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HPBSA Guidelines: Medical Treatment of Chronic
Pancreatitis Goals Medical management of the patient with chronic pancreatitis should focus on relieving symptoms and preventing the development of complications. There are 6 main goals that should be attained: 1. Cessation of alcohol consumption and cigarette smoking 2. Determine the cause of abdominal pain and attempt to relieve it 3. Treat pancreatic exocrine insufficiency 4. Detect and treat endocrine insufficiency EARLY before complications set in 5. Nutritional support 6. Screening for pancreatic adenocarcinoma in cases of hereditary pancreatitis 1. Behaviour modification Complete cessation of alcohol ingestion is recommended to reduce future morbidity and mortality. Furthermore abstinence can in some cases lead to symptomatic improvement and pain relief, while ongoing alcohol ingestion contributes substantially to disease progression1. Cessation of alcohol however does not necessarily prevent disease progression. Alcohol cessation is best achieved by enlisting the help of an alcohol dependency counsellor or psychologist. Patients also need to be advised to stop smoking as this is a strong and independent risk factor for chronic alcoholic pancreatitis2. Recommendations • All patients with chronic pancreatitis should be advised to stop smoking and to abstain from alcohol consumption 2. Treatment of abdominal pain Pain is the commonest and the most significant symptom of chronic pancreatitis. The mechanism of pain is poorly understood and likely multi-factorial. Several factors may exacerbate pain and diagnostic tests may be necessary to search for these, in order to institute appropriate treatment which may entail surgical or endoscopic intervention3. These include: pseudocyst formation, duodenal stenosis, biliary tract stricture, pancreatic cancer and peptic ulcer disease. If these are excluded, medical therapy is initiated using a sequential (step-up) approach. Although the pain of chronic pancreatitis may “burn out” over time, particularly in alcohol related disease, the duration over which this occurs is unpredictable6. Initial therapy consists of simple, non-narcotic episodic analgesia in the form of paracetomol or non-steroidal anti-inflammatory drugs (NSAIDs), together with a low fat diet. Patients who fail to respond should receive a 6-week trial of high-dose pancreatic enzymes (in tablet, uncoated form).3, 6, 12 The recommended dose is equivalent to a formulation containing 16 000 units of lipase per tablet; 12 tablets per day, in divided doses with meals and snacks. A possible mechanism of pain relief from pancreatic enzyme replacement therapies is a reduction in pancreatic stimulation by food–induced CCK. When exogenous pancreatic enzymes are taken with a meal, CCK-releasing factors are degraded and CCK release in response to a meal is reduced. Clinical trials investigating this hypothesis have however shown conflicting results.4, 12. While the majority of trials using enteric-coated preparations demonstrated no benefit, this may reflect failure of the coated preparation to release the enzymes into the feedback-sensitive portion of the duodenum. In contrast, studies using non–enteric-coated tablets have demonstrated a reduction in pain compared to placebo. The effects of uncoated pancreatic enzymes are augmented by acid suppression therapy (either an H2 blocker or a proton pump inhibitor), which reduces the inactivation of the enzymes by gastric acid and increases the amount of protease to reach the duodenum 6, 8. Enzyme therapy appears to be most effective in ‘small-duct’ or ‘minimal change’ CP11. Octreotide, while also effective in reducing pancreatic secretion, is not currently recommended for treating chronic pain3. In subjects with refractory severe pain, narcotic analgesics may be required, starting with the least potent agents and progressing to more potent formulations as necessary. Initially they should only be given on an ‘as needed’ basis. Ideally ongoing regular opioid analgesia is reserved for those in whom endoscopic or surgical therapies are not appropriate and symptoms are intractable. Pethidine appears to be more addictive than other opiates and should be avoided wherever possible. Managing pain in CP is best done in conjunction with an experienced pain therapist who may wish to apply more specialised techniques such as intrapleural blocks. Tricyclic antidepressants, selective serotonin re-uptake inhibitors and combined serotonin and norepinephrine re-uptake inhibitors will alleviate coexistent depression and may ameliorate pain and potentiate the effects of opiates. These agents may alter visceral and central