THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 2, NO.4

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Sphincter of Oddi dysfunction

181

M. S. KHUROO, S. A. ZARGAR, R. MAHAJAN, A. R. EI SHEIKH MOHAMED,M. A. Al KARAWI

INTRODUCTIONEndoscopic retrograde cholangiopancreaticography(ERCP) was introduced in the seventies in Europe andJapan and has become an essential diagnostic and thera-peutic tool for a number of biliary and pancreatic diseases.It allows us to define and alter sphincter anatomy. Withrefinement in the measurement of luminal pressures, ithas become possible to record the manometric charac-teristics of the sphincter of Oddi (SO) in normal individualsand in patients with different diseases. Evidence hasaccumulated that a subgroup of patients with unexplainedbiliary and pancreatic symptoms have abnormal SOpressures or abnormal responses to pharmacologicalagents. This subject has stimulated considerable researchinto whether or not the sphincter of Oddi actually exists.Results of research over the last few years are in favour ofclinical syndromes of sphincter of Oddi dysfunction andthis evidence is presented in the following review.

ANATOMY AND PHYSIOLOGYThe major duodenal papilla is a smooth, nipple-like eleva-tion on the postero-medial wall of the second part of theduodenum. IThe papillary orifice is located at the summitof the papilla of Vater. Biliary and pancreatic ducts in thepapillary region are invested by specialized circular andlongitudinal muscle fibres interdigitating with the juxta-ampullary fibres of the duodenal wall. This area, extendingfrom 4 to 6 mm, is the sphincter of Oddi. The sphinctermaintains a high pressure (about 5 mm Hg above thecommon bile duct pressure) and superimposed on theresting pressure are rhythmic phasic waves which occur ata frequency of 4 to 6 per minute. The SO works like thecardiac muscle and allows filling of the intrasphinctericsegment during diastole (resting interphasic period) andempties its contents during systole (phasic contraction).Bile flow will be enhanced if the basal pressure is low, thefrequency of phasic contractions is increased (tachyoddia),and the phasic contractions are of high amplitude. Thebile flow is impeded if the basal pressure is elevated, the

Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar 190011,India

M. S. KHUROO, S. A. ZARGAR, R. MAHAJANDepartment of Gastroenterology

Armed Forces Hospital, Riyadh, Saudi ArabiaA. R. EI SHEIKH MOHAMED, M. A. Al KARA WI

Correspondence to M. S. KHUROO

© The National Medical Journal of India, 1989

phasic contractions are few and of low amplitude, and thefrequency of phasic contractions is markedly increased toreduce filling-a condition simulating the low cardiac out-put state in tachyarrhythmias.

MANOMETRYSphincter of Oddi manometry is performed in a consciouspatient under light sedation without prior use of hyoscinebutylbromide.>? The patient is advised to fast overnight,and to stop medication as this may alter the pressureprofile. Forty-eight hours prior to the procedure, thepapilla is visualized by a side viewing duodenoscope. Themanometry catheter assembly is passed via the duodeno-scope channel and the sphincter negotiated. Both bile andpancreatic ducts are entered separately and pressuresrecorded by a station pull-through technique in the ducts,across the SO and in the duodenum. Another catheterattached to the endoscope records the duodenal pressurecontinuously during the procedure. Each catheter is 1 mmin its outer diameter and has a side hole 0.8 mm in diametermade 5 mm from the blocked tip. The catheter is perfusedby bubble-free water at a constant rate of 0.5 ml perminute. The pressure is recorded through a transducer ona pre-calibrated polygraph (Fig. 1). Earlier a single catheterwas used to record ductal pressures but now the triplecatheter assembly is used with side holes 2 mm apart.These catheters record sphincteric activity at three sitessimultaneously to define whether peristalsis is antegrade,retrograde or simultaneous. Manometry records bile ductand pancreatic duct pressures as straight waves with mildundulations due to respiratory excursions. Once thecatheter reaches the SO, the sphincteric activity is recordedas basal pressure with phasic activity (Fig. 2). Most of thisphasic activity is antegrade as recorded by the multiplelumen catheter assembly. All pressures are calibratedwith reference to a duodenal pressure of zero. At leastthree measurements are made and the pressures recordedare the mean of three readings. The various pressuresusually obtained and their normal range are provided inTable I.

