今日の臨床サポート

慢性膵炎

著者: 正宗淳 東北大学 消化器内科

監修: 下瀬川徹 みやぎ県南中核病院企業団

著者校正済:2022/04/27
現在監修レビュー中
参考ガイドライン:
  1. 日本消化器病学会:慢性膵炎診療ガイドライン2021(改訂第3版)
患者向け説明資料

概要・推奨   

  1. アルコール性慢性膵炎の治療に断酒指導を行う(推奨度1 OJ)
  1. 慢性膵炎の治療に病期を考慮した栄養療法を行う(推奨度1 OJ)
  1. 慢性膵炎の疼痛治療に非ステロイド抗炎症薬(NSAIDs)が無効な場合は弱オピオイドを使用する(推奨度2 RJG)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
正宗淳 : 講演料(マイランEPD合同会社)[2022年]
監修:下瀬川徹 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 日本消化器病学会により作成された慢性膵炎診療ガイドライン2021(改訂第3版)に基づき、診断、治療方針などの改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 慢性膵炎とは、遺伝的や環境要因その他の危険因子を有し、実質への傷害やストレスに対して持続的な病的反応を生じる個人に起きる、膵臓の病的線維化炎症症候群である。
  1. 膵臓の内部に不規則な線維化、細胞浸潤、実質の脱落、肉芽組織などの慢性変化が生じ、進行すると膵外分泌・内分泌機能の低下を伴う病態である。多くは非可逆性である。
  1. 診断は臨床診断基準に基づいて行う。
  1. 慢性膵炎臨床診断基準2019:表<図表>
  1. 慢性膵炎の特徴的画像所見:表<図表>
  1. 慢性膵炎の組織像:図<図表>
  1. この診断基準では、特徴的な画像所見ならびに組織所見として、確診所見と準確診所見が設けられており、いずれかが認められる場合、慢性膵炎確診または準確診の診断が下せる。
  1. 慢性膵炎診断の手順(アルゴリズム)の準確診所見のみの場合でも、③反復する上腹部痛または背部痛、④血中/尿中膵酵素値の異常、⑤膵外分泌障害、――の3項目中2項目以上が認められる場合には診断を確診に格上げできる。確診、準確診所見を認めないが、③反復する上腹部痛または背部痛、④血中/尿中膵酵素値の異常、⑤膵外分泌障害、⑥1日60g以上(純エタノール換算)の持続する飲酒歴または膵炎関連遺伝子異常、⑦急性膵炎の既往――のいずれか3項目以上と超音波内視鏡またはMRCP、ERCPにて早期慢性膵炎の画像所見が認められた場合、早期慢性膵炎と診断する。アルゴリズム
  1. 成因により、アルコール性と非アルコール性(特発性、遺伝性など)に分類される。アルコール性が成因の約2/3を占め最も多い。
  1. 自己免疫性膵炎と閉塞性膵炎は、病態の可逆性の観点から慢性膵炎として取り扱われない。
  1. まれな成因である遺伝性膵炎は、厚生労働省の難病ならびに小児慢性特定疾病に指定されており、要件を満たした場合に医療費助成の対象となっている。申請し認定されると医療費の自己負担分の一部が公費負担として助成される。
  1.  難病法に基づく医療費助成制度 
  1. 2016年受療患者を対象とした全国調査によると、年間推計受療患者数は56,520人である。有病率としては人口10万人あたり44.5人、新規発症(発病)率は11.6人、患者の平均年齢は約62歳であった。
  1. 男女比は4.8:1と男性に多い。特にアルコール性に限ると男女比は10:1となる。
  1. 女性は男性に比べて、より少ない累積飲酒量で、より若年でアルコール性慢性膵炎を発症するという性差もみられる。
問診・診察のポイント  
  1. 腹痛や背部痛の出現時期、性状、食事との関連を確認する。典型例では、食後、特に脂肪分の多い食事をとった後や飲酒後に症状が出現する。症状は仰臥位で悪化し、前屈位で軽減する。

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文献 

L Gullo, L Barbara, G Labò
Effect of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis.
Gastroenterology. 1988 Oct;95(4):1063-8.
Abstract/Text Exocrine pancreatic function was studied sequentially by means of the secretin-cerulein test in 32 patients with alcoholic chronic pancreatitis to elucidate the long-term course of pancreatic dysfunction, and to determine whether the cessation of alcohol use had any influence on the natural history of pancreatic functional changes caused by this disease. At initial studies, 5 patients had normal pancreatic function, and the remaining 27 had pancreatic insufficiency, which was mild to moderate in most subjects. The final studies, carried out at an average of 7.3 yr (range, 4-11 yr) after the first, showed a significant deterioration in pancreatic function, both in patients who stopped alcohol after the initial study (n = 18) and in those who did not (n = 14). The deterioration, however, was significantly less marked in patients who stopped drinking alcohol than in those who continued. These data indicate that pancreatic functional changes caused by alcoholic pancreatitis progress even after cessation of alcohol use; however, the progression is slower and less severe when alcohol intake is stopped.

PMID 3410221
H Miyake, H Harada, K Kunichika, K Ochi, I Kimura
Clinical course and prognosis of chronic pancreatitis.
Pancreas. 1987;2(4):378-85.
Abstract/Text Course and prognosis of 125 patients with chronic pancreatitis (CP) were evaluated. Follow-up period ranged from 1-20 years with a median of 6.3 years. The following conclusions were obtained. Recent increase of CP in our clinics was ascribed to alcoholic CP and idiopathic CP in the aged. Of 106 patients with pain, 74 showed improvement or disappearance of pain. Drinking habit and observation period were the main factors determining the rate of pain relief. Serial endoscopic retrograde pancreatography (ERP) showed aggravation in 17/47 patients, cholecystokinin-pancreozymin (CCK-PZ) secretin test in 4/40 patients, and oral glucose tolerance test (OGTT) in 7/25 patients. Exocrine function showed improvement in five patients, whereas endocrine function showed none. Improvement or aggravation of exocrine function was closely related to drinking habit. Main complications included 15 cases of peptic ulcer, 19 of pancreatic pseudocyst, and 15 of bile duct stenosis. Twenty-six patients died, often due to malignant neoplasms and diabetic complications. Those who continued drinking as much showed a lower survival rate than those who discontinued or decreased alcohol intake. The socioeconomic status deteriorated often due to pain or alcoholism. Three patients had to degrade jobs and six fell into inactive social life.

PMID 3628235
T Hayakawa, T Kondo, T Shibata, Y Sugimoto, M Kitagawa
Chronic alcoholism and evolution of pain and prognosis in chronic pancreatitis.
Dig Dis Sci. 1989 Jan;34(1):33-8.
Abstract/Text To evaluate the influence of chronic alcoholism on clinical features of chronic pancreatitis in Japan, pain evolution, pancreatic insufficiency, and long-term prognosis were studied by comparing chronic alcoholic pancreatitis (N = 88) with idiopathic pancreatitis (N = 67). The 155 patients with known course of the disease over three years were followed-up further for five more years, and pain evolution was evaluated once at the start and once at the end of the follow-up period. At the time of diagnosis, severe pain (59 vs 33%, P less than 0.001), pancreatic calcification (63 vs 31%, P less than 0.001), advanced exocrine pancreatic insufficiency (72 vs 60%, NS), and overt diabetes (48 vs 17%, P less than 0.001) were more common in alcoholic than in idiopathic pancreatitis, respectively. Pain evolution was similar in both pancreatitis, and the pain decreased with time. The rate of abstinence was higher in groups with pain relief than without in alcoholic pancreatitis. Cumulative mortality rate during the five years was higher in alcoholic than idiopathic pancreatitis (26 vs 10%, P less than 0.01). These results suggest more favorable evolution of the disease can be expected by abstinence from alcohol.

PMID 2910680
P G Lankisch, A Löhr-Happe, J Otto, W Creutzfeldt
Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease.
Digestion. 1993;54(3):148-55.
Abstract/Text The natural course of the classical symptoms of chronic pancreatitis, i.e. pain, exocrine and endocrine pancreatic insufficiency, was followed up in 335 patients over a median of 9.8 years (mean 11.3 +/- 8.3 years). Pain relief was not obtained in the majority of patients, even after a long-term observation of > 10 years, and severe exocrine/endocrine insufficiency, severe duct abnormalities and pancreatic calcifications developed. Alcohol abstinence failed to have a significant beneficial effect on pain. Pancreatic surgery led to pain relief immediately after operation, but later on the pain course between operated and nonoperated patients was not significantly different. Repeated exocrine pancreatic function tests in 143 patients showed that functional exocrine impairment came to a standstill (46%), or improved (11%). At the end of observation, 22% of 335 patients still had normal endocrine function and only 40% required insulin treatment. Alcohol abstinence had a significant beneficial effect on endocrine, but not on exocrine pancreatic insufficiency. Chronic pancreatitis led to a sharp increase in unemployment and retirement. Pancreatic carcinoma occurred in 3% and extrapancreatic carcinoma in 4%. The mortality rate within the observation period was 22%, pancreatitis-induced complications accounted for 13% of these deaths.

