Gut 1994; supplement 3: S5-S10

Octreotide in the treatment of refractory diarrhoeaand intestinal fistulae

M J G Farthing

AbstractPersistent, refractory diarrhoea continuesto be an important clinical problem. Themechanisms involved are associatedwith reduced intestinal absorption andincreased intestinal secretion. Reducedintestinal absorption can result from smallintestinal resection or from disorders inwhich there is damage to the small intes-tine. Motility disorders may also impairabsorptive function. The rationale forusing octreotide in refractory diarrhoea,intestinal motility disorders, and fistulaerelates to its ability to promote intestinalabsorption and inhibit gastric, pancreatic,and intestinal secretion. Several clinicalstudies in patients with short bowelsyndrome have reported a reduction ofintestinal output in patients taking octreo-tide compared with controls. Additionally,a number of studies have shown thatoctreotide improves secretory diarrhoearesulting from neuroendocrine tumours,intestinal infections in AIDS patients, andintestinal graft v host disease. Octreotidemay be of use in patients suffering fromintestinal motility disorders such asthose associated with systemic sclerosis.Octreotide may also be of value in pro-moting closure of gastrointestinal andpancreatic fistulae.(Gut 1994; supplement 3: S5-S10)

Department ofGastroenterology, StBartholomew'sHospital, LondonM J G Farthing

Correspondence to:Professor M J G Farthing,Department ofGastroenterology, StBartholomew's Hospital,London EC1V 7BE.

Persistent, refractory diarrhoea continues to bean important clinical problem both in the devel-oping and industrialised world. Persistentdiarrhoea in young children is almost invariablyassociated with undernutrition, but its complexaetiology has not been clearly defined. Infectiveagents such as the parasites Giardia lamblia andCryptosporidium parvum are well establishedcauses of persistent diarrhoea but otheragents are almost certainly involved. In theindustrialised world, chronic infections are lesscommon but continue to be important causes ofpersistent diarrhoea in immunosuppressed sub-jects with HIV infection. There is an extensivelist of small and large intestinal disorders thatcause chronic diarrhoea, which often presentdiagnostic and treatment problems for clinicians(Table I). Many of these disorders have aspecific aetiology, which responds to appropri-ate treatment but some remain refractory totreatment even though the aetiology may havebeen defined. This group of refractorydiarrhoeas require symptomatic treatnent andin many of these the somatostatin analogue,octreotide, has been shown to make animportant contribution to management.

TABLE I Major causes ofpersistent diarrhoea

Reduced intestinal absorptionMaldigestion Pancreatic insufficiency

Reduced intraluminal bile saltscholestasisliver diseasedrugs (neomycin)

Bacterial overgrowthjejunal diverticulastricturesmotility disorders

Malabsorption Intestinal resectionMucosal defects

Congenital/inheritedInflammatory disorders

Crohn's diseaseradiation enteritisintestinal infectionscoeliac disease

Lymphatic obstructionlymphangiectasiaWhipple's disease

Drugs (laxatives, biguanides, anti-cancerdrugs)

Increased intestinal secretionNeuroendocrine Zollinger-Ellison syndrome

tumours VIPomaSomatostatinomaCarcinoid syndromeMedullary thyroid carcinoma

Infection HIV, AIDS related diarrhoeaCongenital defects Chloridorrhoea, sodium secretory

diarrhoeaInflammatory Inflammatory bowel diseases, graft v host

disorders diseaseDrugs Laxatives

Intestinal losses of fluid, electrolytes, diges-tive enzymes, and nutrients may also occurthrough enterocutaneous fistulae. Most highoutput fistulae will require surgical treatment,but intestinal losses can be reduced dramati-cally by octreotide particularly when used inassociation with intravenous nutrition. As willbecome evident, the rationales for usingoctreotide in both refractory diarrhoea and inhigh output of intestinal fistulae are similar.

Definition of persistent, refractorydiarrhoeaThe definition of persistent diarrhoea is usuallyarbitrarily taken as diarrhoea lasting more than14 days. The definition of diarrhoea should notbe based on stool frequency alone, but shouldinclude increased stool volume (or weight).Normal faecal weight varies in different regionsof the world depending on diet. In the UnitedKingdom, more than 200 g/24 hours isregarded as increased stool weight. In WestAfrica where the traditional diet has a muchhigher fibre content, normal stool weight mayreach 350-400 g/24 hours. Before establishinga diagnosis of persistent diarrhoea, stoolvolume should be measured and shown to begreater than the faecal output of healthyvolunteers in the same geographical location.The term refractory is used to describediarrhoea that has failed to respond either tospecific treatment for a condition of known

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aetiology or a failure to respond adequatelyto standard antidiarrhoeal preparations inconventional doses.