THE EFFECT OF PHARMACOLOGICAL AGENTSThe pharmacological agents whose effect on the SO hasbeen studied include: morphine, nifedipine, hyoscinebutylbromide (Buscopan) and nitrates,?,!(}-!3

Morphine sulphate in a dose of 3 mg intravenouslyincreases the frequency of phasic activity but has no measur-

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THE NATIONAL MEDICAL JOURNAL OF INDIA VOL.2, NO.4

Precalibrated pressure app.

FIG 1. SO manometric system.Tracing

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FIG 2. SO manometric recording of a 25·year·old male withoutany gastrointestinal symptoms (D-duodenum).A: Bile duct (BD) tracing.' B: Pancreatic duct (PD) tracing.

able effect on the amplitude of ductal pressure and basalor phasic contractions (Fig. 3). In an intravenous dose of6 mg or above, it increases the basal and phasic contractionof the SO. Patients with SO dysfunction have an exagge-rated response to morphine and this forms the basis of themorphine-neostigmine test. This response may be relatedto the levels of the opioids or to an altered distribution ofopioid receptors which influence motility in the biliarytract. However, the morphine-neostigmine test has failedto provide reproducible results and it lacks specificity fordiseases of the SO. When compared with controls, patientswho have suspected biliary dyskinesia and dilated bile

. ducts, besides spontaneous changes in the liver enzymesduring episodes of pain, have a higher frequency of druginduced pain and a more frequent rise in serum concentra-tions of aspartate aminotransferase and amylase.

Nifedipine, 10 mg sublingually, has a slow effect on theSO, starting within 5 minutes of administration andextending beyond 15 minutes. It reduces the frequency of

TABLE I. SO manometry. Normal pressure values (all refer toa duodenal pressure of zero). Data collected from 12 volunteers

Pressure (mean ± 1SD)

BD-duodenal gradientPD-duodenal gradient

SO Basal pressureSO Phasic contraction

AmplitudeFrequencyDurationPropagation %

8.6 ± 1.2 mm Hg8.0 ± 2.0mmHg14.9 ± 1.0mm Hg

53.0 ± 6.0mmHg6.5 ± 0.2/minute6.0 second55 (antegrade)25 (simultaneous)20 (retrograde)

SO activity as well as the amplitude of its basal and phasiccontractions. Consequently, the pressures in both bileand pancreatic ducts are also reduced (Fig. 4). WhileGuelrud et al. 12 failed to show any effect on SO motorfunction with 10 mg of sublingual nifedipine, we foundthat 20 mg of nifedipine caused a moderate but significantdecrease of the SO basal pressure in 8 volunteers and amarked effect on SO basal pressures in 9 patients withsuspected biliary dyskinesia. A comparable decrease inthe amplitude, duration and frequency of SO phasic con-tractions was also observed. Therefore, nifedipine isthought to be a useful drug in the treatment of biliarydyskinesia.

Hyoscine butylbromide, 40 mg intravenously, has adramatic effect on SO activity, starting within 30 secondsof administration and lasting for 5 to 10 minutes. Itabolishes the phasic activity of the SO and the bile duct-duodenal pressure gradient (Fig. 3) andis, therefore, an

. effective drug for treating symptomatic episodes of SO

KHUROO et al. : SPHINCTER OF ODD! DYSFUNCTION

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FIG3. SO manometric recording (BD-bile duct; D-duodenum).A: Baseline tracing.B: Increased frequency of phasic contractions of SO 10minutesafter the administration of morphine sulphate.C: Abolition of basal and phasic sphincteric activity withinone minute of the administration of 40 mg hyoscinebutylbromide.

dysfunction. However, as its action lasts only fora shortduration, it is not suitable for long term treatment.

