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Pain is a major clinical manifestation of chronic pancreatitis (CP) and a common indication for surgery in these patients. Pathogenesis of pain in CP is multifactorial and the mechanisms of pain may differ from patient to patient. This can explain why one therapeutic method of treatment of pain does not work in all patients and in different stages of the disease. Two main complimentary pathogenetic theories have been proposed to explain the mechanisms of pain in CP, the neurogenic theory and the theory of increased intraductal/intraparenchymal pressures. According to the neurogenic theory, in CP there are alterations of pancreatic/peripancreatic nerves, exposing them to noxious substances and/or activated immune cells, thereby generating pain (“neuroimmune interaction”). The other theory of intraductal/intraparenchymal hypertension suggests that pain in CP is generated as a result of increased pressures within the pancreatic ductal system and/or pancreatic parenchyma, like the pain in the classic compartment syndrome. The theory of intraductal/intraparenchymal hypertension is strongly supported by the good results of drainage procedures in the surgical management of CP. Pancreatic ischemia, oxygen-free radicals, centrally sensitized pain state, acute exacerbations of CP, development of complications from the pancreas (most commonly, pseudocysts) or adjacent organs (usually, duodenal and/or common bile duct stenosis), etc. are other possible contributing factors. Different patterns of pain have been described in idiopathic (early vs. late onset) and in alcoholic CP. Interestingly, pain is automatically relieved during the natural course of the disease in some patients (the “burn-out” phenomenon), after a relatively long time (from a few years to up to 3 decades). However, this is an unpredictable evolution for the individual patient. Therefore, surgery should be offered when pain is intense and after failure of conservative treatment. Surgical management should be individualized, depending on the particular findings of each patient. The knowledge of the pathophysiologic basis and of natural course of pain in CP is of paramount importance for the surgeon to select appropriate therapy for the individual patient with CP.