Pathophysiology of increased losses fromthe gastrointestinal tractThe mechanisms participating in the produc-tion of persistent diarrhoea can be broadlyclassified into those that are predominantlyassociated with (a) reduced intestinal absorp-tion and (b) increased intestinal secretion.These categories, however, are not mutuallyexclusive; in some disorders such as Crohn'sdisease there may be a combination of the two.During a normal day about nine litres offluid enter the upper gastrointestinal tract.Secretions from salivary glands, stomach,pancreas, and biliary tract contribute aboutseven litres and between 1-5-2 litres are takenin food and drink. About 1-5 litres leave thesmall bowel and enter the colon, the remainderhaving been absorbed by the small intestine.Small intestinal absorption is maximal two tothree hours after a meal, whereas colonicabsorption continues throughout the 24-48hour period of colonic transit. Ninety per centof the fluid entering the colon is absorbed,resulting in an average stool volume of 0-15litres. The colon can increase its absorptivecapacity two to threefold but when this isexceeded diarrhoea follows.

DECREASED ABSORPTIONIt is evident from the description of fluid move-ment in and out of the intestinal tract, that anyloss of absorptive components of the systemcan result in diarrhoea (Table I). A simpleexample of this is extensive small intestinalresection. Subjects with a residual length of150 cm of jejunum or less are likely to havediarrhoea. This is caused simply by a failure toabsorb the basal and meal stimulated secre-tions that enter the small intestine every 24hours.2 3 Despite a short small intestine somepatients can still absorb more than their oralintake (net absorbers) and in general thesesubjects have more than 100 cm of residualsmall intestine. Some, however, have anintestinal effluent that exceeds oral intake (netsecretors) and almost invariably have a residualsmall intestinal length of less than 80-100 cm.2The colon is of vital importance to subjectswith a short small intestine, its presence lead-ing to a reduction in intestinal effluent fromabout 5 litres/24 hours to about 1 5-2 litres/24hours and being equivalent to about 50 cm ofsmall intestine.

Enterocutaneous fistulae are no different,pathophysiologically, from a high jejunostomyafter intestinal resection. The fistula effectivelybypasses the small intestine and colon, leadingto loss of basal and meal stimulated secretionsfrom the upper small intestine. The more distalthe fistula, the lower the output and thus theclinical significance of the losses is reduced.The volume of fistula losses will also be deter-mined by the calibre of the fistula, as this willhave an impact on flow rates.

TABLE II Inflammatory mediators and neurotransmittersthat modulate intestinal transport

Inflammatory mediators of intestinal secretionProstaglandins (PGE2, PGF2a)Leukotrienes (LTD4, LTE4, 5-HPETE, 5-HETE)Kinins (bradykinin)Histamine (H1 receptors)

Secretory neurotransmittersAcetylcholineVasoactive intestinal peptidePeptide histidine-methionineSubstance P5-HT

Persistent diarrhoea caused by impairedintestinal absorption occurs in many disorders,particularly those that result in damage to thesmall intestine with disruption of villous archi-tecture, including conditions such as coeliacdisease, tropical sprue, giardiasis, and rotavirusinfection. Motility disorders may also impairabsorptive function and may be an importantcomponent of some infective and inflam-matory diarrhoeas caused by the release oflocal mediators such as prostaglandins, 5-hydroxytryptamine (5-HT), and other smoothmuscle agonists (Table II).