THE EFFECT OF HORMONESThe effect of cholecystokinin octapeptide (CCK-OP) onthe SO has been studied extensively. 14,15 CCK-OP inhibitsthe basal and phasic activity in normal subjects and inpatients after cholecystectomy. This effect is mediated bystimulation of inhibitory nerves. In 5 of 30 patients withSO dysfunction and elevated basal pressures we found aparadoxical response of the SO to CCK-OP-sphirtctericcontraction rather than relaxation. This response may berelated to the direct effect of the hormone on the SO asthe effect on the inhibitory nerves may be lost followingcholecystectomy. This we feel provides a clue to the possiblepathogenesis of abdominal pain following fatty meals inthese patients who also developed biliary pain whensphincteric spasm was elicited. There is also a report ofabnormal circulatory levels of CCK-OP in patients with

183

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FIG4. SO manometric recording of a 30-year-old female nursewho had cholelithiasis and underwent cholecystectomy10years ago. Five years ago she developed recurrent upperabdominal pain and surgical sphincteroplasty was done. Shecontinued to have recurrent abdominal pain and neededmany hospital admissions.A: Bile duct (BD)-duodenal (D) gradient was zero and theSO had no basal and phasic activity due to the previoussphincteroplasty.B: Solid tracing. Pancreatic duct (PD) pressure was 30 mmHg; SO basal pressure 60'mm Hg (pancreatic dyskinesia) .Broken tracing: 10minutes after 10mg sublingual nifedipinethere was a reduction in the pancreatic duct and SO pressure.

biliary dyskinesia? but this has to be confirmed by otherstudies.

ENDOSCOPIC SPHINCTEROTOMYEndoscopic sphincterotomy eliminates the basal andphasic activity of the SO and abolishes the duodenal-bileduct pressure gradient (Fig. 5) .16 Some studies haveshown that it widens the SO to a mean diameter of 12± 1.4mm and the incision narrows down to 4.2±1.9 mm at oneyear and 2.1 ±0.5 mm at two years. The characteristics ofthe SO after endoscopic sphincterotomy can be dividedinto three groups.

Group 1A papilla with minimal fibrosis or deformity; the SOdiameter at 2 years being 60% of the original diameter.SO manometry reveals no basal or phasic sphinctericactivity and no duodenal-bile duct pressure gradient.

Group 2A papilla with marked deformity but minimal fibrosis; theSO diameter at 2 years being 30% of the original diameter.SO manometry reveals a resurgence of basal and phasicactivity and the development of a duodenal-bile ..iuctpressure gradient.

184

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stone in the bile duct (BD) (D-duodenum).A: Baseline tracing.B: 48 hours after endoscopic sphincterotomy the bile duct andSO pressure has been abolished.

Group 3A papilla with marked fibrosis and deformity; the SOdiameter at 2 years being 20% of the original diameter.SO manometry reveals a high basal pressure withoutphasic activity and a high duodenal-bile duct pressuregradient, the so called sphincteric stenosis.

CLINICAL CONDITIONS AND SPHINCTERDYSFUNCTIONAt present two disease states are suspected to be relatedto sphincter of Oddi dysfunction, viz. post-cholecystectomybiliary dyskinesia and recurrent acute pancreatitis ofundefined cause.v"? A pain similar to biliary colic but ofuncertain nature was recognized by surgeons more thanhalf a century ago. These symptoms were thought to becaused by stenosis or a motility disorder involving the SO,and the entity was called biliary dyskinesia. However,prevailing methods of investigation could not provideevidence that stenosis or motility disorders producedthese symptoms, With the introduction of ERCP andother imaging techniques it has become possible to studythis group of patients more comprehensively. About halfof them have minor symptoms after cholecystectomy butonly 5% develop severe symptoms which necessitatefurther evaluation.? In a study on 154 patients withcholecystectomy and recurrent upper abdominal symptomswe found that some organic disease was identified in 100(Table 11).7 We suspected the remaining 54 patients tohave SO dysfunction and a critical analysis of the symptomsof 32consecutive patients revealed that the disease causedconsiderable disability with multiple major episodes

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL.2, NO.4

TABLE II. Aetiology of the 'post-cholecystectomysyndrome' in 154 patients?

