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Role of somatostatin and its analogues in thetreatment of acute and chronic pancreatitis

MW Biuchler, M Binder, H Friess

AbstractAcute pancreatitis is caused by theactivation of digestive enzymes in the pan-creas and a possible treatment, therefore,is the inhibition of enzyme secretion.This approach is somewhat controversial,however, as it is not clear whetherpancreatic secretion continues to occurduring the course of acute pancreatitis.Animal studies show an appreciablereduction of secretion in the inflamedpancreas, but studies in humans are notconclusive. The use of somatostatin or itsanalogue, octreotide, has been investigatedin several clinical studies. A meta analysisof six individual studies in which somato-statin was given for acute pancreatitisshowed that somatostatin significantlyreduces mortality. A trial in patients withmoderate to severe acute pancreatitisshowed a lower rate (although not statistic-ally significant) of complications inpatients treated with 3X200 and 3X500pugIday octreotide, compared with controlsand patients receiving a lower dose ofoctreotide. A further study showed asignificant reduction in patient controlledanalgesics in patients treated withoctreotide compared with controls. Pain isthe important clinical symptom of chronicpancreatitis, possibly resulting from anincreased intraductal pressure duringsecretion. The effect on pain of the inhibi-tion of pancreatic secretion by octreotidehas been investigated in two studies. Oneshowed no significant reduction in painafter treatment with octreotide for threedays. In the other, in which octreotide wasused for three weeks, significantly less painand analgesic use was recorded duringoctreotide treatment than during placebo.The most common complication ofchronicpancreatitis is the formation of pseudo-cysts. There is some evidence that octre-otide may be usefil in their treatnent.(Gut 1994; supplement 3: S 1 5-S 19)

Department ofVisceral andTransplantationSurgery, University ofBerne, SwitzerlandMW BuchlerM BinderH Friess

Correspondence to:Professor MW Buchler,Department of Visceral andTransplantation Surgery,University of Berne,Inselspital, CH-3010,Berne, Switzerland.

Somatostatin in acute pancreatitisAcute interstitial pancreatitis is a mild andself limiting disease that responds well toconservative treatment.1 2 Therefore, it isassociated with low complication and deathrates. Ten to 20% of all patients with acutepancreatitis, however, develop peripancreaticand intrapancreatic necrosis.3 The release oftoxic and vasoactive substances may lead tomajor systemic and metabolic complicationsfollowed by organ failure and death."

At present, there is no specific and effectivetreatment available for acute pancreatitis.Therefore, treatment, especially of acutenecrotising pancreatitis, consists of sympto-matic treatment in an intensive care unit.1-8The lack of specific treatment for acutepancreatitis is possibly one explanation whythe death rates associated with severe acutenecrotising pancreatitis are still high(10-30/o).1-8

RATIONALE BEHIND THE INHIBITION OFPANCREATIC SECRETION IN PATIENTS WITHACUTE PANCREATITISThe pathogenic principle of acute pancreatitisis autodigestion, which is caused by theactivation of digestive enzymes in the pan-creas.39 Therefore, one therapeutic conceptfor the treatment of acute pancreatitis is theinhibition of exocrine pancreatic enzymesecretion to slow down autodigestion of thepancreatic parenchyma. Before secretioninhibiting substances are adopted as a treat-ment of acute pancreatitis, however, it mustbe established whether pancreatic secretionstill takes place during the course of thiscondition.

EXOCRINE PANCREATIC SECRETION DURINGACUTE PANCREATITISIn animal studiesl' 11 using various pancreati-tis models it has been shown that basal andstimulated pancreatic secretion is reduced inrats or mice with acute pancreatitis. Data onsecretion in the human pancreas during theinflammatory phase of acute pancreatitis arescarce.Regan et al'2 found increased pancreatic

secretion of lipase and trypsin in two of threepatients with acute pancreatitis who were seenin a clinical study on cimetidine and glucagon.Recently, we have reported that in six patientswith mild or moderate acute pancreatitis, basalpancreatic secretion is similar to that in healthysubjects. 13

After an attack of acute pancreatitis, thesecretory capacity of the pancreas becomestemporarily insufficient. The degree of pan-creatic insufficiency depends on the severity ofthe inflammatory process in the pancreas.'1'7It is, however, not known at what pointduring the course of acute pancreatitis thisinsufficiency occurs, and further studies arenecessary to answer this important question.