nerve sensitisation, which are proposed mechanisms of pain in CP11. Antioxidants may be beneficial in reducing pain. A recent randomised, placebo-controlled trial of antioxidant supplementation in chronic pancreatitis evaluated 147 patients over 6 months5. The antioxidant supplementation consisted of daily doses of selenium, ascorbic acid, β-carotene, α-tocopherol and methionine. Overall antioxidant supplementation led to significantly less painful days per month, a reduced need for oral analgesics and fewer hospitalisations. The beneficial effect of these antioxidants on pain relief was already significant at 3 months. Whether this data is sufficient to recommend this intervention remains unclear. Recommendations • Chronic pain should be investigated to exclude pathologies which may be amenable to endoscopic or surgical therapy • Medical treatment of pain should employ a sequential (step-up) approach, commencing with simple, non-narcotic episodic analgesia (paracetomol or non-steroidal anti-inflammatory drugs), together with a low fat diet • If simple analgesia is insufficient for pain control, a 6-week trial of high-dose pancreatic enzymes (in tablet, uncoated form) is appropriate. Acid suppression therapy should be given as an adjunct. • In subjects with refractory severe pain, narcotic analgesics may be required, starting with the least potent agents and progressing to more potent formulations as necessary. • Tricyclic antidepressants, selective serotonin re-uptake inhibitors and combined serotonin and norepinephrine re-uptake inhibitors will alleviate coexistent depression and may ameliorate pain and potentiate the effects of opiates • Managing pain in CP is best done in conjunction with an experienced pain therapist 3. Treat pancreatic exocrine insufficiency Clinically significant malabsorption does not occur until more than 90% of pancreatic function is lost6. Steatorrhea usually occurs before protein deficiency6. Enteric coated preparations are superior to uncoated therapy for the treatment of steatorrhea, as lipase is protected from inactivation by gastric acid 18. Clinical indications for initiating enzyme supplementation are: frank steatorrhoea, weight loss or diarrhoea. It has however been shown that the sensitivity of clinical steatorrhea as a predictor of exocrine dysfunction is only 38%, suggesting that exocrine insufficiency will go undetected and untreated in many patients.13 As such asymptomatic patients with CP may benefit from routine screening for sub-clinical exocrine insufficiency, and receive pancreatic enzyme replacement if identified. This approach is recommended by some experts in the field, but is not validated. A suitable option for screening is the stool acid steatocrit determined on spot samples which is a reliable, easy, and inexpensive test, which when compared with 72 h stool quantitative faecal fat displayed a sensitivity of 100% and a specificity of 95%.14 An alternative method of screening is the fecal elastase test, which is easy to perform, non-invasive, and convenient. Unfortunately these screening tests perform poorly in cases of mild to moderate pancreatic insufficiency. Different formulations vary in lipase, protease, and amylase content. The aim is to provide at least 25 - 40,000 units of lipase per meal and 10-25,000 units of lipase with snacks. Because the cost is variable, one should consider the unit price of the enzyme supplement based on lipase content. The response to treatment is usually measured clinically by weight gain and improvement in symptoms, and the appropriate dose of enzyme replacement therapy needs to be titrated to maximise response. Despite an adequate clinical response malabsorption may persist in some patients and higher doses (up to 60,000 Units of lipase per meal) may be necessary17. Because of the possible risk of fibrosing colonopathy with very high doses of enzyme replacement a ceiling of 75,000 IU of lipase per meal has been recommended by some 18. It is essential that patients are counselled on the timing of enzyme ingestion in relationship to meals (enzymes should be ingested during a meal and not beforehand) Patients who remain symptomatic despite compliance with maximal enteric coated enzyme replacement would benefit from the addition of acid suppressing medication18. Other causes of diarrhoea should also be considered in patients proving refractory, in particular bacterial overgrowth which is common in CP20. Recommendations • Pancreatic enzyme replacement therapy is recommended in patients with clinical features of exocrine insufficiency • Enteric coated preparations are superior to uncoated therapy for the treatment of malabsorption • The preferred dose is a