Aetiological group No. of patients

Biliary lithiasisBiliary ascariasisChronic pancreatitisCholangitisMiscellaneousUnexplained

46231511554

(mean±SD: 11±8; range 3 to 50) of right hypochondrialor epigastric pain over long periods (mean±SD: 7.5±5.2years) requiring many admissions to the hospital andinjections of intravenous analgesics. The pain appeared tobe biliary in origin in 26 patients and pancreatic in 6. Itwas often precipitated by a heavy or a fatty meal. Jaundicewas extremely rare in these patients. Many of them had ahistory of other disorders including migrainous headaches,menstrual difficulties and some had had multiple surgicalprocedures.? Although other disorders such as pepticulceration, urinary tract disease, liver disease andinflammatory bowel disease could have caused similarpain, we excluded these by ultrasound, upper and lowergastrointestinal endoscopy and intravenous pyelography. 7

During symptomatic episodes many of· these patientsrevealed elevated (up to twice normal) serum aspartateaminotransferase, alkaline phosphatase and amylase.ERCP showed a dilated common bile duct (> 12 mm dia-meter and delayed drainage (>45 min) of contrast fromthe biliary tree. The majority of these patients haddeveloped biliary symptoms months or years followingcholecystectomy. However, some of them (5 out of 32)had had similar symptoms with an intact acalculous gallbladder." The criteria for the diagnosis of recurrentidiopathic acute pancreatitis have not been clearly definedbut include patients with three or more episodes of acutepancreatitis in whom relevant investigations have excludedknown precipitating causes.

Abnormal pressure profileSphincter of Oddi dysfunction results in impedance to theflow of bile into the duodenum, resulting in elevated biliaryand pancreatic ductal pressures, dilatation of ducts andelevation of biliary and pancreatic enzymes. The sphinctericpathology may be organic or functional (the latter beingeither neurogenic or myogenic in origin). Broadly, fivetypes of sphincteric manometric abnormalities have beendescribed.2,4,6-9

Type I: Sphincteric stenosisPapillitis and papillary fibrosis result in narrowing of thesphincteric orifice. On SO manometry the basal pressureis raised and is not influenced by hyoscine butylbromide.The phasic waves are either absent or markedly attenuated.Stenosis occurs in patients with biliary lithiasis, in half thepatients with recurrent acute pancreatitis and in a smallselected group of patients with biliary pain followingcholecystectomy. Endoscopic or surgical sphincterotomymay be effective in relieving pain.

KHUROO el al. : SPHINCTER OF ODDI DYSFUNCTION

Type II: Sphincteric spasm (Fig. 6)In this condition there is hypertonicity of the SO withelevated basal pressures. Hyoscine butyl bromide causesa lowering of the SO pressure. 2.3 The phasic waves are fewand of low amplitude-a common abnormality in patientswith biliary pain following cholecystectomy. Nifedipine iseffective in relieving symptoms in most of these patients.If nifedipine treatment fails, endoscopic sphincterotomymay yield good results.

Type III: Paradoxical response to CCK-OPInfusion of CCK-OP causes an increase in basalsphincteric pressure with or without an increase in theamplitude and frequency of phasic contractions. Thisoccurs in 16% of patients with suspected SO dysfunction.The response to endoscopic sphincterotomy is not good.

Type IV: TachyoddiaThere is an increase in frequency of phasic contractions ofthe SO (>8 per minute) and rapid sphincteric phasic con-tractions impede bile flow by reducing diastolic filling.This occurs in one-third of patients with suspected SOdysfunction. The response to endoscopic sphincterotomyhas not been studied.

Type V: Abnormal propagation of phasic contractionsIn this situation about two-thirds of SO phasic contractionsare propagated retrogradely. This occurs in patients withbiliary lithiasis and about a third of patients with suspectedSO dysfunction. Retrograde contractions impede bileflow, increase biliary pressure and promote stagnation.The response to endoscopic sphincterotomy has also notbeen studied.

