Caerulein in the treatment of biliary and renal colic

Pcptide~, Vol. 6. Suppl. 3. pp. 47-51, 1985. ~ Ankho International Inc. Printed in the U.S.A.

0196-9781/85 $3.00 +

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Caerulein in the Treatment of Biliary and Renal Colic C. G R A I F F , 1 M. B E Z Z A , F. Z I L L E R , B. S T R I N G A R I , R. B R E N T A R I , G. B E R T A G N O L L I , F. A P U Z Z O A N D R. M E Z Z E N A

Operative Units o f Geriatric Medicine and Radiology, General Hospital, Cles (Trento), Italy

GRAIFF. C.. M. BEZZA. F. ZILLER. B. STRINGARI, R. BRENTARI, G. BERTAGNOLLI, F. APUZZO AND R. MEZZENA. Cuerulein in the treatment of biliary attd renal colic. PEPTIDES 6: Suppl. 3, 47-51, 1985.--A randomized controlled study has been carried out in order to check the activity of caerulein in the treatment of biliary and renal colic. In 88% out of 107 patients caerulein, 1 ng/kg IV, relieved biliary colic and had no side effects. To elucidate the mechanism of action of the peptide. 22 cholecystectomized patients, showing a dilatation of the common bile duct (CBD), were submitted to caerulein treatment under echo-control. Reduction of CBD caliber was noticed when the dilatation was due to functional obstruction, whereas an organic obstruction of the terminal tract of CBD was found in the non-responding patients. Caerulein appears to be an effective agent in relieving biliary colic through a relaxation of Oddi's sphincter, and may be used in ultrasound differential diagnostics of terminal bile duct obstruction. Caerulein, 75 ng/kg intramuscularly, relieved renal colic in 75% of the examined patients; it is suggested that the effect of caerulein in this syndrome is due to central analgesic action. Caerulein

Biliary colic

Ultrasonic study

Common-bile-duct dilatation

C A E R U L E I N , a decapeptide from the amphibian skin, is closely related in its structure to CCK, especially to CCK-8, with which it shares a common spectrum of biological activity [14, 15, 17, 33]. Like CCK, caerulein displayed in experimental studies a potent stimulant action on gastric acid and pancreatic enzyme secretions, as well as on intestinal motility and gall-bladder contraction, while causing relaxation of the choledocho-duodenal junction [l, 7-9]. On the basis of these experimental data. caerulein has been used in human patients in diagnostics (cholecystography, cholangiography, x-ray examination of the bowel, testing pancreatic function) and in therapeutics (management of intestinal hypomotility syndromes) [l l, 20, 21, 29, 30]. Surprisingly, and apparently in contrast with the above ability of the peptide to induce gallbladder contraction, caerulein has proved to be of value in relief of biliary colic and, later on, also in relief of other painful syndromes [6, 18.25-28, 31]. This paper is intended to present the results of a clinical trial carried out by our group during the past three years, in caerulein treatment of biliary and renal colic. On account of the number of patients considered and of the methods used for the evaluation of the effects of the peptide, this study suggests the use of caerulein in the treatment of biliary colic and, subordinately, of renal colic.

Renal colic

(77 men and 121 women, average age 61 years, ranging from 20 to 86) with the clinical diagnosis of biliary colic were admitted for the study, following informed consent. Out of these 198 patients, 107 were randomly assigned to caerulein treatment and 91 to the treatment with placebo. The study was carried out in double blind fashion. Biliary colic was ascertained by medical history and by physical examination. Patients with proved or suspected cardiac, renal, respiratory or liver failure were excluded from the trial. Contraindications for patient eligibility also included severe systemic disease or active infectious illness. Patients who had previously received drug treatment were not eligible for this study. Final diagnosis was based on the results of further investigations performed on all patients (intravenous cholangiography, retrograde endoscopic cholangiography and/or Computerized Tomography), and, in some cases, also on surgical findings. The criteria for response evaluation were based on subjective pain evaluation by Visual Analog Scale (V.A.S.) [5,18]. The patients were asked for pain evaluation before and every minute after drug administration; relief of pain was considered as C.R. (Complete Remission) when the patient reported disappearance of pain and P.R. (Partial Remission) when a reduction by at least 50% of initial pain intensity was reported. The treatment was considered a failure when the patient didn't report relief of pain during the 20 minute period following drug administration. Side effects following drug administration were recorded. Lyofilized caerulein (ceruletide, a synthetic decapeptide, produced and kindly supplied by Farmitalia Carlo Erba, Milan), dissolved in

METHOD

Biliarv Colic Between January 1982 and December 1984, 198 patients

'Requests for reprints should be addressed to Dott. Claudio Graiff, Presidio Ospedaliero USL C6, Viale Degasperi, 38023 Cles (TN), Italy.

