Aliment Pharmacol Ther 2003; 18: 333–337.
CCK-1 receptor blockade for treatment of biliary colic: a pilot study
A. MA LESCI* , R. PEZZILLIà, M. D’A MATO§ & L. ROV ATI§
*Department of Internal Medicine, University of Milan, Milano, Italy; Division of Gastroenterology Istituto Clinico
Humanitas, Rozzano, Milano, Italy; àDepartment of Internal Medicine and Gastroenterology, Ospedale Sant¢ Orsola, Bologna,
Italy; and §Department of Clinical Pharmacology (Rotta Research Laboratorium), Monza, Italy
Accepted for publication 6 June 2003
SUMMARY
Background: Loxiglumide is a potent and selective
cholecystokinin-1 (CCK-1) receptor antagonist able to
inhibit gall-bladder contraction.
Aim: To assess the effect of CCK-1 receptor blockade on
the pain of patients with biliary colic.
Patients and methods: Fourteen patients with biliary colic
but no suspicion for acute cholecystitis, were randomly
and blindly assigned to loxiglumide (50 mg i.v.) or
hyoscine-N-butyl bromide (20 mg i.v.) treatment. Pain
intensity was monitored by a Visual Analogue Scale.
Patients with less than 80% response at 30 min, were
retreated with a second injection of the same compound.
INTRODUCTION
Symptomatic relief of biliary colic is generally pursued by
administration of anticholinergic antispasmodics fol-
lowed by, if pain does not recede, nonsteroidal anti-
inflammatory drugs or by opioid analgesics. Prevention
of progression to acute cholecystitis is also a goal of
medical therapy in patients with biliary colic as a result
of gall-bladder stones. Recent clinical studies have
mainly focused on the efficacy of prostaglandin inhibi-
tors, as opposed to opioids, in controlling pain and in
preventing short-term complications of biliary colic.1, 2
Conversely, no pharmacological alternative is available
for anticholinergics as drugs for first-line pain control.
Correspondence to: Prof. A. Malesci, Division of Gastroenterology, Istituto
Clinico Humanitas, Via Manzoni, 56, 20089 Rozzano-Milano, Italy.
E-mail: alberto.malesci@humanitas.it; alberto.malesci@unimi.it
 2003 Blackwell Publishing Ltd
doi: 10.1046/j.1365-2036.2003.01688.
Results: Reduction in pain score (mean ± S.E.M.) was
faster and significantly greater in patients treated with
loxiglumide (n ¼ 7) than in controls (n ¼ 7): 88 ± 7%
vs. 47 ± 12% after 20 min, P < 0.05; 92 ± 6% vs.
49 ± 13%, after 30 min, P < 0.05. Only one of seven
patients treated with loxiglumide needed a second
injection at 30 min (vs. six of seven controls,
P < 0.05). No adverse effect was observed after either
treatment.
Conclusions: Loxiglumide is highly effective in
obtaining pain relief in patients with biliary colic.
The analgesic effect of CCK-1 receptor blockade is
superior to that of a conventional anticholinergic
treatment.
Loxiglumide is a well characterized cholecystokinin-1
receptor (CCK-1, formerly CCK-A) antagonist.3, 4 A
dose-dependent inhibitory effect of loxiglumide on gall-
bladder emptying in response to a meal or to cholecy-
stokinin peptides has been extensively documented in
healthy humans. High-doses of loxiglumide can actually
induce gall-bladder distention, even after a meal.5, 6
Pain relief after oral administration of loxiglumide has
been anecdotally reported in patients experiencing
biliary colic after extra-corporeal shock-wave lithotripsy
of gall-bladder stones.7
The aim of this pilot study was to see whether
patients with biliary colic caused by symptomatic
gallstone disease, in the absence of signs or findings
predictive of acute cholecystitis, may benefit from
CCK-1 receptor blockade. The treatment safety was
also verified.
333