A CLINICAL ENTITY OR A MYTH!Defining an abnormal pressure profile for the SO inpatients with unexplained biliary pain does not prove acause and effect relationship between the manometricfindings and the patient's symptoms because the clinicalsymptoms occur intermittently while the SO pressure andmotility abnormalities are constant. However, if patientshave such SO abnormalities jhey may be predisposed torespond abnormally to physiological stimuli. For example,patients with SO dysfunction respond to an infusion ofCCK-OP with a paradoxical increase in SO pressure. IS

Other evidence which links manometric abnormalities tothe patients' symptoms is provided by the results of endo-scopic sphincterotomy. 17,18 These patients benefitedwhile others with normal SO pressures did not. There isthus circumstantial evidence to support the existence of aclinically symptomatic primary dysfunction of the SO inhumans although conclusive proof is not yet available.

MANAGEMENTWhat steps need to be taken in a patient who hasunexplained biliary pain following cholecystectomy orrecurrent acute pancreatitis for which a cause cannot befound even after thorough investigation (Table III)? First,the pattern of symptoms need detailed analysis and allpossible causes of pain should be considered and relevant

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FIG 6. SO manometric recording of a 40-year-old femaleteacher, who had a cholecystectomy done for cholecystitis 2years previously. She then developed recurrent righthypochondrial pain (suspected SO dysfunction).A: Bile duct (BD)-duodenal (D) gradient-80 mm Hg; SObaseline pressure-38 mm Hg (bile duct dyskinesia).B: 10minutes after administration of morphine sulphate 3 mg1.V. there is an increased frequency of phasic contraction ofthe SO.C: Tracing recorded during administration of 40 mg hyoscinebutylbromide intravenously shows that the bile duct-duodenal gradient was abolished immediately. The responseof the SO to the drug suggested that the SO abnormality wassphincteric spasm rather than sphincteric stenosis.

investigations ordered. There must be circumstantial evi-dence for SO dysfunction, viz. elevation of the serum levelsof aspartate aminotransferase, alkaline phosphatase andamylase during symptomatic episodes. At ERCP thepapilla should be carefully observed for scarring anddeformity, and the ductal diameter and drainage assessed.The morphine-neostigmine test should be used as a pro-vocative test to elicit pain so that elevation of the relevantserum enzymes are recorded. 10 Biliary scintigraphy mayhelp define functional obstruction at the papilla of Vater. 19

Manometry is a valuable adjunct for evaluating patientswith suspected SO dysfunction. It reveals abnormalpressure profiles in 50% of such patients. The procedureis used to classify the type of manometric abnormality

186 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 2, NO.4

SUSPECTED SO DYSFUNCTION

ISO MAN10METRY

TACCHYODDIA

PARADOXIC RESPONSE TO CCK-OP

RETROGRADE PROPAGATION OF

PHASIC CONTRACTIONS

IDYS"'!ESIA

NIFEDIPINE

IHIGH BASAL PRESSURE

NO RESPONSE

TO BUSCOPAN

ISTENOSIS

RESPONSE TO

BUSCOPAN

IDYSKINESIA

INIFEDIPINE

IE.S.

S.S. E.S. BALLOON

DILATATION

NORMAL

S.S. Surgical sphincteroplastyE.S. Endoscopic sphincterotomy

TABLE 3 Sphincter of Oddi dysfunction. Flow chart on the result of SO manometryin patients with suspected SO dysfunction

present. This might provide a clue to the pathogenesis ofthe SO dysfunction and may also be a guide to the therapywhich is most likely to be effective. Sphincter stenosis isbest treated by endoscopic sphincterotomy or surgicalsphincteroplasty. Patients with sphincteric spasm or othermanometric abnormalities should be treated with nifedipinestarted in a dose of 10 mg thrice daily and then increaseduntil intolerance or symptomatic relief occurs. The majorityof patients have an excellent response to this regime. Asmall group of patients have either drug side effects or failto respond. Some of these do well after endoscopic sphinc-terotomy. Recently, balloon dilatation of the SO has beenused as a therapeutic measure in SO dysfunction withencouraging results. Its advantage over endoscopic sphinc-terotomy is that it maintains the competence of thesphincter.