INCREASED INTESTINAL SECRETIONThe classic secretory diarrhoeas (cholera,enterotoxigenic E colt) are acute and generallyself limiting, providing adequate fluid andelectrolyte support is given. Intestinal secre-tion, however, is also important in a numberof persistent diarrhoeas particularly thoseassociated with the release of inflammatorymediators within the intestinal wall thatstimulate secretion of fluid and electrolytes(Table II). Bradykinin, a substance liberated inmany inflammatory reactions within the gut,releases arachidonic acid metabolites such asprostaglandins and leukotrienes from sub-epithelial lymphocytes. Some prostaglandinssuch as PGE2 and PGF2 interact with specificreceptors on the basolateral membrane ofenterocytes and activate secretory pathways.These mediators may contribute to the diar-rhoea in inflammatory bowel diseasesand almost certainly play an important partin diarrhoea associated with intestinal ana-phylaxis as a result of sensitisation to food orparasite antigens. Other classic secretagoguesinclude vasoactive intestinal polypeptide, theimportant bioactive substance released fromVIPomas, and 5-HT, an important mediator inthe carcinoid syndrome. These and othersecretagogues are also present in the entericnervous system where they act as secretoryneurotransmitters. Other secretory neurotrans-mitters present within the submucosal andmyenteric plexuses include acetylcholine,substance P, and peptide histidine-methionine(Table II).The effects of these secretagogues rely on

the activation of second messengers, which forcholera toxin, vasoactive intestinal polypep-tide, and PGE2 is cyclic AMP. 5-HT, sub-stance P, and histamine activate the enzymephospholipase C, which produces anotherset of second messengers namely, inositoltriphosphate and diacyl glycerol.

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Octreotide in the treatment of refractory diarrhoea and intestinalfistulae

TABLE III Octerotide in short bowel syndrome: short term studies

Intestinal Intestinal % ReductionPatients length Dose output with

Study (ret) (n) (cm) octreotide (litre/24 hours) octreotide

Williams et al5 1 Not stated 100 jxg/24 hours 4-6 40-50Cooper et a!6 5 Not stated 25 ,ug/hour 4-7 20Rodrigues et al3 4 30-120 50 pIg/6 hours 2-5 About 50Nightingale et a!7 6 25-70 100-300 ,ug/24 hours 3-7-7 0 16-72Ladefoged et a!8 6 40-225 25 ,uglhour 2-3-8-2 About 50

Rationale for the use of octreotide inrefractory diarrhoea and fistulaeSomatostatin and its long acting analogue,octreotide, inhibit intestinal motility, the mostprofound effects being in the small intestine.'Octreotide also inhibits gastric and pancreaticsecretion and intestinal secretion resulting fromvasoactive intestinal polypeptide, PGE2, and 5-HT. Finally, octreotide inhibits the release ofgut peptides such as vasoactive intestinalpolypeptide and peptide histidine-methionineand other mediators of diarrhoea including 5-HT.1 Octreotide also reduces splanchnic bloodflow, which can also have secondary effects onintestinal absorption and secretion.

Octreotide acts by cAMP dependent andindependent mechanisms. Octreotide mayinfluence intestinal secretory function bymodulating calcium fluxes. Octreotide binds tosomatostatin receptors, which have beenidentified on a variety of cell types includingpancreatic exocrine cells, islet cells secretinginsulin, glucagon, and somatostatin and gastricparietal and small intestinal epithelial cells.Octreotide is thought to act by inhibitingadenylate cyclase activity by activating theinhibitory guanine nucleotide (GTP bindingprotein, Gi), which is located on the basolateralmembrane of the enterocyte in close proximityto the somatostatin receptor.

Octreotide in refractory diarrhoea:clinical studies

DIARRHOEA RESULTING FROM DECREASEDINTESTINAL ABSORPTION

Short bowel syndromeDharmsathaphorn et al first reported thebeneficial effects of native somatostatininfusion in patients with short bowel syn-drome.4 Four patients were reported on withstomal outputs of about 2 kg/24 hours.Somatostatin infusion at 4 ,ug/min reducedintestinal effluent by about 35%. After thisreport there were a series of studies with smallnumbers of patients in which octreotide wasgiven either by infusion or bolus doses and theeffect on net fluid and electrolyte absorptionassessed3 5-8 (Table III).

TABLE IV Octerotide in short bowel syndrome: longterm studies

Reduction inDose intestinal

Patients octreotide Duration output AdverseStudy (refi (n) (RgI24 hours) (mth) maintained (%o) effectsCooper et a!6 2 100 4-6 100 None reportedNightingale et a!7 2 100 12 100 None reportedLadefoged et a!8 4 100 21-28 75 None reported

