Epidemiology: chronic pancreatitis (chronic pancreatitis, CP) is an irreversible pathological process caused by various causes of chronic progressive inflammation, destruction and fibrosis of the pancreatic alveoli, pancreatic ducts, often accompanied by tissue calcification, pseudocysts and islet cell reduction or atrophy, the emergence of endocrine and exocrine function of the pancreas. the average age of onset of CP is 48 years, more men than women. The cause of CP in China is biliary in the first place, accounting for 47-65%; followed by idiopathic, alcoholic, genetic and other diseases, alcoholic CP is on the rise in recent years.
Pathogenesis: Most experts believe that CP is the result of the cumulative effect of repeated episodes of acute interstitial pancreatitis or hemorrhagic necrotizing pancreatitis, and that interstitial fibrosis, tissue damage, necrosis and atrophy are a continuous chronic process. It is also believed that CP itself is the primary disease and that multiple episodes of acute pancreatitis can occur during development. The patient starts with obstruction of the secretory pathway of the pancreas, changes in the composition of the pancreatic fluid, protein embolism and calcification in the ducts and alveoli forming pancreatic stones, inhibition of the flow of secretions causing deformation of the ducts, and the onset of atrophic fibrosis of the pancreatic parenchyma. pathological changes of CP continue after the etiology is removed and are associated with autoimmune reactions. 10-30% of CP cannot be traced to a definite cause and are called idiopathic CP [1].
Recent studies have shown the presence of mutations in the cationic trypsinogen (PRSS1), Kazal type 1 serine protease inhibitor (SPINK1) and cystic fibrosis transmembrane conductance regulator (CFTR) genes in patients with CP. mutations in the SPINK1 gene are more prevalent in patients with idiopathic CP and autoimmune pancreatitis, while mutations in the CFTR gene can cause pancreatic follicular cells to The mutation of CFTR gene could increase the cytokine production of pancreatic follicular cells, which could shift the cells from apoptosis to necrosis. The new PRSS1 mutation gene V39A is also involved in CP pathogenesis. The presence of cystic fibrosis gene carrier status in patients with idiopathic CP has also been demonstrated [2].
Clinical manifestations: typical CP cases may present with a pentad of symptoms: epigastric pain, pancreatic calcification, pancreatic pseudocysts, diabetes mellitus and steatorrhea, often clinically characterized by one or some of these symptoms. Less common presentations include subcutaneous fat necrosis, bone marrow fat necrosis, subcutaneous sclerosis, bone pain, and aseptic necrosis of the femoral head. About 4% of patients have complications of pancreatic cancer within 20 years. On physical examination, there can be epigastric pain, abdominal muscle tension, and masses can be found. Systemic edema and ascites can be caused by hypoproteinemia, and a few patients can develop pleural fluid, mostly located in the left side of the chest, which contains high concentration of amylase.
In the early stage of the disease, pathological changes include enlargement of the pancreas due to edema, fat necrosis and hemorrhage, destruction of the gland replaced by fibrosis, dilatation of the pancreatic ducts, and the presence of stones in the ducts. In the resting stage, the peritoneum covering the pancreas is thickened and opaque, with a nodular surface and raised white dots, suggesting previous fat necrosis. In the later stage, the whole pancreas becomes thin and hard with larger fibroid scar formation and calcium deposits, and there may be pseudocysts of various sizes, enlargement of the pancreatic duct, and stone formation in the pancreatic duct.
Diagnosis and treatment: conventional pancreatic tissue biopsy is often difficult to achieve, abdominal ultrasound and CT have a low detection rate of pancreatic tissue lesions and mild abnormalities of the pancreatic duct, endoscopic retrograde cholangiopancreatography (ERCP) shows good pancreatic duct lesions and is considered the gold standard for clinical diagnosis of CP, but it cannot evaluate abnormalities of the pancreatic parenchyma.
