Gut: first published as 10.1136/gut.23.2.98 on 1 February 1982. Downloaded from
Gut, 1982, 23, 98-101
Inhibition of postprandial pancreatic and biliary secretion by loperamide in patients with short bowel syndrome* MARGOT REMINGTON, C RICHARD FLEMING, AND J-R MALAGELADAt From the Gastroenterology Unit, Mayo Clinic, Mayo Foundation, Rochester, Maryland, USA
SUMMARY Patients with the short bowel syndrome are usually afflicted by chronic diarrhoea and treated with opiate drugs, yet little documentation ofthe effects ofsuch drugs on digestive function is available. In the present study we found that acute oral administration ofloperamide resulted in 50% inhibition ofpostprandial trypsin and bilirubin output in patients with short bowel syndrome. These changes are consistent with an opiate effect.
The short bowel syndrome is characterised by seven patients, the ileocaecal valve and a rim of malabsorption ofmany nutrients and malnutrition. ileum adjacent to the valve remained in place. Short Patients with short bowel are often treated with bowel syndrome resulted because of resections for anti-diarrhoeal drugs which have an affinity for either Crohn's disease (five patients) or bowel opiate receptors such as tincture ofopium, codeine, infarction (two patients) secondary to ischaemia. diphenoxyalate, and loperamide. Loperamide, a Two of the patients were on home parenteral new synthetic anti-diarrhoeal drug related to nutrition. Exclusion criteria included active
diphenoxalate,' has been shown to be clinically Crohn's disease as determined by current barium http://gut.bmj.com/ effective in reducing chronic diarrhoea and possibly studies and the surgeon's description of the improving digestive and absorptive function in the remaining bowel at the last operation, a gastro- short bowel syndrome.2 3 Despite the widespread enterostomy or other intestinal bypass procedures, use ofloperamide, there are no studies on the effects pancreatic disease, and liver or biliary tract disease. of the drug on postprandial secretory and motor activity of the gut. We report the influence of this PROCEDURE drug on pancreatic and biliary secretion in patients
Each patient or normal control was intubated on September 24, 2021 by guest. Protected copyright. with short bowels. under fluoroscopic control after an overnight fast with a multilumen intestinal tube and a 14 French Methods gastric tube. 3H-PEG in 0.15 m saline was perfused in the duodenum at the level ofthe ampulla ofVater PATIENT SELECTION at a rate of 2 ml per min. An aspiration site was Seven patients with short bowels and seven healthy located 20 cm distally at the ligament of Treitz. age- and sex-matched controls between the ages of After basal samples were obtained during a 30 27 and 79 years were studied. Criteria for selection minute period, the patient drank a 400 ml meal of short bowel patients for study included small which consisted of a defined formula diet (Ensure) bowel resection of greater than or equal to 100 cm. diluted 2:1 with water as it is frequently consumed Average length of resection was 164 cm and it by patients to make it iso-osmolar (300 mOsm). The involved only the distal small bowel. In three ofthe distribution of nutrients was 14% protein (casein hydrolysates and soy protein), 315% fat (corn oil), and 54.5% carbohydrate (corn syrup solids and *This work was supported in part by Grant AM-26428 from the sucrose). '4C-PEG was mixed in the meal as the National Institutes of Health. marker. Gastric and intestinal samples were tDr Malagelada is the recipient of Research Career Development Award AM-00330 from the National Institute of Health. obtained every 10 nminutes after the meal until Address for reprint requests: Dr J-R Malagelada, GI Unit, St Mary's gastric emptying was completed (less than 5% of Hospital, Rochester, MN 55901, USA. initial marker concentration in gastric sample). Received for publication 1 July 1981 Samples were frozen for subsequent analysis. 98 Gut: first published as 10.1136/gut.23.2.98 on 1 February 1982. Downloaded from