47

48

G R A I F F ET AL. TABLE 1 RESULTS OF CAERULEINTREATMENT(1 ng/kg IV) IN BILIARYCOLIC Relief of pain Final diagnosis Gallstones Choledocholithiasis Papillitis Post-cholecystectomy papillitis Dyskinesia of the biliary tract Gallbladder empyema Early cancer of the biliary tract

Number of patients

complete

partial (>50%)

Failures

58 4 12 9

55 2 11 5

0 1 1 2

3 I 0 2

16

15

0

I

5 3

0 0

2 0

3 3

TABLE 2 EFFECT OF CAERULEINON THE COMMON BILE DUCT (CBD) CALIBEROF PREVIOUSLYCHOLECYSTECTOMIZEDPATIENTS PRESENTINGAN ATTACKOF BILIARYCOLIC Patients (22)

[ULTRASOUNDS I /

~ X

Dilatation of CBD (18)

Dilatation of CBD and echo signs of stones (4) I

[CAERULEIN]~ Reduction of CBD caliber 03)

[ULTRASOUNDSJ

Unchanged caliber of CBD (5)

ICAERULE1N]

Unchanged caliber of CBD (4)

B Papillitis (7)

Dyskinesia of biliary tract (6)

FD, final diagnosis.

Heavy stenosis of Oddi's sphincter (21

Cholelithiasis (7)

saline, was administered by rapid intravenous injection at the dose of I ng/kg. Statistical analysis of the results was performed by Chi-square test. Another group of 22 patients with ultrasonographic patterns of increased caliber of common bile duct (CBD). previously submitted to cholecystectomy and suffering from painful abdominal symptoms similar to biliary colic, were studied under simultaneous echo-control. Drug administration was performed as in the previous group. Patients were admitted for the study when the ultrasonographic examination revealed a dilatation of CBD with or without echo-signs of cholelithiasis in the nearby bile duct. In daily practice we make use of a real time ultrasonic scanner (SRT General Electric-3, 5 MHz), examining patients in the supine and left lateral position: it is thus possible to locate the CBD in front of the portal vein, just beneath the confluence of the right and the left hepatic branches. Using the portal vein as a reference point, it is easy to follow the nearby tract of CBD, while it is often difficult to spot the terminal tract both because of the presence of duodenal gas and of the physical constitution of some subjects. Later on. all patients were examined with intravenous cholangiography and in some cases with retrograde endoscopic cholangiography and/or Computerized Tomograph.v. Remd Colic

Between January 1982 and December 1984, 47 patients (25 men and 22 women, average age 44 years, ranging from 23 to 71), with the clinical diagnosis of renal colic were entered on the study, follo~ ing informed consent. This study was performed using the same general criteria as the biliary colic experiment, particularly regarding eligibility of the patients, evaluation of pain intensity and recording of side effects. Renal colic was ascertained by medical history, physical examination and urine test (microscopic hematuria). The forty-seven patients admitted for the study were divided into four groups, at random, of 10, 12, 14 and II people, respectively. In the first group caerulein, I ng/kg. was administered by rapid intravenous injection; in the second group the peptide. 3 n g k g . was given intravenously in two minutes: in the third group, caerulein, 75 ng/kg, was injected intramuscularly: finally, the fourth group was cho-

49

CAERULE1N IN BILIARY AND RENAL COLIC TABLE 3 RESULTS OF CAERULEIN TREATMENT IN RENAL COLIC

Relief of pain Schedule

Number of patients

complete

partial (>50%)

Failures

Latency

Side effects

10

1

3

6

9 __. 2.2

No

12

6

3

3

12 _+ 3.4

6(r~

14

9

2

3

19 __ 6.9

No

1 ng/kg intravenously 3 ng/kg intravenously 75 ng/kg intramuscularly

FIG. I. Cholecystectomized patient presenting an attack of biliary colic. Sonographic visualization of the common bile duct (CBDI before and 2 min after intravenous caerulein administration (I ng/kgl. It may be seen that the caliber of CBD (between benchmarks) was consistently reduced after caerulein injection. Colic pain was completely relieved. Final diagnosis, confirmed by intravenous cholangiography, was papillitis.