PMID 8359556
W B Strum
Abstinence in alcoholic chronic pancreatitis. Effect on pain and outcome.
J Clin Gastroenterol. 1995 Jan;20(1):37-41.
Abstract/Text The role of alcohol in causing chronic pancreatitis is well-known, but the role of abstinence remains controversial and not well-understood. In this article, I examine the literature dealing with the effect of abstinence on chronic pain and the long-term outcome of chronic pancreatitis. A series of 50 patients with alcoholic chronic pancreatitis from my practice supplements the data. Alcohol consumption > 70 g/day for 7 or more years is characteristic. Moderate to severe abdominal pain is the dominant symptom. When patients stop drinking, abdominal pain disappears in the majority, pancreatic function deteriorates more slowly, the death rate diminishes, and a normal life is often possible. If abdominal pain continues after abstinence and the pancreatic duct remains dilated, a lateral pancreatojejunostomy helps most patients. In many patients not suitable for surgery, pain resolves with time.

PMID 7884175
G de las Heras, J de la Peña, M J López Arias, A C Gonzalez-Bernal, L Martín-Ramos, F Pons-Romero
Drinking habits and pain in chronic pancreatitis.
J Clin Gastroenterol. 1995 Jan;20(1):33-6.
Abstract/Text To study the role that continuous drinking plays in the pain of chronic pancreatitis, we have examined 67 patients with alcoholic chronic pancreatitis with pain and 29 patients without pain, and we report on their alcoholic habits. Drinking habits played a part 92 (67.6%) of 136 times in patients with pain; in 185 without pain, 86 (46.5%) had continued their drinking habit (p < 0.001). Advanced pancreatic exocrine insufficiency was seen in 27 patients; 11 of them had pain during follow-up, whereas 16 did not. The nondrinker rate was similar in patients with and without pain, whereas among 69 patients with better pancreatic exocrine function, 56 had pain episodes and 13 did not. Alcoholic consumers were significantly more in number in the pain group: 70.4% versus 35% of the no pain group (p < 0.002). Our study shows that drinking alcohol in patients with chronic pancreatitis increased the frequency of painful episodes when there was relatively good pancreatic function, whereas in severe pancreatic insufficiency drinking had less influence on the development of pain.

PMID 7884174
Jitsuko Maruki, Jin Kan Sai, Sumio Watanabe
Efficacy of low-fat diet against dyspepsia associated with nonalcoholic mild pancreatic disease diagnosed using the Rosemont criteria.
Pancreas. 2013 Jan;42(1):49-52. doi: 10.1097/MPA.0b013e318255798d.
Abstract/Text OBJECTIVES: The objective of this study was to examine the efficacy of low-fat diet against dyspepsia in patients who had endosonographic evidence of nonalcoholic mild pancreatic disease.
METHODS: Patients with unknown cause of upper abdominal pain suggesting pancreatic disease without a history of alcohol consumption were prescribed a low-fat diet (<20 g of fat/d) for 4 weeks. Based on endoscopic ultrasonographic findings and the Rosemont criteria, the patients were distributed into those with 5 or more minor features of chronic pancreatitis (suggestive group), those with 3 or 4 (indeterminate group), and those with 2 or less (control group). Patients with major features were excluded. Symptom severity was recorded before and after the diet therapy using a 10-cm visual analog scale. Improvement of symptoms was compared among the 3 groups.
RESULTS: Of 45 patients, 14 were in the suggestive group, 18 were in the indeterminate group, and 13 served as controls. Improvement of visual analog scale score was significantly greater in the suggestive group than in the indeterminate group (P < 0.001) and the control group (P < 0.001).
CONCLUSIONS: A low-fat diet may be effective in patients with dyspepsia associated with endosonographic evidence of mild pancreatic disease, who do not habitually drink alcohol.

PMID 22836859
Keisho Kataoka, Junichi Sakagami, Morihisa Hirota, Atsushi Masamune, Tooru Shimosegawa
Effects of oral ingestion of the elemental diet in patients with painful chronic pancreatitis in the real-life setting in Japan.
Pancreas. 2014 Apr;43(3):451-7. doi: 10.1097/MPA.0000000000000038.
Abstract/Text OBJECTIVE: Most patients with chronic pancreatitis develop intractable abdominal pain and malnutrition. A low-fat diet is one of the options used to manage intractable abdominal pain and malnutrition. However, few reports have examined the pain-suppression effect. To investigate the effects of oral ingestion of a low-fat elemental diet composed of purified amino acids on pain and nutritional status in patients with chronic pancreatitis, a multicenter prospective study was conducted.
METHODS: Patients with chronic pancreatitis with symptoms of abdominal pain were enrolled. In addition to meals, patients ingested a low-fat elemental diet composed of purified amino acids for 12 weeks. Before and after treatment, patients were asked to indicate their pain grade using a 100-mm horizontal visual analog scale, and nutritional indices, including body mass index and blood levels of pancreatic enzymes, were measured.
RESULTS: A total of 596 patients were eligible for analysis. Marked pain reduction was observed with a significant decrease of the mean visual analog scale score by 32.9 mm from 52.9 mm after 12 weeks (P < 0.001). There were also significant improvements in nutritional indices.
CONCLUSIONS: An oral low-fat elemental diet composed of purified amino acids, which requires no special treatment procedures, may improve patients' quality of life.

PMID 24622078
Tsukasa Ikeura, Makoto Takaoka, Kazushige Uchida, Hideaki Miyoshi, Kazuichi Okazaki
Beneficial Effect of Low-Fat Elemental Diet Therapy on Pain in Chronic Pancreatitis.
Int J Chronic Dis. 2014;2014:862091. doi: 10.1155/2014/862091. Epub 2014 Apr 14.
Abstract/Text Background & Aims. Chronic pancreatitis (CP) is often associated with abdominal pain, which impairs quality of life. The aim of this prospective study was to clarify whether the use of a low-fat elemental diet (ED) is beneficial for managing pain in patients with CP. Methods. Seventeen CP patients with pain despite fat-restricted dietary and conventional medical treatments were enrolled in this prospective study. These patients received low-fat ED therapy in addition to restricting fat intake for 8 weeks. The change of pain severity was examined by interviewing the patient and status of analgesic use. Results. Mean serum levels of amylase and lipase at 8 weeks after the beginning of low-fat ED therapy decreased compared to those before the therapy. At 8 weeks, pain alleviation after low-fat ED therapy was reported in 15 out of 17 patients (88%). Of these 15 patients, 10 patients reported complete pain disappearance. One of 3 patients with severe or moderate pain requiring analgesic was relieved of analgesic use after low-fat ED therapy. Conclusion. Low-fat ED therapy is useful as means of pain control in CP. The therapy is recommended in outpatients with CP who present with pain despite conventional dietary and medical treatments.

PMID 26464866
M Castiñeira-Alvariño, B Lindkvist, M Luaces-Regueira, J Iglesias-García, J Lariño-Noia, L Nieto-García, J E Domínguez-Muñoz
The role of high fat diet in the development of complications of chronic pancreatitis.
Clin Nutr. 2013 Oct;32(5):830-6. doi: 10.1016/j.clnu.2013.02.002. Epub 2013 Feb 8.
Abstract/Text BACKGROUND: Little is known about risk factors for complications in chronic pancreatitis (CP). High fat diet (HFD) has been demonstrated to aggravate pancreatic injury in animal models. The aim of this study was to investigate the role of HFD in age at diagnosis of CP and probability of CP related complications.
METHODS: A cross-sectional case-case study was performed within a prospectively collected cohort of patients with CP. Diagnosis and morphological severity of CP was established by endoscopic ultrasound. Pancreatic exocrine insufficiency (PEI) was diagnosed by ¹³C mixed triglyceride breath test. Fat intake was assessed by a specific nutritional questionnaire. Odds ratios (OR) for CP related complications were estimated by multivariate logistic regression analysis.
RESULTS: 168 patients were included (128 (76.2%) men, mean age 44 years (SD 13.5)). Etiology of CP was alcohol abuse in 89 patients (53.0%), other causes in 30 (17.9%) and idiopathic in the remaining 49 subjects (29.2%). 24 patients (14.3%) had a HFD. 68 patients (40.5%) had continuous abdominal pain, 39 (23.2%) PEI and 43 (25.7%) morphologically severe CP. HFD was associated with an increased probability for continuous abdominal pain (OR = 2.84 (95% CI, 1.06-7.61)), and a younger age at diagnosis (37.0 ± 13.9 versus 45.8 ± 13.0 years, p = 0.03) but not with CP related complications after adjusting for sex, years of follow-up, alcohol and tobacco consumption, etiology and body mass index.
CONCLUSIONS: Compared with a normal fat diet, HFD is associated with a younger age at diagnosis of CP and continuous abdominal pain, but not with severity and complications of the disease.

Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
PMID 23453638
Stephen J O'Brien, Endashaw Omer
Chronic Pancreatitis and Nutrition Therapy.
Nutr Clin Pract. 2019 Oct;34 Suppl 1:S13-S26. doi: 10.1002/ncp.10379.
Abstract/Text Chronic pancreatitis is a complex and irreversible disease of the pancreas and is associated with significant morbidity and mortality. Nutrition deficiencies in chronic pancreatitis are common and can be atypical in nature. As such, the management of these deficiencies can be individualized for patients. The aim of this review is to discuss the components of nutrition deficiencies in chronic pancreatitis, their management, and the current areas of research that are being explored. The clinical guidelines of major national and international societies were analyzed for recommendations on the nutrition management of chronic pancreatitis. The etiology of nutrition deficiencies in chronic pancreatitis is multifactorial and includes aspects of exocrine and/or endocrine dysfunction, significant abdominal pain, often persistent alcohol consumption, and increased metabolic activity. A large number of patients with nutrition deficiencies are underrecognized and undertreated. Although the majority of these patients can be managed by oral and pancreatic enzyme supplementation, some patients may require enteral tube feeding and, in rare cases, parenteral feeding. Current areas of research include the accurate identification of patients at risk for nutrition deficiencies, optimization of feeding regimens, and research into islet cell autotransplantation.

© 2019 American Society for Parenteral and Enteral Nutrition.
PMID 31535736
Siddharth Singh, Shallu Midha, Namrata Singh, Yogendra Kumar Joshi, Pramod Kumar Garg
Dietary counseling versus dietary supplements for malnutrition in chronic pancreatitis: a randomized controlled trial.
Clin Gastroenterol Hepatol. 2008 Mar;6(3):353-9. doi: 10.1016/j.cgh.2007.12.040.
Abstract/Text BACKGROUND & AIMS: Up to 50% of patients with chronic pancreatitis (CP) are malnourished. There are limited data on the role of dietary intervention in improving the nutritional status of such patients. The aim was to compare the efficacy of medium chain triglyceride (MCT)-enriched commercial dietary supplements with dietary counseling for homemade food in the management of malnutrition in patients with CP.
METHODS: In a randomized controlled trial, consecutive undernourished patients with CP (body mass index [BMI] <18.5 kg/m(2)) at a tertiary care hospital were randomized to receive either dietary counseling for regular homemade food or commercial MCT-enriched dietary supplements for a period of 3 months to compensate for the dietary calorie deficit. All patients received standard management for CP including pancreatic enzyme supplements. Primary outcome measure was improvement in BMI.
RESULTS: Sixty malnourished patients with CP were randomized to counseling group (n = 29; mean age, 32 +/- 10 years; male, 83%) and supplementation group (n = 31; mean age, 28 +/- 10 years; male, 84%). BMI increased in both the counseling group and supplementation group (17.2 +/- 1.7 vs 18.1 +/- 1.8 kg/m(2), P = .001; 16.7 +/- 1.6 vs 18.2 +/- 1.6 kg/m(2), P = .001). There were similar improvements in triceps skinfold thickness, dietary intake, fecal fat, and pain score during a period of 3 months in both groups. There was, however, no significant difference between the counseling and supplementation groups with regard to any of the outcome measures.
CONCLUSIONS: Dietary counseling for a balanced homemade diet is as good as commercial food supplements in improving malnutrition in patients with CP.

PMID 18328440
Nobuo Ashizawa, Tomoyuki Hashimoto, Tatsuya Miyake, Toshihiro Shizuku, Tomonori Imaoka, Yoshikazu Kinoshita
Efficacy of camostat mesilate compared with famotidine for treatment of functional dyspepsia: is camostat mesilate effective?
J Gastroenterol Hepatol. 2006 Apr;21(4):767-71. doi: 10.1111/j.1440-1746.2005.04041.x.
Abstract/Text BACKGROUND: Differentiation between functional dyspepsia and early chronic pancreatitis is difficult because these diseases do not produce specific abnormalities in laboratory testing. The aim of this study was to examine the potential efficacy of camostat mesilate, a protease inhibitor, against functional dyspepsia and to characterize patients with favorable responses.
METHODS: Dyspeptic patients who exhibited no abnormalities on laboratory blood and urine testing, abdominal ultrasonography and upper gastrointestinal endoscopy were randomized to receive camostat mesilate 200 mg three times daily or famotidine 20 mg twice daily for 4 weeks. Symptoms severity was recorded before and at 2 and 4 weeks after starting treatment using a visual analog scale.
RESULTS: Epigastralgia was significantly improved after 2 and 4 weeks of treatment in both groups (P < 0.01); this improvement tended to be more marked in the camostat mesilate group (P < 0.05 at 2 weeks). The beneficial effect of camostat mesilate on epigastralgia was more prominent in chronic alcohol drinkers at 2 weeks (P < 0.05) and 4 weeks (P < 0.01).
CONCLUSIONS: Camostat mesilate is superior to famotidine for relieving epigastralgia in patients with functional dyspepsia. Its pain-relieving effect is greater in patients who habitually drink alcohol.

PMID 16677167
A Brown, M Hughes, S Tenner, P A Banks
Does pancreatic enzyme supplementation reduce pain in patients with chronic pancreatitis: a meta-analysis.
Am J Gastroenterol. 1997 Nov;92(11):2032-5.
Abstract/Text OBJECTIVE: Pancreatic enzyme therapy is widely used in the treatment of pain in chronic pancreatitis. The aim of our study was to perform a meta-analysis to determine whether pancreatic enzyme supplementation significantly decreases abdominal pain in patients with chronic pancreatitis.
METHODS: From a MEDLINE search, we identified, evaluated, and subjected to a meta-analysis, six randomized, double-blind, placebo-controlled trials. Important features of data extraction included the method of subject inclusion, definition of disease, enzyme preparation, response to pancreatic enzyme therapy versus placebo, and modality for measuring response.
RESULTS: In the meta-analysis, the pooled estimate of the percentage of patients per study who preferred enzymes relative to placebo was 52% (95% confidence interval, 45-60%). A test of homogeneity indicated that there was no statistically significant heterogeneity across studies in the percentage of patients preferring enzymes.
CONCLUSION: Statistical analysis demonstrates no significant benefit of supplemental pancreatic enzyme therapy to relieve pain associated with chronic pancreatitis.

PMID 9362186
J Slaff, D Jacobson, C R Tillman, C Curington, P Toskes
Protease-specific suppression of pancreatic exocrine secretion.
Gastroenterology. 1984 Jul;87(1):44-52.
Abstract/Text The purposes of this study were to (a) evaluate the effect of pancreatic extract administered to patients with chronic pancreatitis and recurrent abdominal pain in a placebo-controlled, double-blind crossover study, (b) investigate the effects of acute intraduodenal pancreatic enzyme perfusion on pancreatic secretion, and (c) assess the effect of chronic, noninterrupted pancreatic extract administration on basal and stimulated pancreatic secretion. These studies demonstrated that pancreatic extract decreases abdominal pain and that intraduodenal perfusion with proteases but not with amylase or lipase suppresses pancreatic exocrine secretion in patients with chronic pancreatitis. Chronic administration of pancreatic extract to patients with chronic pancreatitis decreased both basal and stimulated pancreatic exocrine secretion.

PMID 6202586
G Isaksson, I Ihse
Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis.
Dig Dis Sci. 1983 Feb;28(2):97-102.
Abstract/Text In a double-blind study on 19 patients with the diagnosis of chronic pancreatitis, the effects of treatment with a granulated pancreatic enzyme preparation (Pankreon) were compared with those of placebo administration. One week of treatment with each preparation was preceded by one week without any medication. The patients kept daily records of their symptoms, plotting the severity of pain on an analog scale. Weekly assessments of the mean pain level were also made by an examiner questioning the patients. Recordings of body weights and pancreas and liver laboratory tests were done weekly. Fifteen of 19 patients noted less pain during the week of treatment with pancreatic enzymes as compared to that of placebo treatment (P less than 0.05). The average reduction of pain, as calculated for all patients, was 30% as evaluated by both patients (P less than 0.01) and the examiner (P less than 0.05). No differences were found in other parameters examined. A possible explanation of the findings could be an effect on the intraductal pressure by intraluminal trypsin.