Inhibition ofpostprandialpancreatic and biliary secretion in patients with short bowel syndrome 99
EXPERIMENTAL DESIGN duodenal flow can be accurately measured during Each short bowel patient was studied on two gastric emptying ofa meal, despite rapid variations consecutive days with random single blind in flow rates.6 Our duodenal aspiration procedure, administration of either loperamide (6 mg at five as opposed to fixed-volume sampling, closely hours and at 30 minutes before the meal) or an approaches the ideal conditions of recovery equivalent placebo capsule. This dosage is con- proportional to intraluminal flow postulated by sistent with that which may be used in patients with Levitt and Bond.7 This method of quantifying severe short bowel syndrome. Each normal control postprandial pancreatic and biliary outputs has was studied on a single day with administration of been successfully applied in previous studies by our placebo. group"8 and other investigators.9 10
ANALYTICAL METHODS AND Results CALCULATIONS Trypsin and bilirubin concentrations were deter- Trypsin and bilirubin outputs in patients with short mined in duodenal aspirates by methods previously bowels were not significantly different from control used in this laboratory.4 "`C-PEG and 3H-PEG values at any time during the postprandial period. were measured in gastric and duodenal samples by However, when patients with short bowels were dual-isotope 1-scintillation counting (Beckman given loperamide, a significant decrease in fasting Instruments, Fullerton, Ca, USA). Outputs of and postprandial trypsin and bilirubin output trypsin and bilirubin and gastric emptying of the occurred. As shown in Fig. 1, trypsin output in meal marker ("'C-PEG) were quantified by response to the meal was markedly decreased reference to 3H-PEG concentration in duodenal throughout the postprandial period. Trypsin aspirates using formulas previously described in concentration was also significantly reduced after detail.`5 We have previously shown, as well, that loperamide (data not shown), thus indicating that a
Trypsin http://gut.bmj.com/ units/min
Fig. 1 Postprandial trypsin output in short bowelpatients: loperamide vs placebo. The asterisks indicate a significant (P and loperamide (n=7). on September 24, 2021 by guest. Protected copyright. 3.0 2.5 Bilirubin 2.0 mg/min Fig. 2 Postprandial bilirubin output in 1.5 short bowel patients: loperamide vs placebo. The asterisks indicate a significant (P 0 Gut: first published as 10.1136/gut.23.2.98 on 1 February 1982. Downloaded from 100 Remington, Fleming, and Malagelada decreased secretion ofthe enzyme and not merely a cannot be explained by increased resistance at the decrease in pancreatic flow occurred. Although sphincter of Oddi, as concentration as well as total postprandial bilirubin output was also lower in the output of trypsin were decreased. loperamide treated group, individual variability in Normal trypsin and bilirubin outputs in these bilirubin output resulted in fewer significant short bowel patients were not unexpected. differences at 10 minute intervals (Fig. 2). Although patients with extensive proximal small To correct for possible differences in gastric bowel resections may lose sites of secretin and emptying rate, the data were also calculated as cholecystokinin-pancreozymin (CCK-PZ) synthesis cumulative outputs from meal ingestion to the time and hence have decreased pancreatic and biliary that the stomach had emptied 95% of its contents. secretions,'7 the patients in our study had primarily The difference between placebo and loperamide distal small bowel resection. Two of seven patients was significant (Table) with greater than 50% were on home parenteral nutrition; however, each reduction in trypsin and bilirubin outputs after was at his ideal body weight at the time ofstudy and loperamide