In cases of acute pancreatitis after pancreatictransplantation, which might possibly beconsidered a model to study acute pancreatitis

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in humans, exocrine pancreatic function hasbeen shown to be dependent on the degree ofseverity of the pancreatic inflammation.18 Themore severe the transplantation pancreatitis,the less pancreatic secretion was present.

It is known that normal or food inducedendogenous stimulation of the pancreas duringinflammation worsens the course of acutepancreatitis and is absolutely contraindicated.In the basic treatment of the disease, endo-genous stimulation is prevented by oralalimentary abstinence and continuous naso-gastric suction.7 It is still controversial,however, whether basic treatment of acutepancreatitis should include the administrationof secretion inhibiting substances. In a numberof animal studies19-23 the effect of somatostatinand octreotide on the course of acute pan-creatitis was investigated. There were somedifferences in both the experimental set up andthe results of these studies. As some of theinvestigators gave secretion inhibiting sub-stances before induction of acute pancreatitisand as secretion patterns during acute pan-creatitis seem to differ between animals andhumans, the results should not be transferredto the human situation.24The pathophysiological prerequisites for the

use of secretion inhibiting substances for acutepancreatitis have not been fully clarified.Animal data showed a considerable reductionof secretion of the inflamed pancreas.'0 11 Thestudies of human pancreatitis showed normalsecretion function,13 whereas in transplanta-tion pancreatitis, the amount of secretiondepends on the degree of severity of the pan-creatitis.18 There have been too few humanstudies, however, to permit any conclusions tobe drawn. This controversial situation surelywarrants putting the treatment principle'inhibition of pancreatic secretion' to theclinical test.

CLINICAL STUDIES WITH SOMATOSTATIN INACUTE PANCREATITISClinical studies with secretion inhibitingsubstances such as glucagon, calcitonin,and atropine25-28 and studies with proteaseinhibitors like aprotinin and gabexatemesilate,25 29 showed no positive effect on thecourse of acute pancreatitis.

TABLE I Review ofsomatostatin treatment in patients with acute pancreatitis. All sixstudies were prospective placebo controlled studies with a death rate >5% in the placebogroup. Meta analysis of these studies showed a significant reduction in mortality in patientswith somatostatin treatment35

Author Placebo (n) Death (n) Somatostatin (n) Death (n) p

Usadel et al31 41 7 36 4 NSSchondube et al* 23 8 20 3 NSZuniga etalt 5 1 7 2 NSSanchez et al 20 4 27 1 NSChoi et al33 36 2 35 1 NSD'Amico et al32 82 7 82 2 NS

Total 207 29 207 13 p<il0

*Schondube F, Klempa I, Baca I, Menzel J. Nekrotisierende Pankreatitis- ein Beitrag zurstadiengerechten operativen Therapie. Osterreichische Gesellschaft fiir Chirurgie, Lanz, Juni1987. tZuniga J, Garcia L, Ortiz J, Pajares JM. Estudio de la eficacia del tratamiento consomatostatina en pancreatitis agudas graves. Libre de comunicantes de las XIV JomadasHispano-Francesas de Gastroenterologia y X Reunion de la Asociation Castellana del ApartoDigestivo, 39-40, Burgos, 1-3 Octubre, 1987. tSanchez D, Sanchez A, Zurdo JR, Arriaza R,Chimpen V, Portugal J. Pancreatitis aguda. Estudio clinico y terapeutico. Valoracion de lasomatostatin (resumen). Ann Med Inter (Madrid) 1988; (Suppl 3): 40.

