Digestive Diseases and Sciences, I/ol. 41, No. 12 (December 1996)~ pp, 2392-2396

Effect of Octreotide on Sphincter of Oddi Motility in Patients with Acute Recurrent

Pancreatitis A Manometric Study

VINCENZO DI FRANCESCO, MD, GIAMPAOLO ANGELINI, MD, PAOLO BOVO, MD, MARIA BEATRICE CASARINI, MD, MARCO FILIPPINI, MD, BRUNA VAONA, MD,

LUCA FRULLONI, MD, LAURA RIGO, MD, MARIA PAOLA BRUNORI, MD, and GIORGIO CAVALLINI, MD

Sphincter of Oddi dysfunction has been reported as a cause of acute idiopathic recurrent pancreatitis (IRP). Octreotide, a long-acting somatostatin analogue, is an antisecretory drug used in the treatment and prevention of acute pancreatitis. Its action on sphincter of Oddi motility is controversial and no data are available for IRP patients. The aim of this study was to assess sphincter of Oddi motor response to acute administration of octreotide in patients with past attacks of acute pancreatitis without identification of any evident aetiological factor. Six patients (four male, two female; mean age +_- SD, 38.8 +_ 9 years) suffering from acute pancreatitis for at least 3 months before the examination were submitted to sphincter of Oddi manometry. After a basal recording lasting at least 2 min, octreotide, 0.05 mg i.v., was administered and the recording repeated. Intraduodenal pressure was taken as the zero reference and the basal sphincter of Oddi pressure and amplitude and frequency of phasic contractions were calculated before and after octreotide administration. No significant pre- vs post-octreotide differences were observed in basal pressure (41.9 +__ 24 vs 47.5 ___ 33 mm Hg, respectively) or in amplitude of phasic contractions (164.6 __+ 33 vs 170.8 -+ 18 mm Hg). With a latency of about 1 min, octreotide administration caused a high-frequency phasic activity in all cases (mean frequency, 5.5 _+ 2.2 contractions/min before and 9.8 +_- 2 after octreotide; P < 0.04). After the procedure acute pancreatitis (prolonged abdominal pain and serum amylase levels more than three-fold the normal values) developed in five patients. In conclusion, our data suggest that acute administration of octreotide may induce tachyoddia and thus a rise in sphincter of Oddi pressure, with possible impairment of biliary-pancreatic outflow.

KEY WORDS: pancreatitis; sphincter of Oddi motility; octreotide.

Octreotide is the long-lasting analogue of naturally occurring somatostatin, with an antisecretory action on the pancreas (1), and is used in the treatment and

Manuscript received January 18, 1996; revised manuscript re- ceived July 31, 1996; accepted August 20, 1996.

From the Gastroenterology Unit, University of Verona, Verona, Italy.

Address for reprint requests: Dr. V. Di Francesco, Cattedra di Gastroenterologia, Policlinico Borgo Roma, 37134 Verona, Italy.

2392

prevention of acute pancreatitis. Its use in the treat- ment of acute episodes of pancreatitis is debatable (2), but the drug has been successfully utilized in the presence of pancreatic fistulas or pseudocysts, where pancreatic juice secretion is the main factor respon- sible for maintaining the lesion (3, 4). On the other hand, when used in an attempt to prevent post-ERCP pancreatitis, octreotide failed to achieve better results

Digestive Diseases and Sciences, Vot. 41. No. 12 (December t996) [H63-2116/96/12110-2392509.5(I/0 © 1996 Plenum Publishing Corporation

OCTREOTIDE AND SPHINCTER OF ODDI MOTILITY

than placebo (5). One possible explanation suggested for such a disappointing response was an obstructive mechanism at the level of the sphincter of Oddi (SO). The action of octreotide on the SO is controversial: one study in prairie dogs has shown a reduction of SO motility after octreotide infusion (6), whereas it has recently been demonst ra ted that the compound causes an excitatory response of the human SO when given by acute infusion (7). Another study conducted by our group, using ultrasound evaluation of pancre- atic duct diameter after secretin stimulation [US- secretin test (8)], showed an impaired pancreatic out- flow due to octreotide in healthy volunteers (9).

The SO plays a major role in the pathogenesis of IRP, as confirmed by the fact that manometry reveals a dysfunction of the sphincter by manometry in a large percentage of these patients (10). No data are available on SO response to octreotide in patients with IRP.