PMID 6825540
Abstract/Text Ten patients with chronic pancreatitis (with abdominal pain and/or diarrhoea) were treated in a double-blind multiple cross-over trial with Pankreon granules 20 g per day or placebo during three periods of one month each. Pain and bowel habits were recorded. Faecal fat and breath hydrogen (H2) excretion were analyzed during the last days of each treatment period. The pain score was initially low in all patients and was not affected by enzymes. The number of daily bowel movements was reduced from 3.16 to 2.32 (n.s.). Faecal fat excretion per 72 hrs was reduced from 357 +/- 158 mmol free fatty acid to 226 +/- 98 mmol (p less than 0.05). With placebo treatment H2 excretion (from 60 and 180 min after a standard breakfast) was significantly increased compared with 19 healthy volunteers (p less than 0.05). It was not significantly reduced by enzymes. In 28 comparisons the H2 output between 60 and 180 min was correlated to faecal fat. In eight patients the oro-coecal transit-time could be determined by the H2 breath test. The transit-time did not differ from that of ten healthy volunteers and remained unchanged by enzymes. Carbohydrate maldigestion occurs parallel to fat maldigestion in chronic pancreatitis, and is not sufficiently reduced by 20 g of pancreatic enzymes.

PMID 3551051
H Halgreen, N T Pedersen, H Worning
Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis.
Scand J Gastroenterol. 1986 Jan;21(1):104-8.
Abstract/Text The symptomatic effect of pancreatic enzyme substitution therapy was examined in a 4-week double-blind crossover study. Twenty patients, 11 with and 9 without steatorrhoea, were examined. Pancreatic steatorrhoea was reduced from a median of 24 g/day to 10 g/day by the enzyme therapy (P less than 0.01). No significant pain reduction was found in either of the two groups, although there was a tendency to reduction in pain and analgetic consumption in the patients with steatorrhoea when treated with pancreatic enzymes. It is concluded that pancreatic steatorrhoea is still the only indication for pancreatic enzyme therapy.

PMID 3633631
Abstract/Text According to the theory of negative feedback regulation of pancreatic enzyme secretion by proteases, treatment with pancreatic extracts has been proposed to lower pain in chronic pancreatitis by decreasing pancreatic duct pressure. We conducted a prospective placebo-controlled double blind multicenter study to investigate the effect of porcine pancreatic extracts on pain in chronic pancreatitis. 47 patients with pain (41 males, 6 females) due to chronic pancreatitis documented by sonography, endoscopic retrograde cholangiopancreatography, and CT were included. Exclusion criteria were steatorrhea above 30 g/day, gastric or pancreatic resections in the history, and serum bilirubin above 1.5 mg/dl. Patients received pancreatic extracts (acid-protected microtablets; Panzytrat -20,000; 5 x 2 capsules/day; proteases/capsule 1,000 Pharmacopoea europaea units) for 14 days followed by treatment with placebo for another 14 days or vice versa. Pain (graded from 0 to 3) and concomitant use of analgesics (N-butylscopolaminiumbromide and tramadol) were recorded by diary. Physical examination and blood chemistry were done at day -1, 15 and 29. Quantitative stool fat was determined at days -2/-1, 13/14 and 27/28. 43 patients completed the studies. Pain improved in most patients irrespective of whether they started with placebo or verum. There was no significant difference between both treatment arms. We conclude that pancreatic extracts are not very efficient in lowering pain.

PMID 1289173
A Malesci, E Gaia, A Fioretta, P Bocchia, G Ciravegna, P Cantor, I Vantini
No effect of long-term treatment with pancreatic extract on recurrent abdominal pain in patients with chronic pancreatitis.
Scand J Gastroenterol. 1995 Apr;30(4):392-8.
Abstract/Text BACKGROUND: This study was aimed to investigate the effect of long-term treatment with high-protease pancreatic extract on the recurrent abdominal pain of patients with chronic pancreatitis.
METHODS: Twenty-six patients with a firm diagnosis of chronic pancreatitis and a pattern of recurrent pain were recruited and randomly assigned to treatment with pancreatic extract (Pancrex-Duo capsules, each containing 34,375 USP units of protease in enteric-coated microspheres) or placebo, at a dose of four capsules four times daily, for 4 months. At the end of the first period patients were switched to the other medication for the next 4 months. Four patients did not complete the study because of unbearable recurring pain or inadequate compliance with treatment. The other 22 patients daily recorded the presence, intensity, and duration of pain and the consumption of analgesics, for 8 months.
RESULTS: No difference was found when intraindividual records during placebo and extract treatment periods were compared. Conversely, in the second 4 months of follow-up, regardless of the treatment given in the first period, there was a significant reduction in the cumulative pain score (median, 95; range, 0-1005, versus 134; 0-972; p < 0.05), in the number of days (8; 0-132, versus 13; 0-126; p < 0.02) and hours (54; 0-680, versus 80; 0-602; p < 0.05) of pain, and in the analgesic consumption score (0; 0-22, versus 12; 0-44; p = 0.02).
CONCLUSIONS: Chronic supplementation with pancreatic extract is not beneficial in the management of recurrent pain in patients with chronic pancreatitis.

PMID 7610357
O J Rämö, P A Puolakkainen, K Seppälä, T M Schröder
Self-administration of enzyme substitution in the treatment of exocrine pancreatic insufficiency.
Scand J Gastroenterol. 1989 Aug;24(6):688-92.
Abstract/Text The effect of self-administration (ad lib) of pancreatic enzyme substitution (Pancrease) in comparison with the dosage recommended by the manufacturer on abdominal symptoms and nutritional variables was studied in 10 patients with chronic pancreatitis. Both dosages were started in randomized order and they were continued for 4 weeks. Before and after each period of administration the patients were studied physically and weighed, and laboratory tests were performed. In addition, the patients kept daily records of pain (score, 0-3), bowel movements, amount of medication needed for maximum relief of symptoms and other remarks, if any. During self-administration, the number of capsules taken increased (5 +/- 1.3 to 11.4 +/- 2.4; p less than 0.001), the frequency of bowel movements decreased (3.6 +/- 1.4 to 1.6 +/- 0.7; p less than 0.05), and the pain was also relieved significantly (2.2 +/- 0.7 to 1.1 +/- 0.7; p less than 0.05) when compared with the regular dosage. Self-administration of the preparation did not have any significant effects on nutritional variables. Dryness of the mouth was the only complaint during self-administration of the drug in 4 of 10 patients. In conclusion, this study in selected patients with chronic pancreatitis indirectly supports the presence of a negative feedback regulation of exocrine pancreatic secretion in man. Thus, it may be beneficial to try self-administration of pancreatic enzyme substitution in selected patients to achieve maximum relief of symptoms in chronic pancreatitis.

PMID 2479083
László Czakó, Tamás Takács, Peter Hegyi, László Prónai, Zsolt Tulassay, Lilla Lakner, Zoltán Döbrönte, Krisztina Boda, János Lonovics
Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis.
Can J Gastroenterol. 2003 Oct;17(10):597-603.
Abstract/Text GOALS: To evaluate the quality of life (QoL) of patients with chronic pancreatitis before and after pancreatic enzyme replacement therapy in a prospective, multicentre, follow-up study.
STUDY: Two groups of patients were evaluated. Group 1 consisted of 31 patients with newly diagnosed chronic pancreatitis who had never been treated with pancreatic enzyme preparations. Group 2 consisted of 39 patients whose disease was diagnosed on average 3.4 years before the start of the study. The latter group of patients had undergone pancreatic enzyme replacement therapy, but during follow-up this treatment proved to be insufficient. The dose of pancreatic enzyme replacement therapy was tailored in accordance with the degree of pancreatic exocrine insufficiency measured by means of exocrine pancreatic function tests. A modified European Organizaton for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was used to assess QoL.
RESULTS: The social functioning and financial strain were significantly better, while the levels of hope and confidence were significantly reduced in group 1 compared with group 2. A significant gain in body weight and a significantly reduced defecation rate were found in both groups one month after the beginning of the pancreatic enzyme replacement therapy when compared with the pretreatment values. The prevalence of general and disease-specific symptoms and the intensity of pain were reduced in both groups after one month of enzyme substitution therapy. The working ability, the financial strain and the overall QoL scores were improved significantly in both groups, while the cognitive functioning score was found to be significantly improved during the follow-up only in group 1. The overall increase in the QoL score correlated significantly with the increase in body weight and the decrease in defecation number in both groups.
CONCLUSIONS: Pancreatic enzyme replacement therapy in patients with chronic pancreatitis not only reduced the extent of steatorrhea and pain, but also significantly improved a variety of other symptoms and the patient's QoL. Individually tailored enzyme replacement therapy improved the QoL not only in the untreated chronic pancreatitis patients, but also in the inadequately treated group. This study demonstrated that the EORTC QLQ-C30 questionnaire, with the addition of two further questions about steatorrhea, is a useful tool for the evaluation of QoL in patients with chronic pancreatitis.