TABLE II Score system in patients with acute pancreatitis.Fourteen typical complications of acute pancreatitis,including death within 90 days were defined. Individualscoring parameters were weighted according to the clinicalrelevance in acute pancreatitis. The sum of the parameterswas calculated on admission to the hospital and in thefollow up within 30 days2938

Points

Organic complicationsShock 4Sepsis 4Pulmonary insufficiency 3Renal insufficiency 3Peritonitis 3Haemorrhage 3Ileus/subileus 1Metabolic complicationsHypocalcaemia 2Clotting disorders 2Jaundice 1Hyperglycaemia 1Encephalopathy 1Metabolic acidosis 1Death: 30 points (sum of all complications + 1)

The first clinical study in which somatostatinwas used for acute pancreatitis was publishedby Limberg and Kommerell in 1980.30 In astudy of 14 patients they found 'an impressiveclinical improvement in all patients'. Thispromising finding was tested in several con-trolled clinical studies.31-34 Although thepatients treated with somatostatin showed alower complication rate, death rate, and betterbiochemical parameters, statistical significancecould not be established. In a meta analysis35Carballo analysed the statistical quality of sixrandomised studies in which somatostatinwas given for acute pancreatitis (Table I). Inthese individual studies no statistically signifi-cant effect on mortality could be proved. Themeta analysis showed that, taking these sixstudies together, somatostatin significantlyreduces the mortality associated with acutepancreatitis (p<0-01, Table I). Furtherprospective studies with somatostatin or itsanalogues are necessary,36 using sufficientnumbers of patients.

OCTREOTIDE IN ACUTE PANCREATITISWe evaluated the effect of octreotide on thecourse of severe acute pancreatitis in an openprospective phase I/II study. Only patientswith moderate to severe pancreatitis wereincluded in the study. After randomisationeight patients in each group were treated eitherwith 3X 100 ,ug/day, 3X200 p,g/day or 3X500,ug/day octreotide subcutaneously for 10 days.Complications were assessed according to astandard scoring system29 (Table II) onadmission to hospital and in the follow upwithin 30 days.A positive difference between the admission

score and the follow up score was regarded as apositive treatment effect. A total of 24 patients(10 male, 14 female, median age 58 years,median Ranson score 3 4) were treated withoctreotide. One hundred and eight patientswith acute pancreatitis (median Ranson score3 7) served as a historic control group.29 Thethree octreotide groups and the control groupwere comparable with regard to age, sex, andseverity of pancreatitis. Two (8-3%) of theoctreotide treated patients died because of

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Octreotide in acute and chronic pancreatitis

TABLE III Results ofa unicentric prospective trialanalysing the effect of three different doses of octreotide inpatients with moderate to severe acute pancreatitis. Thesum of acute pancreatitis relevant complications wascakulated according to the definition in Table II on admis-sion to the hospital and in the follow up within 30 days. Apositive difference represents a reduction of complications38

Admission Follow up Difference

Control 51 7-2 -2-13X100 pg 5-6 7-1 -1-53X200 pLg 50 2-0 +303X500pLg 5-8 48 +1-0

septic complications, which are still the mostimportant causes of fatal outcome in humanacute pancreatitis.37 There was a lower rate ofcomplications in the groups treated with3X200 and 3X500 jig/day octreotide than inthe low dose octreotide and control groups(Table III). Because of the small number ofpatients the results have no statistical power.38

Octreotide plasma concentrations weremeasured with a specific radioimmunoassayand the Figure shows that they differed withregard to the dose given. Shock had noinfluence on the plasma concentration ofoctreotide.

In a further controlled study39 19 patientswith acute pancreatitis were either treated withoctreotide (250 jig subcutaneously, followedby 0-5 jig/kg/hour) or acted as controls. Asignificant reduction of the patient controlledconsumption of analgesics was seen inoctreotide treated patients compared with thecontrols (p<005). Unfortunately, onlypatients with mild pancreatitis were admittedto this study, so that no conclusion can bemade as to the differences in mortality betweenthe octreotide and control groups. Thepossible analgesic effect of somatostatin inhuman acute pancreatitis has been confirmedin an Italian multicentre study.32

PERSPECTIVESThe mechanism by which somatostatin and itsanalogue octreotide act on acute pancreatitishas been considered to be inhibition of

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exocrine pancreatic function. Anotherexplanation stems from the notion of a'cytoprotective' effect of these substances.40-42Schwedes et al21 induced acute pancreatitis indogs by injecting bile into the ductal systemand found considerably less macroscopic andhistological damage to the pancreas in animalstreated with somatostatin than in the controlgroup. The inhibitory effect of somatostatinon pancreatic secretion could not, however,be solely responsible for these differences.The authors assumed that somatostatin hada further direct protective effect on thepancreatic acinar cells.