These reports contain a heterogeneousgroup of patients with noticeable variation inthe residual intestinal length and not surpris-ingly a broad range of intestinal output(2-0-8.2 litres/24 hours). Nevertheless allstudies reported a reduction in intestinal out-put varying between 16-72% of the drugfree control period. Sodium and generallypotassium losses were also reduced, the secondbeing consistent with the hypothesis thatoctreotide not only inhibits secretion but alsopromotes absorption of fluid and electrolytes.Octreotide has also been shown to reduceileostomy diarrhoea in infants and children.9 10There is some evidence to suggest that

octreotide may in some patients not onlyreduce fluid and electrolyte losses but alsoimprove energy balance by 20-50O/o.3 A secondstudy failed to produce such encouragingresults, however, although one patient wasconverted from negative to positive energybalance during octreotide treatment.7 Theeffects of octreotide on intestinal output can bemaintained for many months at a dose of 100,ug/24 hours6-8 (Table IV). No adverse effectswere reported in this small group of patients.

Octreotide would seem to exert its beneficialeffects in short bowel syndrome not by slowinggastric emptying,5 6 but by retarding smallintestinal transit thus optimising absorption offluid and electrolytes.6 Octreotide also reducessecretions into the upper gastrointestinal tract,particularly gastric and pancreatic secretions.

Congenital microvillous atrophyOctreotide 100 ,ug twice daily reduced faecalsodium, potassium, and chloride losses andincreased urinary output and urinary sodiumexcretion in a young child with this rarecondition. 12

DIARRHOEA RESULTING FROM INCREASEDINTESTINAL SECRETIONOctreotide has been shown to improve secre-tory diarrhoea resulting from neuroendocrinetumours and a variety of infective and inflam-matory conditions of the intestine.

Neuroendocrine tumoursVIPomas - after a report that somatostatincould control diarrhoea in a patient with aVIPoma'3 a series of studies with octreotide100-300 ,ug/24 hours showed reductions instool output from several litres to normal ornear normal stool volumes.'4-17 Up to 90% ofpatients with VIPoma can expect to respond,with the effects maintained long term.Vasoactive intestinal polypeptide plasmaconcentrations decreased in about 60% ofpatients, although a reduction in plasmavasoactive intestinal polypeptide does not nec-essarily correlate with symptomatic benefit.'7

Carcinoid tumours - 5-HT, an importantproduct of carcinoid tumours, is a potentintestinal secretagogue and prokinetic agent.Carcinoid tumours also secrete hormonaland vasoactive substances such as bradykinin,

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substance P, neurokinin A, neuropeptide K,and prostaglandins. Somatostatin infusionreduces carcinoid diarrhoea,'8 as does octre-otide at doses of 50-1000 ,ug/24 hours.19-24Response rates for diarrhoea are 60-90% andreduction in flushing episodes is usuallyachieved. In addition there is often anappreciable general improvement in healthwith increased appetite and weight gain.25

Gastrinoma - octreotide inhibits gastrinrelease and reduces diarrhoea in patients withgastrinoma.2627 Symptomatic control, how-ever, is usually achieved with a proton pumpinhibitor, but octreotide remains an alternativetreatment should other measures fail or are nottolerated.

Intestinal infectionHigh volume watery diarrhoea oftenaccompanies AIDS. A number of small,uncontrolled studies in patients with AIDS,usually infected by Cryptosporidium parvum,have shown that octreotide 50-1500 ,ug/24hours in divided doses can reduce stool fre-quency and stool volumes in some, but not allpatients. ' Cello et al 28 performed a multi-centre, open label clinical trial of octreotide in49 AIDS patients with refractory high volumediarrhoea who had not responded to conven-tional antidiarrhoeal treatment. During 14days treatment, octreotide (150-1000 ,ug/24hours) reduced stool volume and stoolfrequency. Only four patients (8%), however,obtained a complete remission with normalstool volume and 13 patients (27%) experi-enced a partial response with a 50% reductionin stool volume. Diarrhoea returned in allpatients when octreotide was stopped.

Octreotide in HIV infection and AIDSrelated diarrhoea has been evaluated further inmulticentre studies in North America andEurope.' Octreotide was given in increasingdoses from 150-1500 ,ug/24 hours to 77patients, more than half of whom hadenteropathogens identified including Crypto-sporidium parvum, cytomegalovirus, Isosporabelli, and Giardia lamblia. There were 61evaluable patients, 10 ofwhom had a completeresponse (17%) and 17 a partial response(28%), giving an overall response rate of 45%.In the responders, octreotide reduced stoolfrequency and stool volume, and there wasimprovement in the quality of life.The mechanisms by which octreotide

improves AIDS related diarrhoea has not beenstudied in detail although it seems possible thatit is related to its ability to promote fluid andelectrolyte absorption and to prolong smallintestinal transit.