The sensitivity and specificity of ultrasound endoscopy (EUS), which has high resolution and reflects both pancreatic parenchyma and pancreatic duct abnormalities, are 95.1% and 64.4%, respectively.The common manifestations of pancreatic parenchymal abnormalities under EUS are echogenic unevenness with scattered dotted strong echogenicity (calcification), simple echogenic unevenness and no echogenicity (pseudocysts), and common pancreatic duct abnormalities are main pancreatic duct stenosis, lumen dilatation, irregularity, lateral wall increase and lateral wall echogenicity. In China, urinary pancreatic peptide test and fecal elastin are the most commonly used tests to evaluate the exocrine function of the pancreas.
The CP diagnostic criteria developed by the Chinese Medical Association in 2005 used the following four items as the main basis.
① Typical clinical manifestations (abdominal pain, symptoms of pancreatic exocrine insufficiency);
②Pathological examination to confirm;
(iii) imaging CP pancreaticobiliary manifestations;
④laboratory examination of pancreatic exocrine insufficiency manifestations.
① is necessary for diagnosis.
②positive can confirm the diagnosis.
①+③ can basically confirm the diagnosis.
①+④ are suspected patients.
CP is difficult to cure completely. Internal treatment includes diet control, strict abstinence from alcohol, nutritional support, pancreatic enzyme replacement method, symptomatic treatment and control of complications. If there is no obvious effect of internal treatment for 3-6 months, surgery is appropriate to relieve pancreatic duct obstruction, relieve pain and ensure the smooth flow of pancreatic juice and bile. Transendoscopic intervention is the progress and development trend of CP treatment, safe and reliable, part of the work has replaced surgery.
Pain characteristics of chronic pancreatitis
60-100% of patients with CP complain of abdominal pain. Pain is divided into two types A and B, accounting for about 50% each. The former is recurrent intermittent pain, suggesting an acute attack of CP; the latter is persistent, progressive aggravation and cluster-like pain. the degree of CP pain is very sharp, drilling or dull pain, often in the left upper abdomen or epigastrium, around the umbilicus, can be dissipated to the back, bilateral quarter ribs, anterior chest, scapula and other places. The abdominal pain lasts from a few hours to a few days at the beginning, and becomes more frequent and longer as the disease progresses.
The abdominal pain is often accompanied by nausea and vomiting, but the pain is not relieved after vomiting. Eating, especially a high-fat, high-protein diet and alcohol consumption often trigger severe episodes of abdominal pain. Exertion seems to make abdominal pain worse. Episodes of abdominal pain may also be accompanied by fever or jaundice. Intermittent episodes may be asymptomatic or present only with indigestion. The abdominal pain may be relieved to some extent in sitting, forward leaning, bent knee, or prone position and worsened in supine position. The application of general analgesics for abdominal pain is not effective.
Mechanisms of chronic pancreatitis pain
Nerve cell excitation in the pancreas is not perceived under normal conditions, and nociceptive action potentials are generated only when there is an abnormal or very strong stimulus. Pain signals can be transmitted through peripheral nerves such as the visceral nerve, vagus nerve, spinal nerve and phrenic nerve. The visceral nerve is the most important nerve transmitting pancreatic pain, and the spinal nerve seems to be able to perceive back pain caused by inflammation that has extended beyond the normal range of the pancreas. Abdominal pain can also be transmitted relayly through the dorsal tract of the spinal cord, the thalamic tract of the spinal cord.The mechanisms of CP pain occurrence may involve the following.
Intraductal hypertension and/or intrapancreatic parenchymal hypertension due to pancreatic duct stones or stenosis (septal compartment syndrome). Increased pancreatic pressure can interfere with nerves, affect blood flow, alter local pH and cause local retention of harmful substances, activating action potentials. Induced cholecystitis, cholelithiasis and other biliary disorders can also cause pain. However, some studies have confirmed that intrapancreatic duct and common bile duct pressure do not correlate with the degree of abdominal pain, and only pancreatic parenchymal hypertension correlates with the degree of pain.
Pancreatitis-associated neuritis: degeneration, necrosis and fibrosis of the pancreatic parenchyma, narrowing of the innervation zone, thickening and edema of the nerve fibers, and invasion by inflammatory cells. The nerve sheath is destroyed, and the nerve fibers lose their barrier effect against harmful substances such as pancreatic enzymes and kinins and are easily stimulated to cause pain. However, it is difficult to confirm the correlation between intractable pain and morphological changes in the pancreas by gross changes in the pancreas, histomorphology, and imaging.