In a double blind randomised clinical study,Choi et a133 saw a 'beneficial local effect' ofsomatostatin and that 'local inflammation wassuppressed by somatostatin treatment'. Jenkinset al43 studied the effect of somatostatin andoctreotide on the reticuloendothelial system inrats with acute pancreatitis and recordedincreased hepatic and splenic reticuloendo-thelial system activity. Furthermore, octreotidewas shown to significantly reduce endotoxinconcentrations in the serum. In patients withcirrhosis of the liver and portal hypertensionoctreotide increased the phagocyte activity ofthe monocytes.44 According to Jenkins et althese results confirmed the cytoprotectiveeffect of somatostatin and octreotide, whichwas originally postulated by Zsabo andUsadel.40 41 Overall the cytoprotective effect ofoctreotide seems to be a new and interestingfeature in inflammatory disorders. Furtherstudies are necessary to investigate theinfluence of this effect in acute pancreatitis.To date, no conclusive evidence is available

for or against the use of somatostatin oroctreotide in acute pancreatitis. The efficacy ofsomatostatin or octreotide can only be provedin clinical studies. The results of a randomised,controlled multicentre trial with a studypopulation of 300 patients, which is currentlybeing started, will provide useful informationon the future use of these substances formedical treatment of acute pancreatitis.

Chronic pancreatitisChronic pancreatitis is defined as the irrevers-

-U- 3 x 100 ,ug ible focal, segmental, or diffuse destruction of_ 3 x 200 jg the pancreatic parenchyma. Four hypothetical-.-3 x 500 igg concepts have been posed to explain the

pathogenic mechanisms of chronic pancreatitis.According to Sarles,45 the chronic intake of

alcohol, which is the most important aetio-logical factor of chronic pancreatitis, causes achange in pancreatic secretion with theformation of protein plugs and calcificationsin the ductal system of the pancreas. A

_________________ , second hypothesis is based on the notion ofspontaneous activation of intraparenchymalproteases, which leads to small areas of

I I I I I I I pancreatic necrosis followed by fibrosis.462 3 4 5 6 7 8 9 10 Furthermore, oxidative stress caused by

Day increased levels of free radicals and disorders ina concentration of octreotide in eight patients hepatic detoxification47 and direct toxic effectsute pancreatitis. Octreotide (3x100 ,ug, of ethanol on pancreatic acinar and ductal cellsXS00 ,ug) was given three times daily byinjection for 10 days. The concentration of are considered to play an important part in temeasured with a specific radioimmunoassay. pathophysiology of chronic pancreatitis.48

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TABLE IV Symptoms and complications in 223 patientswith chronic pancreatitis49

Frequency (%o)

Pain 90Pancreatic insufficiency 19Diabetes mellitus

Insulin dependent 17Non-insulin dependent 20

Pseudocysts<6 cm 43>6cm 12

Ascites 2Stenosis of duodenum 6Portal hypertension 4

The most recent classification of chronicpancreatitis45 distinguishes between fourgroups: (a) lithogenic pancreatitis, the largestgroup, which consists of five subgroupsaccording to the type of stone; (b) obstructivepancreatitis, which is caused by obstructionof the pancreatic ducts before the onset ofpancreatitis; (c) inflammatory pancreatitis;(d) pancreatic fibrosis.

Pain, either intermittent or persistent, is themajor clinical symptom of chronic pancreatitis,even in the early stage of the disease. As thedisease progresses, the characteristic triad ofsymptoms develops with pain, maldigestion,and diabetes mellitus. Roughly 40% ofpatients with chronic pancreatitis developcomplications49 (Table IV).Treatment for chronic pancreatitis includes:

elimination of the cause: alcohol abuse;treatment of pain; treatment of pancreaticinsufficiency; treatment of complications.