sen for treatment with placebo. The treatment was considered a failure when the patient reported unchanged pain intensity during the 45 minute period following drug administration. RESULTS

Biliary Colic (a) First study. Caerulein, administered by rapid IV injection, was very effective in relieving biliary colic. In 88 patients (82.2~c) a complete remission of pain was observed and partial remission (ranging from 50 to 80% of initial pain intensity) in 6 patients (5.6%); failure rate was 12.2%. These results are presented in Table 1 with reference to ascertained final diagnosis. Placebo treatment, performed in 91 patients,

was effective in 4 cases, while it was a failure in 87 patients. Statistical comparison between caerulein treatment and placebo revealed a highly significant difference (p<0.001). There were no complaints of side effects. (b) Second study. As previously stated, an ultrasonographic study on the effects of caerulein on the CBD caliber was carried out on a group of patients who, after having been previously subjected to cholecystectomy, presented an attack of biliary colic accompanied by dilatation of the CBD. CBD was considered to be dilated when its caliber was found to be larger than 4--5 mm. This size is reported as a maximum standard diameter of CBD before and also after cholecystectomy [2]. Some authors have gauged the CBD in patients before and after cholecystectomy; no compensatory dilatation has been noticed [22-24].

50 Therefore, the finding of a CBD whose caliber is larger than 4-5 mm has to be related to a functional or organic obstructive cause [3]; it is generally believed that a CBD diameter over the average size, due to loss of elasticity of the connective fibres of the bile duct wall, can be rarely observed, in absence of obstructive causes except in very old patients [23]. It has been shown, in animal experiments, that biliary tract dilatation can precede jaundice in obstructive choledocholithiasis [32]. We have examined 22 patients, all having an hematic index of bilirubin below 1 mg/dl: 18 (Agroup) presented only a dilatation of the CBD ranging from 7 to 13 mm; the others (B-group) an increased CBD caliber accompanied by cholelithiasis of the nearby bile duct. Caerulein was administered to all patients at the usual IV dose of 1 ng/kg. Ultrasound control showed in 13 patients of the A-group a reduction of the CBD diameter, and in 5 patients no change. Complete and prompt remission of colic pain was observed only in patients presenting a reduction of the CBD caliber. These patients were further checked by intravenous cholangiography and retrograde endoscopic cholangiography: in 7 patients a papillitis with moderate narrowing of Oddi's sphincter was found, in the other 6 the final.diagnosis was dyskinesia of the biliary tract. In the 5 non-responding patients of the A-group, further radiological studies revealed the presence of lithiasis in the terminal part of CBD (3 cases) or a sclerosis of the Oddi's sphincter (2 cases). The 4 patients of the B-group, in whom ultrasound indicated both a dilatation of CBD and the presence of choledocholithiasis, did not respond to caerulein. Successive radiological examination confirmed the ultrasound diagnosis. Results obtained in ultrasonographic study ofcholecystectomized patients are summarized in Table 2. Renal Colic (a) First group. Ten patients were treated with an IV injection of 1 ng/kg caerulein, as patients suffering from biliary colic. Only 1 complete remission of pain and 3 partial remissions (50-70%) were observed as opposed to 6 failures. No side effects were recorded. In all partially-responding patients pain reappeared within 80--160 rain. Subsequent conventional spasmolytic therapy was successful in 5 patients. (b) Second group. In 12 patients, the intravenous dose of caerulein was raised from 1 to 3 ng/kg. Half of the patients benefited by complete remission of pain and 3 by partial remission. There were only 3 failures (25%). However, the greater effectiveness of the higher dosage of caerulein was balanced by the high incidence of short-lasting, but unpleasant side-effects (nausea, vomiting, abdominal cramps, flushing). Only one of the non-responding patients reacted subsequently to conventional spasmolytic treatment. (c) Third group. The 14 patients of this group received caerulein by intramuscular route at a dose of 75 ng/kg. Complete response was observed in 9 cases, partial response in 2, with 3 failures. There was no complaint of side effects. The non-responding patients also failed to respond to conventional spasmolytic treatment and needed morphine. Results are summarized in Table 3. The 11 patients of the placebo group presented only two partial remissions of pain. Statistical analysis performed on the three caerulein groups has shown an evident trend for the third group: differences were significant (p<0.05) when comparing the first to the second or the third group; whereas no significant differences emerged between the second and

G R A I F F ET AL. the third group. Comparison between the caerulein groups and the placebo group was highly significant (p<0.001).