The aim of this study was to assess sphincter of Oddi motor response to acute administration of oct- reotide in patients with IRP.

MATERIALS AND METHODS

Patients. The study sample consisted of six patients (four male, two female; mean age --- SD, 38.8 - 9 years) who had experienced two or more documented episodes of acute pancreatitis without any known aetiological factor (bile stones, alcohol abuse, hyperlipidemia, etc.) at least 3 months before the examination. All patients had been pre- viously submitted to ERCP which showed a normal pancre- atic and biliary duct. Two patients had previously been operated on by open cholecystectomy 2 and 8 years before the onset of pancreatitis.

Methods. After informed consent had been obtained, fasted patients were sedated with diazepam, 10 mg i.v., and then submitted to SO manometry. The procedure was per- formed using a triple-lumen catheter, measuring 1.7 mm in diameter, with three side-holes at 2-mm intervals (Arnor- dorfer Medical, USA), perfused with sterile water at a rate of 0.25 ml/min per channel by means of a low-compliance pneumohydraulic pump (Mui Diagnostic, USA), connected via pressure transducers to a computerized recording sys- tem (Polygram, Synectis, Sweden). The catheter was intro- duced deep into the papilla of Vater through a side-view video duodenoscope (Olympus JF100) and its position was checked before manometry recording by gently aspirating pancreatic juice or bile via one of the channels.

A basal recording lasting at least 2 min was obtained at the level of the SO high-pressure zone, identified by 2-ram station pull-through. Without withdrawing the catheter from the duct, a second pull-through recording was per- formed in the same sphincter after octreotide (Sandostatin; Sandoz Italy) administration, 0.05 mg i.v.

Duodenal activity was monitored visually, and in two

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patients a single-lumen perfused catheter was taped to the endoscope to record duodenal motility simultaneously.

lntraduodenal pressure was taken as a zero reference, and basal SO pressure, amplitude and frequency of phasic contractions, area under the curve, and motility index (am- plitude × frequency of phasic contractions) were calculated before and after octreotide administration.

Statistical analysis was performed using the nonparamet- ric Wilcoxon rank-sum test for paired data.

RESULTS

SO manometry recordings were obtained from the biliary sphincter in four cases and from the pancreatic sphincter in two. Tracings from four of the six pa- tients showed the presence of SO dysfunction: three had stenosis (basal pressure >40 mm Hg) before octreotide administration; one presented tachyoddia (frequency of phasic contractions >7/min).

No significant differences were observed before and after octreotide either in basal pressure (41.9 - 24 vs 47.5 _+ 33 mm Hg, respectively) (Figure 1) or in amplitude of phasic contractions (164.6 -4- 33 vs 170.8 +- 18 mm Hg). With a latency of about 1 min, octreotide administration caused a high-frequency phasic activity, in all cases >7 contractions/min (mean frequency; 5.5 - 2.2 contractions/min before and 9.8 _ 2 after octreotide; P < 0.04) (Figure 2). Figure 3 shows the actual SO manometry recordings before and after octreotlde administration in one patient from the series. Shortly after drug injection a clear rise in phasic activity is observed. The area under the curve and the motility index calculated at 1-min in- tervals were significantly increased after octreotide (Table 1).

The rise in SO activity preceded a rise in duodenal activity in all cases both as observed visually and as recorded manometrically.

Digestive Diseases and Sciences, Vo/. 41, No, 12 (December 1996) 2393

DI FRANCESCO ET AL

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After the procedure acute pancreatitis (prolonged abdominal pain and serum amylase elevation to more than three-fold the normal values) developed in five patients. In all five cases the acute pancreatitis was

TABLE 1. SO MANOMETRY PARAMETERS IN Six PATIENTS BEFORE AND AFTER OCTREOTIDE ADMINISTRATION, 0.05 mg i.v.

(MEAN ± SD)*

B e f o r e oc t reo t ide A f t e r oc t reo t ide P

Basal pressure (ram Hg) 41.9 ± 24 47.5 _ 33 NS PC amplitude (ram Hg) 164.6 ± 36 170.8 _ 18 NS PC frequency (n/rain) 5.5 +- 2.2 9.8 ± 2 0.04 Area (ram Hg × sec) 1939 + 886 2537 ± 1016 0.04 Motility index 85 +- 396 1688 ± 378 0.022

* PC, phasic contraction; P value, Wilcoxon rank sum test.

mild: it resolved within 48 hr with only medical treat- ment; in no case did ultrasound show pancreatic lesions.