The increased production of neurotransmitters promotes and aggravates inflammation and causes pain, and there is a significant increase in nerve growth factor and calcitonin gene-related peptide and substance P in the dorsal root ganglion that receives pancreatic sensation in the pancreas of CP rats, and the degranulation products of mast cells in the pancreas of CP patients with painful symptoms are 3.5 times higher than those of normal patients, so it is speculated that the degranulation products of mast cells may activate or sensitize nociceptive nerves.
The level of antioxidants in the blood of patients with alcoholic CP is significantly lower, suggesting that free radicals mediate their pathological process. The imbalance in the production and scavenging of reactive oxygen species due to smoking and harmful chemicals leads to damage of pancreatic alveolar tissue, and the reduced intake and deficiency of certain micronutrients (vitamin E, manganese, magnesium, choline, riboflavin, copper, sulfur, etc.) in the body also aggravate oxidative stress damage and may be associated with the development of pain.
Increased central sensitivity and nociceptive sensitization: CP nerve injury, especially when accompanied by chronic inflammation, strong and persistent visceral injurious sensory signals to the central nervous system can lead to a significant increase in central nociceptive sensitivity and can activate brainstem vulnerability to the posterior horn of the spinal cord, causing permanent changes in the central pain signal processing system, which in turn produces spontaneous central neuropathic pain. This pain lacks sensitivity in response to morphine treatment and visceral plexus destruction.
Control of pain in chronic pancreatitis
CP pain is first considered for medical treatment, and only when it cannot be resolved are measures such as nerve block and disfiguring resection, endoscopic lithotripsy, drainage and stent placement considered, followed by surgical decompression, drainage and pancreatic resection. The study found no difference in long-term outcomes between surgical and medical treatment, which may be due to the natural “disease ignition” effect. The authors still believe that surgery is an effective treatment for CP patients who have failed medical and endoscopic treatment, and that surgery is necessary for about 15-20% of CP patients with pseudocyst infection, rupture and bleeding.
1. Endoscopic treatment: CP pain is closely related to the chronic pathological process, and strict abstinence from alcohol is necessary for all other treatments. Mild and moderate pain can be relieved to varying degrees by general medical treatment such as antispasmodics, digestive enzyme preparations, analgesics, and growth inhibitor derivatives [26]. Inhibition of gastric acid secretion can enhance the inhibitory effect of exogenous pancreatic enzymes on pancreatic secretion and relieve clinical symptoms; negative feedback regulation of pancreatic exocrine function by high-dose pancreatic enzyme preparations can also effectively relieve pain.
Under normal conditions, cholecystokinin-releasing peptide (CCK-RP) in the duodenum is degraded by pancreatic protease denaturation. in patients with CP, pancreatic secretion is inadequate and increased pancreatic secretion due to enhanced CCK activity will elevate intrapancreatic ductal pressure and aggravate abdominal pain. the CCK receptor antagonist cloglumide 600 mg/day can effectively relieve CP pain. Exogenous antioxidants such as dimethyl sulfoxide and allopurinol can relieve pain to some extent or reduce the amount of analgesic.
2. Endoscopic treatment: Despite appropriate life conditioning and medical treatment, recurrent acute attacks of intractable pain, especially in those with significant increase in intrapancreatic pressure, many scholars advocate early surgical decompression to stop or reverse the course of the disease, improve the progressive loss of endocrine and exocrine functions, and relieve pain. With endoscopic decompression therapy alone, about 2/3 of CP patients can have long-term complete or basic pain relief.