PMID 14571298
Mohammad Yaghoobi, Julia McNabb-Baltar, Raheleh Bijarchi, Peter B Cotton
Pancreatic Enzyme Supplements Are Not Effective for Relieving Abdominal Pain in Patients with Chronic Pancreatitis: Meta-Analysis and Systematic Review of Randomized Controlled Trials.
Can J Gastroenterol Hepatol. 2016;2016:8541839. doi: 10.1155/2016/8541839. Epub 2016 Apr 24.
Abstract/Text Background. Pancreatic enzyme supplementation is widely used to treat pain in patients with chronic pancreatitis, despite little evidence for efficacy. We performed a systematic review of the literature and a meta-analysis to investigate its effectiveness. Methods. All randomized controlled parallel or crossover trials in patients with chronic pancreatitis comparing pancreatic enzyme supplementation to placebo were included. The main outcome was improvement in pain score or reduced analgesic consumption. Two independent reviewers extracted data. Mantel-Haenszel random effect model meta-analysis was used whenever methodologically appropriate. Results. Five out of 434 retrieved studies were included in the systematic review. All studies used relatively similar methodology. Four studies using enteric-coated pancreatic enzyme supplementation failed to show any improvement in pain as compared to placebo. The only study using non-enteric-coated enzymes did show reduction in the pain score. There was significant heterogeneity among studies in both analyses. Random model meta-analysis of three studies showed no significant difference in the mean of daily pain score (mean difference: 0.09 (1.57-1.39), p = 0.91) or average weekly analgesic consumption (mean difference: -0.30 (-2.37-1.77), p = 0.77) between the periods of administering pancreatic enzyme supplementation versus placebo. Conclusion. Pancreatic enzyme supplements do not seem to relieve abdominal pain in patients with chronic pancreatitis and should not be prescribed solely for this purpose, given their significant cost and potential side effects.

PMID 27446871
Nusrat Shafiq, Surinder Rana, Deepak Bhasin, Promila Pandhi, Puja Srivastava, Surjit S Sehmby, Raj Kumar, Samir Malhotra
Pancreatic enzymes for chronic pancreatitis.
Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006302. doi: 10.1002/14651858.CD006302.pub2. Epub 2009 Oct 7.
Abstract/Text BACKGROUND: The efficacy of pancreatic enzymes in reducing pain and improving steatorrhoea is debatable and the evidence base for their utility needs to be determined.
OBJECTIVES: To evaluate the efficacy of pancreatic enzymes in patients with chronic pancreatitis. The specific objectives were to compare the following: 1) pancreatic enzyme versus placebo; 2) different pancreatic enzyme preparations and 3) different dosage schedules of the enzyme preparations. We evaluated the following outcomes: change in frequency of abdominal pain, duration of pain episodes, intensity of pain, weight loss, steatorrhoea, faecal fat and quality of life.
SEARCH STRATEGY: We devised a search strategy to detect all published and unpublished literature and the search included CENTRAL (The Cochrane Library 2009, issue 1), MEDLINE (1965 to February 2009) and EMBASE (1974 to Feburary 2009). We handsearched reference lists and published abstracts from conference proceedings to identify further relevant trials. The date of the last search was April 2009.
SELECTION CRITERIA: Randomised controlled trials with or without blinding. We included abstracts or unpublished data if sufficient information was available.
DATA COLLECTION AND ANALYSIS: Two authors independently extracted and pooled the data pertinent to study outcomes. We combined continuous data using standardised mean difference (SMD) with 95% confidence interval (CI) and calculated the odds ratio (OR) for dichotomous data (95% CI).
MAIN RESULTS: Ten trials, involving 361 participants, satisfied the inclusion criteria. All the trials were randomised; two had a parallel design while the remainder had a cross-over design. Although some individual studies reported a beneficial effect of pancreatic enzyme over placebo in improving pain, incidence of steatorrhoea and analgesic consumption, the results of the studies could not be pooled for these outcomes. With the use of pancreatic enzymes, we observed a non-significant benefit for weight loss (kg) (SMD 0.06; 95% CI -0.23 to 0.34); a significant reduction in faecal fat (g/day) (SMD -1.03; 95% CI -1.60 to -0.46) and non-significant difference in subjects' Clinical Global Impression of Disease Symptom Scale (SMD -0.63; 95% CI -1.41 to 0.14). We found no significant benefit in reducing faecal fat with any particular schedule of enzyme preparation or type of enzyme.Another small study did not show any significant benefit of timing the administration of enzyme preparations in relation to meals on faecal fat.
AUTHORS' CONCLUSIONS: The role of pancreatic enzymes for abdominal pain, weight loss, steatorrhoea, analgesic use and quality of life in patients with chronic pancreatitis remains equivocal. Good quality, adequately powered studies are much warranted.

PMID 19821359
J Mössner, V Keim, C Niederau, M Büchler, M V Singer, P G Lankisch, B Göke
[Guidelines for therapy of chronic pancreatitis. Consensus Conference of the German Society of Digestive and Metabolic Diseases. Halle 21-23 November 1996].
Z Gastroenterol. 1998 May;36(5):359-67.
Abstract/Text
PMID 9654702
C H Wilder-Smith, L Hill, W Osler, S O'Keefe
Effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis.
Dig Dis Sci. 1999 Jun;44(6):1107-16. doi: 10.1023/a:1026607703352.
Abstract/Text Tramadol and morphine were compared for treatment of severe chronic pancreatitis pain and their interaction with gut motor function. Oral tramadol or morphine doses were titrated double-blinded and randomized for five days in 25 patients and pain, side effects, bowel function, orocecal and colonic transit, anal resting pressure, and rectal distension thresholds were measured. Pain intensities (mean+/-SD, 0 = none, 100 = unbearable) before treatment and on day 4 were 75+/-19 and 8+/-13 with tramadol (P < 0.001), and 65+/-21 and 5+/-6 with morphine (P < 0.001). On day 4, 67% of patients with tramadol and 20% with morphine rated their analgesia as excellent (P < 0.001) with mean respective doses of 840 mg (range: 80-1920) and 238 mg (20-1125). Orocecal transit was unchanged after five days of tramadol, but increased with morphine (P < 0.05). More patients had prolonged colonic transit times with morphine by day 5 (P < 0.05). Rectal distension threshold pressures increased only with tramadol (P < 0.01). It is concluded tramadol and morphine are potent analgesics in severe chronic pancreatitis pain when individually titrated. Tramadol interfered significantly less with gastrointestinal function and was more often rated as an excellent analgesic than morphine.

PMID 10389680
Harsha Moole, Amy Jaeger, Matthew L Bechtold, David Forcione, Deepak Taneja, Srinivas R Puli
Success of Extracorporeal Shock Wave Lithotripsy in Chronic Calcific Pancreatitis Management: A Meta-Analysis and Systematic Review.
Pancreas. 2016 May-Jun;45(5):651-8. doi: 10.1097/MPA.0000000000000512.
Abstract/Text OBJECTIVES: This is a meta-analysis and systematic review to assess the overall utility and safety of Extracorporeal shock wave lithotripsy (ESWL) in chronic calcific pancreatitis. Primary outcomes are pain relief, narcotic usage, ductal clearance, quality of life, and pancreatic exocrine and endocrine function.
METHODS: Studies involving ESWL in chronic calcific pancreatitis with main pancreatic duct stones greater than 5 mm and patients that failed conservative pain management were included. Fixed and random effects models were used to calculate the pooled proportions.
RESULTS: Initial search identified 1471 reference articles, in which 184 articles were selected and reviewed. Data were extracted from 27 studies (N = 3189) which met the inclusion criterion. The pooled proportion of patients with absence of pain at follow-up was 52.7% (95% confidence interval [95% CI], 50.85-54.56) and mild to moderate pain at follow-up was 33.43% (95% CI, 31.40-35.50). Quality of life improved in 88.21% (95% CI, 85.43-90.73) and complete ductal clearance was 70.69% (95% CI, 68.97-72.38) in the pooled patients.
CONCLUSIONS: The ESWL is an effective and safe management option in patients with chronic calcific pancreatitis patients with main pancreatic duct stone size greater than 5 mm who did not get adequate pain relief with conservative management.