DISCUSSION

The results of the present study indicate that acute administration of octreotide induces an excitatory effect on the SO motility in IRP patients.

These data, showing an higher motor activity of the SO after octreotide, are consistent with those ob-

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Fig 3. Triple-channel manometr ic recording from the SO before and after (arrow) octreotide, 0.05 mg i.v, in a patient from the present series.

2394 Digestive Diseases and Sciences, I/oi. 41, No+ 12 (December 1996)

OCTREOTIDE AND SPHINCTER OF ODDI MOTILITY

tained in a study on patients with biliary-type pain, which demonst ra ted the same higher frequency of contract ions (7). We did not found the same in- creased basal pressure with a decreased amplitude of contract ions repor ted in the paper by Binmoeller et aL A possible explanation for this discrepancy may be the different system sensitivity, which may greatly influence the basal line of the recording (i.e., the basal pressure) when the frequency is very high. In o ther words, our computer ized system, which can more promptly record the fall of pressure back to basal between contractions, may have elim- inated an overest imation of the basal pressure. Ampli tude of phasic contractions is calculated as peaks from the baseline and than can be underes- t imated in this condition.

An inhibitory effect was obtained both with natu- rally occurring somatostatin in the rabbit (11) and with octreotide in prairie dogs (6). No manometric data are available for somatostatin or octreotide ef- fects on SO motility in normal subjects.

The human SO exhibits positive immunoreactivity for somatostatin (12), but the effect of this hormone on SO motility has yet to be clarified. Studies con- ducted in experimental animals suggest that soma- tostatin acts mainly through modulation of other me- diators; in particular, it stimulates the relaxant substances VIP and NO via GABAergic pathways and inhibits the excitatory action of opiates (13, 14). The overall result is inhibition of the smooth muscle of the gut. Conversely, intestinal motility studies have shown that somatostatin exerts an excitatory effect on duodenal and ileal motility, since the hormone is capable of evoking an induced phase III motility at this level (15). During the duodenal activity front, SO motility has been reported to increase, with possible protective action against duodenobiliary or pancre- atic reflux (16).

In the present study the rise in SO activity, charac- terized mainly by an induced tachyoddia, invariably preceded an induced rise in duodenal activity. Thus a direct influence of duodenal activity on the SO can be ruled out. High phasic contraction frequency may result in an obstructive mechanism at SO level, caus- ing impaired outflow of bile and pancreatic juice. In particular, the shorter diastolic filling time between contractions may reduce pancreatic outflow with higher intraductal pressure. This has been demon- strated in the Australian possum (17) and is suggested by the frequency of acute pancreatitis following the procedure, which is much higher than in patients submitted to standard SO manometry (data not re-

Digestive Diseases and Sciences. VoL 41. No. 12 (December 19961

ported). Due to the short recording period allowed by perendoscopic manometry, the long-term action of octreotide on the SO cannot be demonstrated. How- ever, a recent study conducted by our group, using the US-secretin test to assess pancreatic duct diameters, has demonstrated a prolonged effect (>60 min) of octreotide on pancreatic outflow. In healthy volun- teers, after octreotide injection at the same dose used in the present study, the secretin-stimulated pancre- atic duct dilatation was much more prolonged than without octreotide (9).

In conclusion, acute octreotide administration evokes high contractile activity at the SO level. This effect may impair pancreatic juice drainage or trigger or worsen pancreatitis in patients with IRP. Since a small cohort has been studied, the results must be confirmed by further observations.

ACKNOWLEDGMENTS

The study was partially funded by a 40% 1993 Italian Ministry of the University and Scientific Technolo~ Re- search (MURST) grant.

REFERENCES

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2. Baxter JN, Imrie CW, McKay CJ: Acute pancreatitis and octreotide. Lancet 49:12-13. 1991

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DI F R A N C E S C O ET A L

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17. Liu YF, Saccone GTP, Thune A, Baker RA, Harvey JR, Toouli J: Sphincter of Oddi regulates flow by acting as a variable resistor to flow. Am J Physiot 262:G683-G689, 1992

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