minimum of 25 - 40,000 units of lipase per meal and 10-25,000 units of lipase with snacks. • The response to treatment is measured clinically by weight gain and improvement in symptoms • The appropriate dose of enzyme replacement therapy needs to be titrated to maximise response. • Patients who remain symptomatic despite compliance with maximal enteric coated enzyme replacement would benefit from the addition of acid suppressing medication 4. Detect and treat endocrine insufficiency EARLY before complications set in. Up to 70% of patients with chronic pancreatitis will eventually develop impaired glucose tolerance. The probability of endocrine insufficiency increases progressively within ten years of disease onset7. The diagnosis of endocrine insufficiency must be pursued early and aggressively by checking regular hemoglobin A1c (HBA1C) levels, fasting blood glucose or performing oral glucose tolerance testing. The optimal form of screening is debatable. Recently an International Expert Committee with members appointed by the American Diabetes Association, the European Association for the Study of Diabetes, and the International Diabetes Federation recommended the use of HBA1C (at a level of ≥ 6.5) rather than glucose for the diagnosis of diabetes15. This is a significant departure from previous guidelines. Advantages of HBA1C is that it can be done without fasting and also shows much lower variation within individuals compared to blood glucose. Most pancreatic diabetics whose glycaemic control is refractory to dietary manipulation will eventually require insulin. Oral hypoglycaemics have little role to play in advanced disease19. Pancreatic diabetics are at higher risk of experiencing severe hypoglycemia than other forms of diabetes; as a consequence of impaired glucagon secretion, malnutrition and concomitant hepatic dysfunction due to alcohol abuse. Hence patients with one or more episodes of severe hypoglycemia may benefit from relaxation of glycemic targets; such as eliminating glycosuria, rather than tight control of blood levels. Long-term complications of pancreatic diabetes depend largely on the duration of the diabetes. Life expectancy is reduced, mainly due to persistent alcohol and nicotine abuse (cardiovascular disease, malignant tumours). Treatment of pancreatic diabetes should aim at optimising glucose control in order to prevent complications, while avoiding hypoglycaemia Recommendations • The diagnosis of endocrine insufficiency must be pursued early and aggressively by checking regular HBA1C levels, fasting blood glucose or performing oral glucose tolerance testing. • Treatment of pancreatic diabetes should aim at optimising glucose control in order to prevent complications, while avoiding hypoglycaemia 5. Nutrition Protein-calorie malnutrition is common in patients with chronic pancreatitis and is often multifactorial, due to abdominal pain, malabsorption, diabetes, altered gut motility and coexistent alcoholism16. There is no specific ‘chronic pancreatitis diet’. In general small meals and a diet low in fat and high in protein and carbohydrates are recommended, especially in patients with steatorrhea. The degree of fat restriction depends upon the severity of fat malabsorption; generally an intake of less than 40-60 grams per day is tolerated. Specific recommendations include a daily diet of 2500-3000 calories, protein intake of 1.0 to 1.5 g/kg/day and < 30-40% of total calories consumed as fat per day16. Medium chain triglycerides are directly absorbed by the small intestine without requiring lipase. They can be used to supplement lipids and caloric intake in patients with severe fat malabsorption, although their use is hindered by unpalatability. Malabsorption of the fat soluble vitamins (A, D, E, and K) may also occur, although clinically symptomatic vitamin deficiency is rare. Vitamin B12 deficiency can also develop. Vitamin B-12 is absorbed in the terminal ileum complexed to intrinsic factor. When vitamin B-12 enters the stomach, it binds haptocorrin (or R-protein). The haptocorrin is degraded in the small intestine by pancreatic enzymes, thus releasing B-12 which then binds to intrinsic factor. In patients with pancreatic insufficiency, vitamin B-12 can remain bound to haptocorrin and is not available for absorption by the terminal ileum. Patients with ongoing alcohol abuse are also at risk of thiamine (vitamin B1), riboflavin (vitamin B2) and pyridoxine (vitamin B6) deficiencies. Vitamins should be replaced if serum levels indicate a deficiency. Osteopaenia is a recognised complication of chronic pancreatitis and a one-off assessment of bone mineral density (DEXA) should be considered9 Recommendations • There is no