PMID 26580454
P Díte, M Ruzicka, V Zboril, I Novotný
A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis.
Endoscopy. 2003 Jul;35(7):553-8. doi: 10.1055/s-2003-40237.
Abstract/Text BACKGROUND AND STUDY AIMS: Invasive treatment for abdominal pain due to chronic pancreatitis may be either surgical or endoscopic, particularly in cases of ductal obstruction. To date, the data published on the effectiveness of these two forms of therapy have been mostly retrospective, and there have been no randomized studies. A prospective, randomized study comparing surgery with endoscopy in patients with painful obstructive chronic pancreatitis was therefore conducted.
PATIENTS AND METHODS: Consecutive patients with pancreatic duct obstruction and pain were invited to participate in a randomized trial comparing endotherapy and surgery, the latter consisting of resection and drainage procedures, depending on the patient's individual situation. Patients who did not agree to participation and randomization were also further assessed using the same follow-up protocol.
RESULTS: Of 140 eligible patients, only 72 agreed to be randomized. Surgery consisted of resection (80 %) and drainage (20 %) procedures, while endotherapy included sphincterotomy and stenting (52 %) and/or stone removal (23 %). In the entire group, the initial success rates were similar for both groups, but at the 5-year follow-up, complete absence of pain was more frequent after surgery (37 % vs. 14 %), with the rate of partial relief being similar (49 % vs. 51 %). In the randomized subgroup, results were similar (pain absence 34 % after surgery vs. 15 % after endotherapy, relief 52 % after surgery vs. 46 % after endotherapy). The increase in body weight was also greater by 20 - 25 % in the surgical group, while new-onset diabetes developed with similar frequency in both groups (34 - 43 %), again with no differences between the results for the whole group and the randomized subgroup.
CONCLUSIONS: Surgery is superior to endotherapy for long-term pain reduction in patients with painful obstructive chronic pancreatitis. Better selection of patients for endotherapy may be helpful in order to maximize results. Due to its low degree of invasiveness, however, endotherapy can be offered as a first-line treatment, with surgery being performed in case of failure and/or recurrence.

PMID 12822088
Michael J Farnbacher, Steffen Mühldorfer, Markus Wehler, Bernhard Fischer, Eckhart G Hahn, H Thomas Schneider
Interventional endoscopic therapy in chronic pancreatitis including temporary stenting: a definitive treatment?
Scand J Gastroenterol. 2006 Jan;41(1):111-7. doi: 10.1080/00365520510024098.
Abstract/Text OBJECTIVE: In the past 15 years there have been tremendous advances in endoscopic management of chronic pancreatitis (CP). However, the value of endoscopic pancreatic stenting is still debatable.
MATERIAL AND METHODS: In 98 patients suffering from symptomatic CP (84 M, 14 F, 49+/-12, age range 23-83 years) endotherapy including temporary stenting of the pancreatic duct was performed. After final stent removal, indicating the primary end-point of endotherapy, 96 patients were followed for 35+/-28 (8 days-111) months. All data were assessed retrospectively.
RESULTS: As well as other endoscopic procedures, a total of 358 prostheses were inserted in the pancreatic duct and left in place for 3+/-1 (1 day-11) months. Total stent treatment time was 10+/-10 (6 days-49) months. At 46+/-27 (4-111) months after limited endotherapy, 57 patients had no need for secondary intervention, two-thirds were even without further pain sensations. In 22 patients, surgical treatment and in 17 patients further endoscopic therapy became necessary, which was significantly correlated with continued alcohol consumption.
CONCLUSIONS: Temporary stent placement as a part of interventional endoscopic therapy in CP shows a high rate of technical and long-term clinical success, with no need for secondary treatment in a remarkable number of patients. Continued cessation of alcohol consumption supports the treatment benefit significantly.

PMID 16373284
K F Binmoeller, P Jue, H Seifert, W C Nam, J Izbicki, N Soehendra
Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: long-term results.
Endoscopy. 1995 Nov;27(9):638-44. doi: 10.1055/s-2007-1005780.
Abstract/Text BACKGROUND AND STUDY AIMS: Endoscopic pancreatic stent drainage has been reported to relieve pain due to chronic pancreatitis in patients with ductal outflow obstruction. However, data regarding the long-term results, as presented here, have hitherto been lacking.
PATIENTS AND METHODS: Over a nine-year period, 93 patients (65 males, mean age 49 years) with narcotic-dependent pain due to chronic pancreatitis and with a dominant pancreatic duct stricture visualized by endoscopic retrograde cholangiopancreatography (ERCP), were treated by stent drainage. The duration of pain prior to treatment averaged 5.6 years. The stents were exchanged according to symptoms, and removed if the stricture was judged to be adequately dilated after stenting.
RESULTS: Sixty-nine patients (74%) reported complete (n = 46) or partial (n = 23) pain relief at six months. In this group of "early responders", 60 patients experienced sustained improvement during a mean follow-up of 4.9 years (nine had recurrent pain after a mean of 1.2 years). Stents were removed in 49 patients after a mean of 15.7 months; during a mean follow-up of 3.8 years, 36 patients remained pain-free, and 13 had a relapse of pain (11 were retreated by endoscopic drainage and subsequently became pain-free). Complications seen included mild pancreatitis (n = 4) and abscess formation secondary to stent clogging (n = 2). Most patients experienced a regression of the ductal dilation after stenting.
CONCLUSION: In selected patients, early responders to pancreatic stent drainage are likely to benefit over the long term. Stent removal after stricture dilation may be associated with continued pain relief.

PMID 8903975
Usama Ahmed Ali, Johanna M Pahlplatz, Wiliam H Nealon, Harry van Goor, Hein G Gooszen, Marja A Boermeester
Endoscopic or surgical intervention for painful obstructive chronic pancreatitis.
Cochrane Database Syst Rev. 2012 Jan 18;1:CD007884. doi: 10.1002/14651858.CD007884.pub2. Epub 2012 Jan 18.
Abstract/Text BACKGROUND: Endoscopy and surgery are the treatment modalities of choice in patients with obstructive chronic pancreatitis. Physicians face the decision between endoscopy and surgery for this group of patients, without clear consensus.
OBJECTIVES: To assess and compare the effectiveness and complications of surgical and endoscopic interventions in the management of pain for obstructive chronic pancreatitis.
SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE and the Conference Proceedings Citation Index; and performed a cross-reference search. Two review authors performed the selection of trials independently.
SELECTION CRITERIA: All randomised controlled trials (RCTs) investigating endoscopic or surgical interventions for obstructive chronic pancreatitis. All trials were included irrespective of blinding, number of patients randomised and language of the article.
DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from the articles. The methodological quality of included trials was evaluated. Authors were requested additional information in the case of missing data.
MAIN RESULTS: We screened 2082 publications and identified three eligible trials. Two trials compared endoscopic intervention to surgical intervention. These included a total of 111 patients, 55 in the endoscopic group and 56 in the surgical group. A higher proportion of patients with pain relief was found in the surgical group compared to the endoscopic group (partial or complete pain relief: RR 1.62, 95% confidence interval (CI) 1.11 to 2.37; complete pain relief: RR 2.45, 95% CI 1.18 to 5.09). Surgical intervention resulted in improved quality of life and improved preservation of exocrine pancreatic function in one trial. The number of patients did not allow for a reliable evaluation of morbidity and mortality between the two treatment modalities. One trial compared surgical intervention to conservative treatment. It included 32 patients: 17 in the surgical group and 15 in the conservative group. The trial showed that surgical intervention resulted in a higher percentage of patients with pain relief and better preservation of pancreatic function. The trial had methodological limitations and the number of patients was relatively small.
AUTHORS' CONCLUSIONS: For patients with obstructive chronic pancreatitis and dilated pancreatic duct, this review showed that surgery is superior to endoscopy in terms of pain control. Morbidity and mortality seemed not to differ between the two intervention modalities, but the small trials identified do not provide sufficient power to detect the small differences expected in this outcome.Regarding the comparison of surgical intervention versus conservative treatment, this review has shown that surgical intervention in an early stage of chronic pancreatitis seems to be a promising approach in terms of pain control and pancreatic function. Confirmation of these results is needed in other trials due to the methodological limitations and limited number of patients of the present evidence.