Endoscopic treatment is less invasive and less painful, and is currently a popular method of treating CP. The goal of endoscopic treatment of CP is to relieve pancreatic duct obstruction, relieve pain, and stop the progression of CP. Retrograde bile duct drainage via endoscopy can unblock bile duct drainage and relieve bile stasis and cholangitis. Internal pancreatic duct drainage Patients with pancreatic duct stenosis with proximal dilatation can be treated with balloon or dilatation catheter alone. Endoscopic pancreatic sphincterotomy (EPS) is usually performed simultaneously with biliary sphincterotomy, and can also be performed with probe or balloon dilation, nasopancreatic duct drainage (ENPD), pancreatic duct stent placement, pseudocyst drainage, and removal of protein emboli or stones. Extracorporeal shock wave lithotripsy before stone removal can improve the stone removal rate. Immediate clinical improvement was reported in 60 of 70 CP patients with EPS. The success rate of stone removal in lithotripsy treatment was 71.9%, and the symptom improvement rate was 67.7%. Ultrasonic endoscopic puncture and drainage of pancreatic pseudocysts compressing tissues can be performed with good results by introducing the contents of the cyst into the stomach or duodenum or jejunum.
The polylactic acid-barium sulfate (PLA-BaSO4) stent is a biodegradable stent. studies in animal models of CP have shown that the stent degrades completely only after 3 months of placement and has no toxic side effects. Temporary stent placement as part of the endoscopic treatment of CP patients has a high technical and long-term clinical success rate, and a significant number of patients do not require secondary treatment. Some scholars have also blocked the pancreatic duct by endoscopic injection of sclerosing agent or acrylic gel into the pancreatic duct, so that the exocrine function of the pancreas can be atrophied and the endocrine function can be preserved, and analgesic effects can be obtained, but there is a lack of comparative data on long-term effects.
3. Surgical treatment: The main purpose of surgery is to control pain, while the impact on the endocrine and exocrine functions of the pancreas should be minimized. The normal range of pancreatic duct diameter is 4~5 mm, and pancreatic duct diameter greater than 7 mm in CP patients is considered a typical indication for drainage, while the so-called “small pancreatic duct” with diameter less than 3 mm should be considered for pancreatic resection. There are three main types of surgery: correction of abnormal anatomy, pancreatectomy and denervation. It is believed that the number of pancreatic exocrine deficiencies is significantly increased after pancreatic-jejunostomy, therefore, from the perspective of preserving pancreatic function, early decompression surgery is not advisable.
The lateral pancreas-jejunostomy is the most widely used surgical pancreatic drainage decompression procedure with the most satisfactory results and is suitable for patients with increased pancreatic duct diameter. There were no fatalities and the complication rate was 19.6% within 30 days after surgery, and the overall quality of life index of patients improved by 37.5~80% and the pain score decreased by 95%. Sixteen cases (43%) developed diabetes mellitus and 29 cases (78%) had well preserved pancreatic exocrine function.
A small percentage of CP patients developed pancreatic adenocarcinoma, so pancreatic resection may be considered for those with intractable pain. The pain relief rate of pancreatic mass resection (3 months to 11 years) was 80%, which was higher than that of those with drainage alone (67%), and the Whipple procedure showed a higher success rate. Patients with CP without pancreatic duct dilatation mostly require resection of most of the pancreas including the head of the pancreas, with pain relief rates of 70-80%, but the procedure is devastating, and diabetes mellitus and chronic pancreatic exocrine insufficiency are common complications. Duodenum-preserving pancreatic head resection (DPRHP, Beger procedure) has gradually replaced pylorus-preserving pancreatic head resection for the treatment of painful CP, with a surgical success rate of 75-80% and good results in those with local inflammatory enlargement of the pancreatic head and poor long-term results in those without enlargement.
Although total pancreatectomy removes the basis of pain caused by the pancreas, the mortality rate is high (5%), and it is difficult to control endocrine and exocrine secretion after surgery. It is only suitable for familial pancreatitis and small duct disease with pancreatic atrophy and calcification, and the treatment of common CP should be very cautious.