Intestinal graft v host diseaseThe intestinal tract is a target for graft v hostdisease after bone marrow transplantation.Diarrhoea can be severe with high stoolvolumes and associated undernutrition.Conventional antidiarrhoeal agents are oftenineffective. Octreotide 300-1200 ,ug/24 hourshas been used in the treatment of high volume

diarrhoea (3 litres/24 hours) in a patient withintestinal graft v host disease with a 50%reduction in stool volume. Diarrhoea returnedwhen octreotide was stopped and wascontrolled again when reintroduced.29

DIARRHOEA RELATED TO INTESTINAL MOTILITYDISORDERS

Diabetes mellitusDisturbance of bowel function is common inpatients with diabetes mellitus with persistentdiarrhoea occurring in up to 20% of patients,usually in association with autonomicneuropathy. Diarrhoea can be severe anddebilitating and cause a severe deterioration inquality of life. Several case reports suggest thatoctreotide 150-300 ,ug/24 hours can reducehigh volume diarrhoea from several litres/24hours to less than one litre.3033 The effect canbe maintained for many months and is oftenassociated with a considerable improvement inthe quality of life. Additional benefits such asimprovement in postural hypotension and areduction in insulin requirements may also beseen.

Coeliac plexus blockWatery diarrhoea has been reported in twopatients after coeliac plexus block.33 It wasassumed that this was related to acute sym-pathetic denervation of the small and largeintestine. Octreotide (200 [ug/24 hours)reduced stool frequency and normalised stoolconsistency in one patient.33

Systemic sclerosisGastrointestinal involvement is common inpatients with systemic sclerosis. Fifty per centexperiencing some form of small boweldysfunction. Impaired small bowel motilitypredisposes to bacterial overgrowth withassociated diarrhoea and intestinal mal-absorption. Octreotide restored migratingmotor complexes in patients with systemicsclerosis, reduced bacterial overgrowth, andimproved abdominal symptoms includingnausea, bloating, and abdominal pain.34

Irritable bowel syndromeA patient with acromegaly and irritable bowelsyndrome, which was diagnosed before theonset of acromegaly, was treated with somato-statin.35 There was rapid relief of theabdominal symptoms, which was thought to beindependent of the treatment of acromegaly. Itmight be hypothesised that irritable bowelsyndrome is associated with a degree of'somatostatin deficiency', but fasting and mealstimulated concentrations of plasma somato-statin are normal in patients with this condi-tion.36 Octreotide does, however, have aprofound inhibitory effect on small intestinaltransit both in healthy subjects and in patientswith diarrhoea predominant irritable bowelsyndrome.37 Although this case is of interest,

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Octreotide in the treatment of refractory diarrhoea and intestinalfistulae S9

the widespread use of octreotide cannot berecommended for patients with irritablebowel syndrome, although a therapeutic trialmight be considered in patients with severe,intractable symptoms in whom all othertreatment has failed.

Octreotide in gastrointestinal andpancreatic fistulaeThe first indication that octreotide might be ofvalue in promoting closure of gastrointestinaland pancreatic fistulae came from the earlyuncontrolled studies with native somatostatin.More than 150 patients have been reported bymany investigators. Overall fistula output wasreduced by 50-90% and closure of the fistulawas judged to have been enhanced in about80% of the patients treated.1 In general,somatostatin was used as adjunctive treatmentin combination with intravenous nutrition,with fistula closure occurring in 5-11 days. Itmust be remembered, however, that spon-taneous fistula closure occurs in patientsreceiving intravenous nutrition, providingthere is no distal obstruction or ongoingintestinal injury and therefore the results ofuncontrolled studies must be evaluatedcritically. 1

Because of these apparently encouragingresults, octreotide has been used in a largenumber of patients with fistulae with morethan 130 such patients reported in publishedworks. Most are case reports of small numbersof patients without adequate control data.'Octreotide has been used at doses of 100-600,ug/24 hours and most studies report at least a50% reduction in fistula output during the first24 hours. Closure time varies enormously andit is almost impossible to come to any firm con-clusions as to whether time to closure wassignificantly reduced by the use of octreotide.It seems possible, however, that reduction infistula output will have nutritional benefits andmake fluid, electrolyte, and nutrient lossesearlier to treat.