specific diet that patients should be advised to follow • Small meals and a diet low in fat and high in protein and carbohydrates are advisable. The degree of fat restriction depends upon the severity of fat malabsorption. • Medium chain triglycerides can be used to supplement lipid and caloric intake in patients with severe fat malabsorption refractory to enzyme replacement. • Patients are at risk of fat soluble vitamin (A, D, E and K) and B12 deficiency • Osteopaenia is a recognised complication of chronic pancreatitis and a one-off assessment of bone mineral density (DEXA) should be considered 6. Screening for pancreatic adenocarcinoma It is currently recommended that patients with hereditary pancreatitis enter a screening program, beginning at the age of 40 years10. Screening should be done yearly. Imaging options include EUS, multiphasic helical CT or MRI/MRCP. The use of ERCP is controversial given the invasive nature of this investigation. The imaging modality of choice will vary depending on the capabilities and preferences of the institution or hospital. The value of screening other forms of chronic pancreatitis is unclear and not currently recommended. However as CP (regardless of aetiology) is a known risk factor for cancer occurrence, any significant change in symptoms should prompt further investigation. Recommendation • Patients with hereditary pancreatitis should enter a screening program for adenocarcinoma beginning at the age of 40 years • Routine screening of other forms of chronic pancreatitis for adenocarcinoma is not currently recommended but any significant change in symptoms should prompt further investigation. 7. Autoimmune Chronic Pancreatitis Special mention must be made of Auto-Immune CP as alternative therapies, notably corticosteroids, may be effective treatment. It was felt that this topic was a distinct entity and beyond the scope of this guideline. References 1. Gullo L, Barbara L, Labo G. Effect of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis. Gastroenterology 1988;95:1063-8. 2. Maisonneuve P, Lowenfels AB, Mullhaupt B, et al. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005;54:510-4. 3. Warshaw AL, Banks PA, Fernàndez-Del Castillo C. AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology 1998;115:765-76. 4. Brown A, Hughes M, Tenner S, et al. Does pancreatic enzyme supplementation reduce pain in patients with chronic pancreatitis: a meta-analysis. Am J Gastroenterol 1997;92:2032-5. 5. Bhadwaj P et al: A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis. Gastroenterology 2009;136:149-159 6. Ahmad SA, Wray C, Rilo HL, et al. Chronic pancreatitis: recent advances and ongoing challenges. Curr Probl Surg 2006;43:127-238. 7. Malka D, Hammel P, Sauvanet A, et al. Risk factors for diabetes mellitus in chronic pancreatitis. Gastroenterology 2000;119:1324-32. 8. Heijerman HG, Lamers CB, Bakker W. Omeprazole enhances the efficacy of pancreatin (pancrease) in cystic fibrosis. Ann Intern Med.1991;114:200 9. Haaber AB, Rosenfalck AM, Hansen B, et al. Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency. Int J Pancreatol 2000;27:21-7. 10. Ulrich CD. Pancreatic Cancer in Hereditary Pancreatitis: Consensus Guidelines for Prevention, Screening and Treatment. Pancreatology 2001;1:416–422 11. Lieb J.G, Forsmark CE, Review article: pain and chronic pancreatitis. Aliment Pharmacol Ther.2009; 29, 706–719 12. Winstead Ns, Wilcox CM Clinical Trials of Pancreatic Enzyme Replacement for Painful Chronic Pancreatitis – A Review. Pancreatology 2009;9:344–350 13. Dumasy V, Delhaye M, Cotton F. Fat Malabsorption Screening in Chronic Pancreatitis. Am J Gastroenterol 2004;99:1350-1354 14. Amann ST, Josephson SA, Toskes PP. Acid steatocrit: A simple, rapid gravimetric method to determine steatorrhea. Am J Gastroenterol 1997;92:2280–4 15. International Expert Committee. International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327–34 16. Scolapio JS, Malhi-Chowla N, Ukleja A. Nutrition Supplementation in Patients with Acute and Chronic Pancreatitis. Gastroenterol Clin North Am 1999;28:695-707 17. Dominguez-Munoz JE, Iglesias-Garcia J, Vilarino-Insua M, et al. 13C-mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2007;5:484-448. 18. Krishnamurty DM, Rabiee A, Jagannath SB, et al. Delayed release pancrelipase for treatment of pancreatic exocrine insufficiency associated with chronic pancreatitis. Ther Clin Risk Manag 2009; 5:507-20 19. B. I. Joffe, W. P. U. Jackson, S. Bank, et al Effect of oral hypoglycaemic agents on glucose tolerance in pancreatic diabetes. Gut 1972;13:285–288. 20. Trespi E, Ferrieri A. Intestinal bacterial overgrowth during chronic pancreatitis. Curr Med Res Opin 1999; 15: 47-52 |