For CP patients with pain without pancreatic duct dilatation, Takeshisa Hiragaoka designed a total pancreatic plexus resection with preservation of the pancreas, in which the sensory nerves and sympathetic postganglionic fibers innervating the pancreas are completely disconnected near the possible proximity to the pancreas, and the pancreas is completely freed behind the peritoneum so that the pancreas becomes connected to the abdominal cavity only by the bile duct, portal vein, gastroduodenal, and inferior mesenteric veins, resulting in four patients who underwent surgery in As a result, the four patients who underwent the procedure were completely pain-free for 2 to 9.4 years and had no significant extra-pancreatic organs or endocrine-related complications of the pancreas. Denervation of the splenopancreatic flap refers to the removal of the head of the pancreas and dissection of the caudal part of the body from the pancreatic bed to achieve the effect of denervation. This procedure is suitable for patients with lesions limited to the head of the pancreas and small diameter of the pancreatic duct, preserving the relationship between the pancreas and related abdominal organs, with a hospital morbidity and mortality rate of less than 1% and a pain relief rate of 89% at 3.6 years after surgery, with only 5.5% of patients experiencing hypoglycemia.
4, analgesic special therapy: the application of analgesic drugs is generally divided into three stages: first trial of non-narcotic analgesics such as acetaminophen, the second stage of the choice of different strength of narcotic analgesics. The second stage is to use different strengths of narcotic analgesics. Codine can make the oddi’s sphincter spasm and aggravate the obstruction of the pancreatic duct, and so does morphine, while tramadol is certainly effective and has little side effects, so it should be preferred. Other analgesic preparations such as prednisolone and hypericum hydrobromide can also be used or used in rotation. In the third stage, for patients with severe abdominal pain, different dosage forms and doses of opioid μ-receptor agonists (morphine, fentanyl, methadone, etc.) are used, with the minimum effective dose being appropriate. Long-acting extended-release morphine-like preparations help to reduce drug dependence, while rapid-onset single injections, especially pethidine intramuscularly, are not reasonable for CP analgesia.
Opioid κ-receptor agonists specifically inhibit visceral primary afferent impulses and relieve pain of visceral origin, with few severe constipation, sedation, vomiting, and respiratory depression reactions. The only κ-receptor agonist currently on the market is oxycodone hydrochloride, but no systematic studies of its use in the control of CP have been reported. Most patients may not be satisfied with analgesic drugs alone, and the combination of sedatives (tranquilizers) and antispasmodics (belladonna, atropine, scopolamine) can improve the analgesic effect, and small doses of narcotics can be used for severe pain, such as 0.5% procaine intravenous drip can often achieve better analgesic effect. Addictive narcotic sedatives should be used sparingly,
The dose should be reduced or stopped in time when the symptoms are relieved.
In cases where severe pain is difficult to relieve, local anesthetic injections of the abdominal plexus can be tried for analgesia. The patient is placed in the prone position, and under the guidance of X-ray or CT, the puncture reaches the visceral nerve site at the anterolateral margin of the first lumbar vertebra, and the nerve blocking effect is detected by injection of medium- and short-acting local anesthetics. If the analgesic effect is good, then inject 25 ml of 50% ethanol or 10 ml of anhydrous ethanol, which can achieve long-term analgesic purpose. The treatment is prone to postural hypertension, and the patient should lie flat for 24 hours after treatment. The short-term analgesic effect of ethanol ventral plexus block is good, but it can only be maintained for about 2 months, and few of them are effective after 4 months, and the second ethanol block is mostly ineffective.
The ability of thalamic neurons to respond to duodenal dilation was reduced in rats with dorsal nerve dysfunction; dorsal nerve dysfunction diminished the electrical signals in the thalamus, and the behavioral response of the pancreas to bradykinin-stimulated pain was reduced. The above studies suggest that pain information from the pancreas is mainly transmitted through the dorsal nerve. Therefore, it seems possible that interrupting the conduction pathway of the dorsal nerve effectively relieves pancreatic pain. There have also been individual reports of satisfactory results with trial of regional electrical stimulation of peripheral nerves to control intractable abdominal pain.
The analgesic effect of ultrasound endoscopy-guided ethanol abdominal plexus block has been reported to be significantly better than that of CT-guided block. The lumpectomy of visceral neurectomy and destruction of abdominal ganglion is simple and easy to control CP abdominal pain with few complications, which is worth promoting. Paravertebral sympathetic nerve block or epidural anesthesia can also be tried for analgesia. It has been confirmed that percutaneous percutaneous radiofrequency ablation of visceral nerves can also provide effective analgesia with few side effects and is suitable for debilitated patients. The complete degree of resection is closely related to the analgesic effect.