Pancreatic fistulaeOne prospective randomised study of 16patients with pancreatic ascites has beenreported. Octreotide 200 VLg/24 hours wasgiven with intravenous nutrition and theresults compared with a group of patientsreceiving intravenous nutrition alone. Fistulaclosure occurred in six of eight patients in eachgroup although the time to closure was signifi-cantly reduced in the octreotide group (13 v 32days) (p

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22 Vinik AI, Moattari AR. Use of somatostatin analog inmanagement of carcinoid syndrome. Dig Dis Sci 1989; 34(suppl): 14-27.

23 Chayvialle JA. Sandostatin and carcinoid tumours inFrance: experience in the Lyon area. Digestion 1990; 40(suppl 1): 23-6.

24 Woods HF, Bax NDS, Ainsworth I. Abdominal carcinoidtumours in Sheffield. Digestion 1990; 4 (suppl 1): 17-22.

25 Smith S, Anthony L, Roberts U, et al. Resolution ofmusculoskeletal symptoms in the carcinoid syndromeafter treatment with the somatostatin analog octreotide.Ann Intern Med 1990; 112: 66-8.

26 Vinik Al, Tsai ST, Moattari AR, et al. Somatostatinanalogue (SMS 201-995) in the management of gastro-enteropancreatic tumors and diarrhea syndromes. Am JMed 1986; 81 (suppl 6B): 23-40.

27 Mozell E, Woltering EA, O'Dorisio TM, et al. Effect ofsomatostatin analog on peptide release and tumor growthin the Zollinger-Ellison syndrome. Surg Gynecol Obstet1990; 170: 476-84.

28 Cello JP, Grendell J, Basuk P, et al. Controlled clinical trialof octreotide for refractory AIDS-associated diarrhoea.Gastroenterology 1990; 98 (suppl 1): Al 63.

29 Bianco JA, Higano C, Singer J, et al. The somatostatinanalog octreotide in the management of the secretorydiarrhea of the acute intestinal graft-versus-host diseasein a patient after bone marrow transplantation.Transplantation 1990; 49: 1194-5.

30 Tsai S-T, Vinik AI, Brunner JF. Diabetic diarrhoea andsomatostatin. Ann Intern Med 1986; 104: 894.

31 Dudi RJ, Anderson DS, Forsythe AB, et al. Treatment ofdiabetic diarrhea and orthostatic hypotension with

somatostatin analogue octreotide. Am . Med 1987; 83;584-8.

32 Mourad FH, Gorard D, Thillainayagam AV, Colin-JonesD, Farthing MJG. Effective treatment of diabetic diar-rhoea with the somatostatin analogue, octreotide. Gut1992; 33: 1578-80.

33 Dean AP, Reed WD. Diarrhoea - un unrecognised hazardof coeliac plexus block. Aust NZ J Med 1991; 21: 47-8.

34 Soudah HC, Hasler WL, Owyang CH. Effect of octreotideon intestinal motility and bacterial overgrowth in sclero-derma. NEnglJIMed 1991; 325: 1461-7.

35 Talley NJ, Turner I, Middleton WR. Somatostatin andsymptomatic relief of irritable bowel syndrome. Lancet1987; ii: 1114.

36 O'Donnell U, Wass JA, Farthing MJG. Plasma somato-statin concentrations in irritable bowel syndrome. AlimentPharmacot Therap 1991; 5: 659-63.

37 O'Donnell LJ, Watson AMJ, Cameron D, Farthing MJG.Effect of octreotide on mouth-to-caecum transit time inhealthy subjects and in the irritable bowel syndrome.Aliment Pharmacol Therap 1990; 4: 177-81.

38 Haffejee AA, Singh B, Simjee AE. Somatostatin in the man-agement of internal pancreatic fistula. Gastroenterology1991; 100 (suppl): A274.

39 Nubiola P, Badia JM, Martinez-Rodenas F, et al. Treatmentof 27 post-operative enterocutaneous fistulas with thelong, half-life somatostatin analogue SMS 201-995. AnnSurg 1989; 210: 56-8.

40 Nubiola-Calonge P, Badia JM, Sancho J, et al. Blind evalu-ation of the effects of octreotide (SMS 201-995), asomatostatin analogue, on small bowel fistula output.Lancet 1987; ii: 672-4.

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