There is much to be learned about dysfunction of the SOand with the use of newer techniques the importance ofthis inaccessible muscle is being much better understood.

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2 Toouli J, Roberts-Thomson LC. Endoscopic manometry of thesphincter of Oddi. J Gastroenterol HepatoI1987;2:431-42.

3 Geenen JE, Hogan WJ, Dodds WJ, Stewart ET, Arndorfer RC.Intraluminal pressure recording from the human sphincter of Oddi.Gastroenterology 1980;78:317-24.

4 Meshkinpour H, Mollot M, Eckerling GB, Bookman L. Bile ductdyskinesia. Clinical and manometric study. Gastroenterology1984;87:759-62.

5 Torsoli A, Corazziari E, Habib FI, et al. Frequencies and cyclicalpattern of the human sphincter of Oddi phasic activity. Gut1986;27:363-9.

6 Burnett DA. Taking the pressure off the sphincter of Oddi. Gastro-enterology 1984;87:971-4.

7 Khuroo MS, Zargar SA, Mahajan R. Biliary and pancreatic dys-kinesia: Clinical and manometric study with evaluation of drugtherapy with nifedipine. Dig Dis Sci 1986;31:304S.

8 Toouli J , Roberts-Thomson IC, Dent J, Lee J. Manometric disordersin patients with suspected sphincter of Oddi dysfunction. Gastro-enterology 1985;88:1243-50.

9 Toouli J, Roberts-Thomson IC, Dent J, Lee J. Sphincter of Oddimotility disorders in patients with idiopathic recurrent pancreatitis.Br J Surg 1985;72:859-63.

KHUROO et al. : SPHINCTER OF ODor DYSFUNCTION

10 Roberts-Thomson IC, Toouli J. Abnormal responses to morphine-neostigmine in patients with undefined biliary type pain. Gut1985;26:1367-72.

11 Toouli J, Collinson T, Bushell M, Iannos J. Effect of morphine onsphincter of Oddi (SO) motility. Gastroenterology 1984;86:1282.

12 Guelrud M, Mendoza S, Rossiter G, Ramirez L, Barkin J. Effect ofnifedipine on sphincter of Oddi motor activity: Studies in healthyvolunteers and patients with biliary dyskinesia. Gastroenterology1988;95:1050-5. .

13 Staritz M, Porlla T, Ewe K, Meyer Zum Buschenfelde KH. Effectof glyceryl trinitrate on the sphincter of Oddi motility and baselinepressure. Gut 1985;26:194-7.

14 Toouli J, Hogan WJ, Geenen JE, Dodds WJ, Arndorfer RC. Actionof cholecystokinin. octapeptide on sphincter of Oddi basal pressureand phasic wave activity in humans. Surgery 1982;92:497-503.

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16 Geenen JE, Toouli J, Hogan WJ, et al. Endoscopic sphincterotomy:Follow up evaluation of effects on the sphincter of Oddi. Gastro-enterology 1984;87:754-8.

17 Roberts-Thomson IC, Toouli J. Is endoscopic sphincterotomy fordisabling biliary type pain after cholecystectomy effective? Gastro-intest Endosc 1985;31:370-3.

18 Geenen J, Hogan WJ, Toouli J, Dodds WJ, Venu R. A prospectiverandomised study of the efficacy of endoscopic sphincterotomy forpatients with presumptive sphincter of Oddi dysfunction. Gastro-enterology 1984;86:1086.

19 Shaffer EA, Hershfield NB, Logan K, Kloiber R. Cholescintigraphicdetection of functional obstruction of the sphincter of Oddi. Effectof papillotomy. Gastroenterology 1986;90:728-33.