PMID 22258975
Jan G D'Haese, Güralp O Ceyhan, Ihsan Ekin Demir, Elke Tieftrunk, Helmut Friess
Treatment options in painful chronic pancreatitis: a systematic review.
HPB (Oxford). 2014 Jun;16(6):512-21. doi: 10.1111/hpb.12173. Epub 2013 Aug 29.
Abstract/Text BACKGROUND: Longlasting and unbearable pain is the most common and striking symptom of chronic pancreatitis. Accordingly, pain relief and improvement in patients' quality of life are the primary goals in the treatment of this disease. This systematic review aims to summarize the available data on treatment options.
METHODS: A systematic search of MEDLINE/PubMed and the Cochrane Library was performed according to the PRISMA statement for reporting systematic reviews and meta-analysis. The search was limited to randomized controlled trials and meta-analyses. Reference lists were then hand-searched for additional relevant titles. The results obtained were examined individually by two independent investigators for further selection and data extraction.
RESULTS: A total of 416 abstracts were reviewed, of which 367 were excluded because they were obviously irrelevant or represented overlapping studies. Consequently, 49 full-text articles were systematically reviewed.
CONCLUSIONS: First-line medical options include the provision of pain medication, adjunctive agents and pancreatic enzymes, and abstinence from alcohol and tobacco. If medical treatment fails, endoscopic treatment offers pain relief in the majority of patients in the short term. However, current data suggest that surgical treatment seems to be superior to endoscopic intervention because it is significantly more effective and, especially, lasts longer.

© 2013 International Hepato-Pancreato-Biliary Association.
PMID 24033614
Zaynab A R Jawad, Charis Kyriakides, Madhava Pai, Chris Wadsworth, David Westaby, Panagiotis Vlavianos, Long R Jiao
Surgery remains the best option for the management of pain in patients with chronic pancreatitis: A systematic review and meta-analysis.
Asian J Surg. 2017 May;40(3):179-185. doi: 10.1016/j.asjsur.2015.09.005. Epub 2016 Jan 6.
Abstract/Text Controversy related to endoscopic or surgical management of pain in patients with chronic pancreatitis remains. Despite improvement in endoscopic treatments, surgery remains the best option for pain management in these patients.

Copyright © 2017. Published by Elsevier Taiwan.
PMID 26778832
David C Whitcomb, Glen A Lehman, Galina Vasileva, Ewa Malecka-Panas, Natalya Gubergrits, Yannan Shen, Suntje Sander-Struckmeier, Steven Caras
Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: A double-blind randomized trial.
Am J Gastroenterol. 2010 Oct;105(10):2276-86. doi: 10.1038/ajg.2010.201. Epub 2010 May 25.
Abstract/Text OBJECTIVES: Pancreatic-enzyme replacement therapy (PERT) is the standard of care to prevent maldigestion, malnutrition, and excessive weight loss in patients with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP) or pancreatic surgery (PS). Our objective was to assess the efficacy and safety of a new formulation of pancrelipase (pancreatin) delayed-release 12,000-lipase unit capsules (CREON) in patients with EPI due to CP or PS.
METHODS: This was a double-blind, randomized, multicountry, placebo-controlled, parallel-group trial enrolling patients ≥18 years old with confirmed EPI due to CP or PS conducted in clinical research centers or hospitals. After a 5-day placebo run-in period (baseline), patients were randomized to pancrelipase (72,000 lipase units per meal; 36,000 per snack) or placebo for 7 days. All patients received an individually designed diet to provide at least 100 g of fat per day. The primary efficacy measure was the change in coefficient of fat absorption (CFA) from baseline to end of the double-blind period, analyzed using non-parametric analysis of covariance. Secondary outcomes included the coefficient of nitrogen absorption (CNA), clinical symptoms, and safety parameters.
RESULTS: In total, 25 patients (median age of 54 years, 76% male) received pancrelipase and 29 patients (median age of 50 years, 69% male) received placebo. Th e mean ± s.d. change from baseline in CFA was significantly greater with pancrelipase vs. placebo: 31.9 ± 18.6 vs. 8.7 ± 12.4 % ( P < 0.0001) [corrected]. Similarly, the mean ± s.d. change from baseline in CNA was greater for pancrelipase vs. placebo: 35.2 ± 29.1 vs. 8.9 ± 28.0 % ( P = 0.0005) [corrected].Greater improvements from baseline in stool frequency, stool consistency, abdominal pain, and flatulence were observed with pancrelipase vs. placebo. Treatment-emergent adverse events (TEAEs) were reported in five patients (20.0%) in the pancrelipase group and in six (20.7%) in the placebo group; the most common were gastrointestinal (GI) events and metabolism/nutrition disorders. There were no treatment discontinuations due to TEAEs.
CONCLUSIONS: Pancrelipase delayed-release 12,000-lipase unit capsules were effective in treating fat and nitrogen maldigestion with a TEAE rate similar to that of placebo in patients with EPI due to CP or PS.

PMID 20502447
N Gubergrits, E Malecka-Panas, G A Lehman, G Vasileva, Y Shen, S Sander-Struckmeier, S Caras, D C Whitcomb
A 6-month, open-label clinical trial of pancrelipase delayed-release capsules (Creon) in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery.
Aliment Pharmacol Ther. 2011 May;33(10):1152-61. doi: 10.1111/j.1365-2036.2011.04631.x. Epub 2011 Mar 21.
Abstract/Text BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is necessary to prevent severe maldigestion and unwanted weight loss associated with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP) or pancreatic surgery (PS).
AIM: To assess the long-term safety and efficacy of pancrelipase (pancreatin) delayed-release capsules (Creon) in this population.
METHODS: This was a 6-month, open-label extension of a 7-day, double-blind, placebo-controlled study enrolling patients ≥18 years old with confirmed EPI due to CP or PS who were previously receiving PERT. Patients received individualised pancrelipase doses as directed by investigators (administered as Creon 24 000-lipase unit capsules).
RESULTS: Overall, 48 of 51 patients completed the open-label phase; one withdrew due to the unrelated treatment-emergent adverse event (TEAE) of cutaneous burns and two were lost to follow-up. The mean age was 50.9 years, 70.6% of patients were male, 76.5% had CP and 23.5% had undergone PS. The mean±s.d. pancrelipase dose was 186960±74640 lipase units/day. TEAEs were reported by 22 patients (43.1%) overall. Only four patients (7.8%) had TEAEs that were considered treatment related. From double-blind phase baseline to end of the open-label period, subjects achieved a mean±s.d. body weight increase of 2.7±3.4 kg (P<0.0001) and change in daily stool frequency of -1.0±1.3 (P<0.001). Improvements in abdominal pain, flatulence and stool consistency were observed.
CONCLUSIONS: Pancrelipase was well tolerated over 6 months and resulted in statistically significant weight gain and reduced stool frequency in patients with EPI due to CP or PS previously managed with standard PERT.

© 2011 Blackwell Publishing Ltd.
PMID 21418260
V Thorat, N Reddy, S Bhatia, A Bapaye, J S Rajkumar, D D Kini, M M Kalla, H Ramesh
Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis--a double-blind, placebo-controlled study.
Aliment Pharmacol Ther. 2012 Sep;36(5):426-36. doi: 10.1111/j.1365-2036.2012.05202.x. Epub 2012 Jul 4.
Abstract/Text BACKGROUND: Pancreatic exocrine insufficiency (PEI) results in maldigestion, leading to abdominal pain, steatorrhoea, malnutrition and weight loss.
AIM: To assess the efficacy and safety of pancreatin (Creon 40000 MMS) in treating PEI due to chronic pancreatitis (CP).
METHODS: This was a 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study in India. Men and women ≥18 years of age with proven CP and PEI [defined as a coefficient of fat absorption (CFA) ≤80% during run-in phase] were randomised 1:1 to pancreatin or placebo (two capsules orally per main meal, one with snacks). The primary outcome measure was change in CFA from baseline to end of double-blind treatment (analysis of covariance).
RESULTS: Of 62 patients randomised (34 pancreatin, 28 placebo), 61 completed treatment; one patient in the placebo arm withdrew consent before completion. Patient characteristics were similar in both groups except for the proportion of men (pancreatin 82% vs. placebo 68%). Patients receiving pancreatin had a statistically significant greater improvement in fat absorption from baseline to the end of double-blind treatment compared with those receiving placebo, with a least squares mean change (95% CI) in CFA of 18.5% (15.8-21.2) vs. 4.1% (1.0-7.2), respectively. This resulted in a treatment difference of 14.4% (10.3-18.5); P = 0.001. Patients receiving pancreatin also had a statistically significant greater improvement in nitrogen absorption and greater reductions in mean stool fat, stool frequency and stool weight compared with those receiving placebo. Treatment-emergent adverse events occurred in 12 patients on pancreatin and in seven on placebo; none led to study discontinuation.
CONCLUSIONS: The results provide evidence for the efficacy of pancreatin (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis, and confirm that this formulation is well tolerated, with a good safety profile, at the dose administered.