334 A. MALESCI et al.
PATIENTS AND METHODS
Patients
Patients were selected from referrals for abdominal pain
to the Emergency Department of the Ospedale Sant¢
Orsola- M. Malpighi (Bologna, Italy) over a 6-month
period, on the basis of stringent diagnostic criteria
indicating noncomplicated biliary colic caused by
gallstone disease.
Inclusion criteria were: (1) age 18–70 years; (2)
typical abdominal pain in the right upper quadrant
lasting for less than 5 h; (3) stone disease of the gall-
bladder proven by abdominal ultrasound, performed in
the 6 months preceding the study and confirmed in the
emergency unit upon arrival, with no evidence of
dilated common bile duct; (4) no previous pharmaco-
logical treatment; (5) ability of the patient to commu-
nicate.
Patients were excluded if acute cholecystitis was
suspected on the basis of one of the following: (1)
abdominal guarding, severe diffuse tenderness or locali-
zed rebound tenderness; (2) rectal temperature exceed-
ing 37.5 C; (3) white blood cell count exceeding
10,000/mm3. Abnormal serum levels of amylase,
transaminase levels two times higher than normal
values, bilirubin levels over 2 mg/dL and creatinine
levels over 2 mg/dL were additional exclusion criteria.
Finally, a medical history positive for diseases possibly
mimicking a biliary colic (irritable bowel disease, peptic
ulcer or gastro-oesophageal reflux disease, chronic
pancreatitis, colonic diverticulitis, renal disease, por-
phyria) or contraindicating anticholinergic treatment
(glaucoma, prostatic hypertrophy, cardiac tachy-
arrhythmia), prevented their inclusion in the study.
The study protocol was approved by the Ethical
Committee of the Sant’Orsola Hospital.
A written informed consent was obtained from each
patient enrolled in the study.
Treatment modalities
The study was designed as a randomised, double-blind,
and parallel group study. Patients were randomly
assigned to treatment with either loxiglumide or
hyoscine-N-butyl bromide, in a double-blind fashion.
Undistinguishable sterile and pyrogen-free ampoules of
loxiglumide (50 mg/10 mL) and hyoscine-N-butyl bro-
mide (20 mg/10 mL) were prepared at Rotta Research
Laboratorium (Monza, Italy). Randomisation in blocks
 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 333–337
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of four treatments was generated using a random
numbers table. Each enrolled patient was associated to
a treatment code which was kept in a sealed envelope
to be opened only in case of emergency. The study was
kept blind up to locking of database when the
randomisation code was opened. Each patient was
given one ampoule by slow intravenous injection. A
second ampoule of the same drug initially administered
was injected 30 min after the first treatment in
patients with persistent pain (more than 80% of basal
pain score).
Evaluation methods
Efficacy of treatment on abdominal pain was assessed
on a self-evaluation basis by visual-analogue scale
(VAS). Patients were asked to rate the severity of
abdominal pain on a 10-cm VAS ranging from ‘no pain’
to ‘unbearable pain’. Rating was marked with a pen
immediately before the first injection and every 10 min
thereafter for 60 min. The need for a 30-min second
injection (in a case of less than 80% response) and for
further treatment with nonsteroidal anti-inflammatory
drugs or opioids at 60 min, were also taken as
parameters of efficacy. Patients were followed-up for at
least 48 h after treatment administration for possible
relapses of pain or complications.
The safety of treatment was assessed by looking for and
reporting any possible clinical adverse event and by
having blood test and urine analysis routinely per-
formed 24 h after test drug administration.
Statistical analysis
A sample size of 25 patients for each arm of treatment
was originally calculated. This calculation was based on
expectation of response (greater than 50% reduction of
basal VAS score) in 80% of patients treated with
loxiglumide and in 40% of subjects treated with
hyoscine-N-butyl bromide. As a result of the very slow
recruitment of patients fulfilling the entry criteria, an
interim analysis was made after the enrolment of
14 patients.
Student’s t-test was used to verify the absence of
significant differences in demographic and clinical
continuous variables between the two arms of treat-
ment (Table 1), and to compare the mean values of
pain score reduction at different times (Figure 1).
Fisher’s Exact test was applied for comparison of
 13652036, 2003, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2036.2003.01688.x, Wiley Online Library on [09/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
LOXIGLUMIDE AND BILIARY COLIC 335

Table 1. Demographics and clinical fea-

Hyoscine-N-butyl Loxiglumide
tures of patients enrolled in the study
bromide (n ¼ 7) (n ¼ 7) P value

Sex (M : F) 3:4 2:5 > 0.5

Age (year) 54.3 ± 4.0 48.0 ± 4.7 0.294
Duration of pain (h) 2.5 ± 0.5 1.9 ± 0.2 0.269
Number of previous biliary colics 3.0 ± 1.5 3.7 ± 1.5 > 0.5
Pain score at enrolment 7.7 ± 0.5 6.3 ± 0.7 0.106

100 hyoscine–N–butyl bromide Pain relief was obtained more rapidly after loxiglumide
80 treatment than after hyoscine-N-butyl bromide admin-
60
istration (Figure 1). A single injection of 50 mg of
loxiglumide induced a reduction in pain score (mean ±
pain score (% of basal)