administration. was taking food by mouth. Hence, pancreatic insufficiency secondary to the absence of intra- Table Mean postprandial trypsin and bilirubin outputs* in luminal nutrition and prolonged parenteral healthy individuals and patients with short bowel syndrome nutrition'8 or protein calorie malnutrition'9 cannot on loperamide or placebo explain our results. Health (n=7) Short bowel (n=7) Bilirubin serves as a marker of bile flow, which, Placebo Loperamide like pancreatic secretion, should not be impaired after distal small bowel resection. Bile acids, on the Trypsin 8-8 6-4 2.6 resections output NS p Inhibition ofpostprandialpancreatic and biliary secretion in patients with short bowel syndrome 101 3Tytgat GN, Huibregtse K, Dagevos J, van den Ende A. '2Konturek J, Tasler J, Cieszkowski M, Jaworek J, Coy DH, Effect of loperamide on fecal output and composition in Schally AV. Inhibition of pancreatic secretion by well-established ileostomy and ileorectal anastomosis. Am enkephalin and morphine in dogs. Gastroenterology 1978; J Dig Dis 1972; 22:669-76. 74:851-5. 4Go VLW, Hofmann AF, Summerskill WHJ. Simultaneous `Roze C, Dubrasquet M, Chariot J, Vaille C. Central measurements of the total pancreatic, biliary and gastric inhibition of basal pancreatic and gastric secretion by B- outputs in man using a perfusion technique. endorphin in rats. Gastroenterology 1980; 79:659-64. Gastroenterology 1970; 58: 321-8. '4Sacchetti G, Rancoroni L, Mandelli V, Rocca F, Magni E. 5Brunner H, Northfield TC, Hofmann A, Go VLW, Effects ofanalgesic agents in emptying ofthe gallbladder in Summerskill WHJ. Gastric emptying and secretion of bile man. Eur J Clin Pharmacol 1976; 10:127-3 1. acids, cholesterol and pancreatic enzymes during digestion. '5Rowlands EN, Chapman WP, Taylor A, Jones CM. Duodenal perfusion studies in healthy subjects. Mayo Clin Multiple balloon kymograph recording of the comparative Proc 1974; 49:852-9. action of morphine and placebos on the motility of the 6Meerof, JC, Go VLW, Phillips SF. Gastric emptying of upper small intestine in man. Surg Gynecol Obstet 1950; liquids in man. Quantification by duodenal recovery 91:129-37. marker. Mayo Clin Proc 1973; 48:728-32. `Hallenbeck G. Biliary and pancreatic intraductal pressures. 'Levitt MD, Bond J. Use ofthe constant perfusion technique Handbook ofPhysiology, sect 6, vol 2, 1962; 1007-25. in the non-steady state. Gastroenterology 1977; 73:1450-2. "7Miller LJ. Clain JE, Malagelada J-R, Go VLW. Control of 8Malagelada J-R, Go VLW, Summerskill WHJ. Different human postprandial pancreatic exocrine secretion: a gastric pancreatic and biliary responses to solid-liquid or function of the gastroduodenal region. Dig Dis Sci 1979: homogenized meals. Dig Dis Sci 1979; 24:10 1-10. 24:150-4. 9Johansson C, Lagerlof HO, Ekelund K, Kulsdom N, '8Kotler DP, Levine GM. Reversible gastric and pancreatic Larsson I, Nylind B. Determination ofgastric secretion and hyposecretion after long-term total parenteral nutrition. evacuation, biliary and pancreatic secretion, intestinal N Engl J Med 1979; 300:241-2. absorption, intestinal transit time and flow ofwater in man. '9Barbezat GO, Hansen JDL. The exocrine pancreas and Scand J Gastroenterol 1972; 7:489-99. protein-calorie malnutrition. Pediatrics 1968; 42:77-92. '0MacGregor I, Parent J, Meyer JH. Gastric emptying of 20Hofmann AF, Danzinger RG. Physiologic and clinical liquid meals and pancreatic and biliary secretion after significance of ileal resection. Surg Ann 1972; 4:305-25. subtotal gastrectomy or truncal vagotomy with pyloro- 2'DiMagno EP, Go VLW, Summerskill WHJ. Relations plasty. Gastroenterology 1977; 72:206-11. between pancreatic enzyme outputs and malabsorption in "Ambinder RF, Schuster MM. Endorphins: New gut peptides severe pancreatic insufficiency. N Engl J Med 1973; http://gut.bmj.com/ with a familiar face. Gastroenterology 1979; 77:1132-40. 228:813-5. on September 24, 2021 by guest. Protected copyright.