© 2012 Blackwell Publishing Ltd.
PMID 22762290
Tetsuhide Ito, Makoto Otsuki, Hisato Igarashi, Yasuyuki Kihara, Ken Kawabe, Taichi Nakamura, Nao Fujimori, Takamasa Oono, Ryoichi Takayanagi, Tooru Shimosegawa, Research Committee of Intractable Diseases of the Pancreas
Epidemiological study of pancreatic diabetes in Japan in 2005: a nationwide study.
Pancreas. 2010 Aug;39(6):829-35. doi: 10.1097/MPA.0b013e3181ca3da4.
Abstract/Text OBJECTIVES: There have been few epidemiological studies on pancreatic diabetes. In this study, we determined the incidence and pathology of pancreatic diabetes in Japan.
METHODS: We examined the epidemiology of pancreatic diabetes in Japan in 2005 by using a nationwide stratified random-sampling method. Especially, we focused on newly developed diabetes in association with the occurrence of pancreatic disease (true pancreatic diabetes).
RESULTS: A total of 19,500 individuals received treatment for true pancreatic diabetes, accounting for 0.8% of patients with diabetes. Prevalence was estimated to be 15.2 per 100,000 with an annual onset incidence of 1.1 per 100,000. With regard to the complications in true pancreatic diabetes, the incidence of retinopathy was lower than that in types 1 and 2 diabetes. Among true pancreatic diabetes with chronic pancreatitis, alcoholic pancreatitis was found in the largest sector. Furthermore, as many as 53.7% were continuous drinkers, and 66.7% received insulin therapy. The frequency of hypoglycemia was high in regular drinkers treated with insulin. Hypoglycemia was a major cause of death in patients who were on insulin and continuous drinkers.
CONCLUSION: We clarified the epidemiology of pancreatic diabetes in Japan. Patients with chronic pancreatitis-associated pancreatic diabetes should receive lifestyle guidance focused on drinking cessation.

PMID 20182396
C Couet, P Genton, J P Pointel, J Louis, P Gross, E Saudax, G Debry, P Drouin
The prevalence of retinopathy is similar in diabetes mellitus secondary to chronic pancreatitis with or without pancreatectomy and in idiopathic diabetes mellitus.
Diabetes Care. 1985 Jul-Aug;8(4):323-8. doi: 10.2337/diacare.8.4.323.
Abstract/Text In a retrospective study, we compared the prevalence of retinopathy in two groups of 88 diabetic patients (84 men, 4 women) with either diabetes mellitus secondary to chronic pancreatitis (CP-DM group) or idiopathic diabetes mellitus (I-DM group). The patients of these two groups were pair-matched according to age (48.7 +/- 1.1 versus 48.8 +/- 1.0 yr in CP-DM and I-DM groups, respectively; mean +/- SEM), sex, duration of diabetes (7.96 +/- 0.56 versus 8.08 +/- 0.8 yr) and therapy (80 on insulin and 8 on oral hypoglycemic agents in each group). Retinopathy was assessed by bilateral ophthalmoscopic examination of the fundus after pupillary dilation in all 176 patients and by fluorescein angiography in 47 patients with CP-DM and 35 patients with I-DM. Forty-one percent of patients in the CP-DM group and 45.5% of patients in the I-DM group had diabetic retinopathy (P greater than 0.5). In each group, patients with retinopathy were older than patients without retinopathy (51.6 +/- 1.3 versus 46.7 +/- 1.8 yr in the CP-DM group, P less than 0.01, and 52.1 +/- 1.5 versus 46.0 +/- 1.2 yr in the ID-M group, P less than 0.01). They had diabetes of longer duration (10.9 +/- 1.0 versus 5.9 +/- 0.6 yr in the CP-DM group, P less than 0.001, and 10.5 +/- 1.0 versus 6.0 +/- 0.6 yr in the ID-M group, P less than 0.001). The prevalence of retinopathy increased parallel to the duration of diabetes in a similar way in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 4042797
L Gullo, M Parenti, L Monti, R Pezzilli, L Barbara
Diabetic retinopathy in chronic pancreatitis.
Gastroenterology. 1990 Jun;98(6):1577-81. doi: 10.1016/0016-5085(90)91093-l.
Abstract/Text Using fluorescein angiography, we studied the prevalence and characteristics of diabetic retinopathy in 40 patients with chronic pancreatitis complicated by diabetes and in 40 type 1 diabetics with comparable duration of diabetes. Retinopathy was found in 19 pancreatitis patients (47.5%) and in 20 type 1 diabetic patients (50%); it was background, minimal, or mild to moderate, without impairment of visual function, in all 19 pancreatitis patients and in 17 of the 20 type 1 diabetics. In the remaining three idiopathic diabetics, retinopathy was background of severe degree in two and proliferative, with impairment of vision, in one. No differences between patients with and without retinopathy were observed in fasting blood glucose, glycosylated hemoglobin, serum cholesterol, or triglyceride levels. The only significant difference (p less than 0.001) was the greater duration of diabetes in patients with retinopathy when compared with those without it (10.8 +/- 5.7 vs. 5.2 +/- 3.9 yr in pancreatitis patients; 11.2 +/- 5.0 vs. 5.1 +/- 3.5 yr in type 1 diabetics; mean +/- SD). Contrary to what is generally believed, the results indicate that the risk of retinopathy and the characteristics of this complication in patients with chronic pancreatitis and secondary diabetes are similar to those in patients with idiopathic diabetes.

PMID 2338195
S Larsen, J Hilsted, E K Philipsen, H Lund-Andersen, H H Parving, H Worning
A comparative study of microvascular complications in patients with secondary and type 1 diabetes.
Diabet Med. 1990 Nov;7(9):815-8. doi: 10.1111/j.1464-5491.1990.tb01498.x.
Abstract/Text The prevalence of retinopathy, albuminuria, and neuropathy were assessed in 25 patients with insulin-requiring diabetes secondary to chronic pancreatitis and in 25 patients with Type 1 (insulin-dependent) diabetes, matched for age at diabetes onset (secondary, 39 +/- 11 (+/- SD) years vs Type 1, 38 +/- 11 years) and duration of diabetes (10 +/- 6 vs 10 +/- 7 years). The prevalence of retinopathy was significantly higher in Type 1 diabetic patients (52%) than those with secondary diabetes (20%) (p less than 0.02). Median urinary excretion of albumin was 9 (range 1-206) mg 24-h-1 in patients with Type 1 diabetes and 7 (1-90) mg 24-h-1 in patients with secondary diabetes (NS). One secondary diabetic patient and five Type 1 diabetic patients had microalbuminuria (NS). Vibration perception threshold (measured at the big toe) was identical in the two groups of patients, and no patient had a threshold indicating somatic neuropathy (biothesiometry greater than 20 V). Retinopathy is more frequent in patients with Type 1 diabetes than in patients with insulin-requiring diabetes secondary to chronic pancreatitis. Retinopathy is so frequent in the latter group, however, that regular ophthalmoscopic examination is still required.

PMID 2148135
L Rosa-e-Silva, R B Oliveira, L E Troncon, M C Foss, C S Souza, L Gallo
Autonomic nervous function in alcohol-related chronic pancreatitis.
Pancreas. 2000 May;20(4):361-6. doi: 10.1097/00006676-200005000-00004.
Abstract/Text Patients with alcohol-related chronic pancreatitis (ARCP) often have peripheral neuropathy, but no data on the occurrence of autonomic neuropathy (AN) are available for this condition. To assess the autonomic function and the significance of its abnormalities for the prognosis of ARCP, 18 patients with ARCP and associated diabetes mellitus (P-DM group), 10 with ARCP without evidence of diabetes mellitus (P group), 17 patients with insulin-dependent diabetes mellitus (IDDM group), and 18 healthy controls answered a structured questionnaire and underwent three standardized cardiovascular (CV) tests that yielded six different parameters for autonomic nerve function. Patients with at least one symptom plus two abnormal results on CV tests were regarded as having AN. ARCP patients were followed up for 48 months and mortality rates were recorded. The proportions of patients with AN were 66.6% in the P-DM group, 30.0% in the P group, and 29.4% in IDDM patients. Seven of 15 ARCP patients with AN died during follow-up, compared with one of 13 of those without AN (p < 0.037). In conclusion, AN is commonly found in ARCP patients and carries an ominous prognosis.

PMID 10824689

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