40
20
0
100
loxiglumide
80
60
40
20 ∗ ∗
∗ ∗
0 (P ¼ 0.02). Even after re-treatment of patients who
0 10 20 30 40 50
minutes after treatment
Figure 1. Pain reduction in patients with biliary colic after i.v.
injection of a CCK-1 receptor antagonist (50 mg of loxiglumide,
lower panel), or of an anticholinergic drug (20 mg of hyoscine-
N-butyl bromide, upper panel). Data are expressed as percent of
pre-treatment pain scores on a visual analogue scale. —— (thin
line), individual patients; —n— (thick line), mean values. At
30 min, a second injection of the same drug initially administered
was given to patients with less than 80% response.
discrete variables and responses in the two subgroups of
patients. A P-value of < 0.05 was considered
significant.
RESULTS
Out of more than 30 patients evaluated for biliary colic,
only 14 eligible patients completed the study. After
disclosure of treatment codes, seven patients were
recognised as treated with loxiglumide and seven with
hyoscine-N-butyl bromide. The demographic and clin-
ical characteristics of the two treatment subgroups are
shown in Table 1. There were no statistically significant
differences between the two subsets regarding sex, age,
number of previous episodes of biliary colic, and
duration or intensity of pain at the time of enrolment.
S.E.M.) significantly greater than that observed after
*p < 0.05 vs. hyoscine–N–
injection of 20 mg of hyoscine-N-butylbromide:
butyl bromide 88 ± 7% vs. 47 ± 12% after 20 min, P < 0.05;
2nd injection at 30 min 92 ± 6% vs. 49 ± 13% after 30 min, P < 0.05. The
second injection administered after 30 minutes was
necessary (< 80% response) in only one of seven (14%)
patients treated with loxiglumide vs. six of seven (86%)
of patients treated with hyoscine-N-butyl bromide
60 required it, patients in the loxiglumide arm had a
significantly greater decrease in pain score: 98 ± 2% vs.
59 ± 16% at 40 min, P < 0.05. At 60 min all patients
treated with loxiglumide were pain-free, whereas three
of seven controls still had considerable pain (P ¼ 0.2).
Consequently, 60 minute-rescue treatment with a
nonsteroidal anti-inflammatory drug (ketoprofene),
was only needed in three patients who had been treated
with hyoscine-N- butyl bromide. At the 24 h follow-up,
none of the patients treated with loxiglumide had a pain
relapse, whereas four of seven controls had persistence
or recurrence of pain (P ¼ 0.07). No patient, in either
arm, developed acute cholecystitis, acute cholangitis,
jaundice or acute pancreatitis. No patient required early
surgery.
No adverse event was observed in either arm of
treatment. Laboratory tests performed 24 h after treat-
ment did not show any biochemical variation when
compared with basal evaluation.
DISCUSSION
The original aim of the study was to test the
analgesic effect and safety of CCK-1 receptor blockade,
as compared with anticholinergic treatment, in a
larger population of patients with biliary colic.
However, the stringent entry criteria of the study

 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 333–337


336 A. MALESCI et al.
protocol prevented an easy enrolment. In particular,
patients referring to a single institution had to be
carefully selected for untreated and noncomplicated
biliary colic. Not only patients with fever, peritoneal
irritation or abdominal guarding, but also patients
simply at risk from acute cholecystitis (leucocytosis
> 10 000 WBC, thickened gall-bladder wall, pain
duration more than 5 h) were to be excluded. Then,
we decided to analyse data from 14 enrolled patients
simply to verify whether a multicentre and less
restrictive study was warranted.
For the above mentioned reasons, it was somewhat
surprising for a small study to clearly demonstrate
that the CCK-1 receptor antagonist loxiglumide is
more rapidly efficacious than a commonly used
anticholinergic drug in relieving pain of patients with
moderately severe biliary colic. This obviously repre-
sents a great difference between the two treatments
in their response rate. We chose to compare loxiglu-
mide with hyoscine-N-butyl bromide because it would
have been unethical to conduct a placebo-controlled
study.8 The dose of the anticholinergic drug was
that routinely employed in clinical settings. On the
other hand, we did not use prostaglandin inhibitors
or opioid analgesics because, in our country, these
drugs are not generally used as first-line pain
controllers in case of nonsevere or noncomplicated
biliary colics.
The great efficacy of loxiglumide treatment in control-
ling biliary pain prompts further and larger studies to
investigate the potential benefit of CCK-receptor antag-
onists in preventing acute cholecystitis, which is the
most feared complication of biliary colic. In addition, the
safety profile of these compounds suggests their use for
high-risk surgical candidates undergoing recurrent
biliary colics. In this respect, even oral administration
of loxiglumide is expected to obtain gall-bladder relax-
ation.9 Finally, CCK-receptor antagonists might be
tested in subjects symptomatic for biliary colics, but
without evidence of gallstones, to possibly select
patients who can benefit from cholecystectomy.
Besides demonstrating the clinical benefit of a novel
drug, our study contributes to a better understanding of
the mechanism of pain in patients with biliary colic. The
dramatic effect of loxiglumide on the acute pain of
biliary colics, most likely mediated by the blockade of
CCK-1 receptors on the smooth muscle cells of the
gallbladder,4 strongly supports the concept that the pain
of a biliary colic is merely due to mechanical stimuli,
 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 333–337
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i.e. stretching and forceful contraction of the muscular
layers of the gall-bladder wall.10 We can also postulate a
primary role of CCK, as opposed to the role possibly
played by the cholinergic system,11, 12 in determining
the gall-bladder contraction which underlies a biliary
colic.
We conclude that loxiglumide, a potent and selective
CCK-1 receptor antagonist, is rapidly effective in
controlling pain caused by noncomplicated biliary colic.
Further studies with CCK-receptor antagonists in
patients with biliary pain are warranted.
ACKNOWLEDGEMENTS
We are indebted to Professor Guido Adler (Ulm,
Germany) and to Professor Cristoph Beglinger (Basel,
Switzerland), who designed the original protocol of the
study.
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 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 333–337