DISCUSSION

B i l i a o Colic

Some fundamental data have emerged from our clinical trial of caerulein in patients suffering from attacks of biliary colic: first that the peptide was very effective in relieving pain in uncomplicated colic ( this is in full agreement with results by other authors [6, 25-28, 31]): second that caerulein acted through a peripheral mechanism of action, involving relaxation of the sphincter of Oddi; and third that caerulein may be of value in the differential diagnosis of functional and organic obstruction of the CBD. The dose of caerulein capable of relieving pain was as low as 1 ng/kg, given by intravenous injection. The benefit was prompt and free from side effects. The most satisfactory results were obtained in patients showing gallbladder stones or biliary tract d.vskinesia, as well as in patients affected by papillitis, especially when accompanied by inflammatory oedema, with no or moderate sclerosis of the Oddi's sphincter. On the contrary. failures were frequent when papillitis had caused a heav.~ sclerotic narrowing of the choledocho-duodenal junction. In patients with choledocholithiasis presenting an hematic bilirubin index below I mg/dl, caerulein was similarly effective. whereas failures were common when choledocholithiasis had caused bile duct obstruction with jaundice. In the cholecystectomized patients, in whom an ultrasonic study was performed during caerulein treatment. reduction of abnormal CBD caliber and simultaneous relief of pain occurred only in the absence of any mechanical biliary obstruction, due to intrinsic or to extrinsic diseases. It should be stressed here that CCK-8 (which is virtually identical to caerulein) did not produce any change in the sonographic appearance of the CBD in normal patients [16]. The extremely low level of the effective;caerulein dosage, the promptness of action, the results of sonographic investigation in cholecystectomized patients, as well as results of animal experiments [19], point decidedly to a peripheral point of attack of the peptide. In fact, all available data suggest that relief of pain in biliary colic produced by caerulein is due to relaxation of the sphincter of Oddi, permitting the bile to be discharged into the duodenum, with following decrease in intraductal pressure and reduction of distension of the bile ducts. In addition to its therapeutic value it is possible that caerulein is also useful in the differential ultrasound diagnosis between functional and organic biliary obstruction. Within a couple of minutes, the harmless injection of I ng/kg caerulein will re-establish a flow of bile hindered by spasm. with no effect in the case of mechanical obstruction. R e m d Colic

Effects of caerulein in relieving renal colic were considerably less constant and evident than those observed for biliary colic. As shown in Table 3 the most effective and harmless way of administration of caerulein was the intramuscular injection. The intravenous administration of 3 ng/kg peptide was similarly effective, but the incidence of side effects was exceedingly high. This is in accordance with results reported by other authors [18]. It should be added

CAERULEIN

IN B I L I A R Y A N D R E N A L C O L I C

51

that e v e n in the c a s e o f c o m p l e t e relief o f colic a t t a c k , s o m e p a t i e n t s e x p e r i e n c e d r e a p p e a r a n c e o f pain within a few h o u r s . In this s i t u a t i o n a r e a s o n a b l e c o n c l u s i o n s e e m s to be that c a e r u l e i n t r e a t m e n t of renal colic, b e c a u s e o f its inn o c u i t ~ , d e s e r v e s f u r t h e r e x t e n s i v e clinical trials to deftnitel.v e s t a b l i s h the p o s i t i o n o f t h e peptide, c o m p a r e d to t h a t of o t h e r c o n v e n t i o n a l drugs. C o n c e r n i n g the m e c h a n i s m o f a c t i o n of c a e r u l e i n in relief o f r e n a l colic o n e m u s t a d m i t the e x i s t e n c e of an a n t i n o c i c e p t i v e a n d / o r s e d a t i v e e f f e c t o f the peptide, involving d i r e c t l y or i n d i r e c t l y the C N S , a n d i n d e p e n d e n t o f s m o o t h m u s c l e r e l a x a t i o n , w h i c h h a s n e v e r b e e n o b s e r v e d in

the urinary tract. This i n t e r p r e t a t i o n is in a c c o r d a n c e with e x p e r i m e n t a l d a t a o b t a i n e d in a n i m a l s a n d m a n , d e m o n s t r a t ing that c a e r u l e i n p o s s e s s e s c o n s p i c u o u s a n a l g e s i c a n d s e d a t i v e effects, p e r h a p s partly a t t r i b u t a b l e to r e l e a s e o f f l - e n d o r p h i n a n d s u b s t a n c e P [4, 12. 13, 33, 34]. A n elegant, p e r t i n e n t s t u d y on the effects o f c a e r u l e i n in a m o d e l of visceral pain, h a v i n g close a n a l o g y to h u m a n r e n a l colic, h a s b e e n carried o u t by B r a s c h a n d Z e t l e r [10]. T h e y o b s e r v e d that the fall o f arterial p r e s s u r e p r o d u c e d in a n a e s t h e t i z e d rats b y renal pelvis d i s t e n s i o n w a s a b o l i s h e d b y small subc u t a n e o u s a m o u n t s of c a e r u l e i n (6 p-g/kg), the p e p t i d e b e i n g 400-500 t i m e s more p o t e n t t h a n m o r p h i n e .