MANAGEMENT OF PAIN ASSOCIATED WITH

CHRONIC PANCREATITIS BY OCTREOTIDE

Analgesics are usually indispensable in thetreatment of the pain associated with chronicpancreatitis, although the possible polytoxico-mania in these patients makes their useundesirable. An alternative method of paintreatment is based on the theory that pain mayresult from increased intraductal pressureduring stimulation of pancreatic secretion.46Therefore, the inhibition of pancreaticsecretion should influence the chronic painsyndrome in patients with chronic pancreatitis.Enzyme substances given in high dosesimproves exocrine pancreatic insufficiency andreduces the pain in some patients, presumablyas a result of feedback regulation.46The effect of direct inhibition of pancreatic

secretion on pain associated with chronic pan-creatitis was investigated in two independentstudies. Malfertheiner et al 50 in a double blindrandomised crossover study of 10 patientsinvestigated the influence of 3X250 pug/daysubcutaneously octreotide on pain. All patientsreceived either octreotide treatment or placebofor three days in random order at two dayintervals. The investigators saw no significantpain reduction after octreotide.

Another study group5l conducted a similarinvestigation in six patients with chronicpancreatitis and recurrent abdominal pain.The patients received 3X 100 ,ug/day sub-cutaneously octreotide for three weeks andplacebo for one week. During the octreotide

treatment there was less pain and analgesic userecorded than during treatment with placebo(p<0 05). The authors concluded thatoctreotide provides relief of chronic abdominalpain associated with chronic pancreatitis insome, but not in all patients.The discrepancy in these two clinical studies

is difficult to explain. It might be that the dif-ferent treatment times (three days comparedwith three weeks) had an effect on the successof the treatment. The results of a multicentrestudy carried out in the US, which should soonbe available, are expected to provide furtherinformation on the use of octreotide to treatpain associated with chronic pancreatitis.

TREATMENT OF COMPLICATIONS ASSOCIATEDWITH CHRONIC PANCREATITISThe most common complication associatedwith chronic pancreatitis is the formation ofintra or extrapancreatic pseudocysts. Smallpseudocysts (2-6 cm) usually produce noclinical symptoms, while larger cysts (>6 cm)are often very painful and can cause haemor-rhage, abscess, stenosis of the pancreatic duct,and bile duct obstruction, as well as stenosis ofthe duodenum.46 49 Various authors havepointed out the beneficial effect of octreotidein the treatment of pancreatic pseudocysts.Gullo and Barbara52 treated seven patientswith chronic pancreatitis who had developedpancreatic pseudocysts with 3x 100 jig/dayoctreotide for two weeks. Four of sevenpatients responded immediately to theoctreotide treatment and the mean size of thepseudocysts decreased by 42%. Furthermore,all four patients were completely pain free.

Morali et a153 reported on an infected pan-creatic pseudocyst in which percutaneousevacuation was not successful. After one weekof treatment with 300 ,ug/day octreotide, thecyst shrunk from 8 cm to 1 cm and drainagesecretion decreased from 200 mI/day to 30mi/day. Similar results in the treatment ofpancreatic pseudocysts that had persisted afterpercutaneous drainage were reported byBarkin et al 54 in a total of three patients.

In some cases, octreotide has also beenreported to successfully treat ascites resultingfrom pancreatic disorders.55 56

PERSPECTIVESThe new approach to the treatment of compli-cations associated with chronic pancreatitisby somatostatin analogues is encouraging.Octreotide, a potent inhibitor of exocrine basaland stimulated pancreatic secretion, has beensuccessfully used to prevent postoperativecomplications after pancreatic surgery57 andto treat pancreatic fistulae.58 The treatmentof pancreatic pseudocysts and ascites withoctreotide is the logical extension of thismanagement concept.

Further studies are required, however, tofind out if octreotide or the combination ofpercutaneous catheter drainage and octreotidetreatment can reduce the rate of surgerynecessary for symptomatic pseudocysts.

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Octreotide in acute and chronic pancreatitis S19

It has been suggested that the damagedpancreas reacts less effectively to the inhibitoryeffect of somatostatin on pancreatic exocrinesecretion.59 The positive results,52-58 however,of octreotide in patients with chronic pancre-atitis show that secretion inhibiting substancesmay be a new treatment concept in suchpatients.

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