

During pancreatic flares, trypsin may activate proteinase activated receptor 2 (PAR-2) on nociceptors and sensitize the response of transient receptor potential vanilloid (TRPV1) active fibres. These produce substance P (SP), the key molecule in “neurogenic inflammation” that is antegrade transported to the tissue and activates blood cells and vessels.

Figure 3.

Schematic illustration of the different neurobiological mechanisms involved in pancreatic pain: (1) Peripheral nerve damage in the pancreas with ectopic activity resulting in stimulus-dependent and spontaneous pain. (2) Sprouting of non-nociceptive nerve afferents into areas of the spinal cord that normally transmit nociceptive information resulting in allodynia. (3) Sprouting of sympathetic neurons (black) into the dorsal horn neurons rendering the system sensitive to sympathetic activity. (4) Sensitisation and phenotypic changes of spinal neurons due to the increased afferent barrage. (5) Defects in the normal inhibition of the incoming nociceptive information from (a) interneurons and (b) descending tracts arising in the brainstem (black). (6) Abnormal coding of the afferent input from somatic areas and other viscera resulting in increased referred pain areas and viscero-visceral hyperalgesia. (7) Reorganisation and structural changes in the brain that encodes complex sensations such as affective, evaluative, and cognitive responses to pain.