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18. Libert, M., W. Stekke, R. Askenasi and C. C. Schulman. Utilisation de la c~rulrine comme antalgique dans le traitement de la colique n~phr~tique. Etude preliminaire. Acta Ther 8: 145-150, 1982. 19. Lin, T. M. and G. F. Spray. Effect of pentagastrin, cholecystokinin, caerulein and glucagon on the cboledochal resistance and bile flow of conscious dog. Ga.stroenteroh;gy 56: 1178, 1969. 20. Lorber, S. H., K. Phaosawasdi, M. S. Lapayowke and H. J. Woloshin. Einfluss yon Ceruletid auf die Roentgenuntersuchung des Dfinndarms. Therapiewoche 31: 2744-2752, 1981. 21. Monti. C., G. P. Baraldi, C. Malagola, G. Ermini and M. Mattei. The role of caerulein in the differential diagnosis of commonbile-duct stenosis. Radh~h~gy 129: 611-614, 1978. 22. Mfiller, P. R., J. T. Ferrucci, Jr., J. F. Simeone, E. van Sonnenberg, D. A. Hall and J. Wittemberg. Observations on the distensibility of the common bile duct. Radiology 142: 467-472, 1982. 23. Mtiller, P. R., J. T. Ferrucci, Jr., J. F. Simeone, J. Wittemberg, E. van Sonnenberg, A. Polansky and R. J. Isler. Post cholecystectomy bile duct dilatation: wit or reality? Am J Roentgenol 136: 355-358, 1981. 24. Niederau, C., J, M~iller, A. Sommemberg, T. Scholten, J. Erckenbrecht, W. P. Fritsch, T. Brusten and G. Strohmeyer. Extrahepatic bile ducts in healthy subjects, in patients with cholelithiasis and in post-cholecystectomy patients: a prospective ultrasonic study. J Clin UItra,wmnd i 1: 23-27. 1983. 25. Pardo, A., F. Celotti and C. de Paolis. Ceruletide analgesia in biliary colic. CIh~ Pharmacol Ther 36:510--514, 1984. 26. Praga, C., A. Santamaria, G. Lucani and W. Montorsi. Rapid relief of biliary colic by ceruletide. 6th World Congress of Gastroenterology. Madrid. 5-7 June 1978, Abstracts, p. 87. 27. Saggioro. A. Wirkung verschiedener Dosen yon Ceruletid auf die Schmerzen der Gallenkolik. Therapiewmhe 31: 2787-2789, 1981. 28. Santamaria, A., G. Lucani, M. Montorsi and C. Praga. Action de la crruleline sur la colique hepatique. Nouv Press M~'d 8: 2482, 1982. 29. Sargent, E. N., W. Boswell and J. Hubsher. Cholecystokinetic cholecystography: efficacy and tolerance studies of ceruletide. Am ,I Roentgem~l 130: 1051-1055, 1978. 30. Schindler, G., J. Pirschel and S. Grehn. Optimisierung der peroralen Cholezyst-cholangiographie mit Ceruletid. Fortst'hr Rocntt:(,t~str 130: 423-431, 1979. 31. Stanciu, C., I. Triandaf, M. Stoian, E. Tricoveano. N. Triandaf, R. Stanciu, M. Frasin and C. Cijevski. Ceruletid in der Behandlung der Gallenkolik. Therapiewoche 31: 2789-2790, 1981. 32. Zeman, R., K. Taylor, I. Burrelm and J. Gold. Ultrasound demonstration of anicteric dilatation of the biliary tree. Radiology 134: 68%692, 1980. 33. Zetler, G. Analgesia and ptosis caused by caerulein and cholecystokinin octopeptide (CCK-8). Ne,ropharnlaC~dogy 19: 415-422, 1980. 34. Zetler, G. Central effects of ceruletide analogues. Peptides 2: Suppl 2, 65-69, 1981.