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Role of antispasmodics in the treatment of irritable bowel
syndrome
Anita Annaházi, Richárd Róka, András Rosztóczy, Tibor Wittmann
Anita Annaházi, Richárd Róka, András Rosztóczy, Tibor Wit-
tmann, First Department of Medicine, University of Szeged,
6720 Szeged, Hungary
Author contributions: All of the authors drafted and revised the
article and revised and approved the final version.
Correspondence to: Tibor Wittmann, MD, PhD, Professor,
First Department of Medicine, University of Szeged, Korányi fa-
sor 8-10, 6720 Szeged,
Hungary. wittmann.tibor@med.u-szeged.hu
Telephone: +36-62-545189 Fax: +36-62-545185
Received: September 28, 2013 Revised: January 8, 2014
Accepted: April 1, 2014
Published online: May 28, 2014
Abstract
Irritable bowel syndrome (IBS) is a long-lasting, relaps-
ing disorder characterized by abdominal pain/discom-
fort and altered bowel habits. Intestinal motility impair-
ment and visceral hypersensitivity are the key factors
among its multifactorial pathogenesis, both of which
require effective treatment. Voltage-gated calcium
channels mediate smooth muscle contraction and en-
docrine secretion and play important roles in neuronal
transmission. Antispasmodics are a group of drugs that
have been used in the treatment of IBS for decades.
Alverine citrate, a spasmolytic, decreases the sensitivity
of smooth muscle contractile proteins to calcium, and
it is a selective 5-HT1A receptor antagonist. Alverine, in
combination with simethicone, has been demonstrated
to effectively reduce abdominal pain and discomfort in
a large placebo-controlled trial. Mebeverine is a muscu-
lotropic agent that potently blocks intestinal peristalsis.
Non-placebo-controlled trials have shown positive ef-
fects of mebeverine in IBS regarding symptom control;
nevertheless, in recent placebo-controlled studies,
mebeverine did not exhibit superiority over placebo.
Otilonium bromide is poorly absorbed from the GI
tract, where it acts locally as an L-type calcium chan-
nel blocker, an antimuscarinic and a tachykinin NK2
WJG 20th Anniversary Special Issues (4): Irritable bowel syndrome
TOPIC HIGHLIGHT
receptor antagonist. Otilonium has effectively reduced
pain and improved defecation alterations in placebo-
controlled trials in IBS patients. Pinaverium bromide is
also an L-type calcium channel blocker that acts locally
in the GI tract. Pinaverium improves motility disorders
and consequently reduces stool problems in IBS pa-
tients. Phloroglucinol and trimethylphloroglucinol are
non-specific antispasmodics that reduced pain in IBS
patients in a placebo-controlled trial. Antispasmodics
have excellent safety profiles. T-type calcium channel
blockers can abolish visceral hypersensitivity in animal
models, which makes them potential candidates for the
development of novel therapeutic agents in the treat-
ment of IBS.
© 2014 Baishideng Publishing Group Inc. All rights reserved.
Key words: Irritable bowel syndrome; Motility; Treat-
ment; Calcium channel blockers; Spasmolytics
Core tip: Treatment of irritable bowel syndrome (IBS)
must target intestinal motility alterations and visceral
hypersensitivity. Antispasmodics have been used in
the treatment of IBS for decades, and large placebo-
controlled trials have recently been conducted on their
efficacy. Alverine citrate, in combination with simethi-
cone, effectively reduced abdominal pain and discom-
fort; while otilonium bromide also improved defecation
problems. Pinaverium bromide regulated impaired mo-
tility and reduced stool complaints. Phloroglucinol and
trimethylphloroglucinol reduced pain in IBS patients.
Mebeverine was recently found to be effective only in
non-placebo-controlled trials. Antispasmodics are con-
sidered safe. T-type calcium channel blockers could
represent a future therapeutic option in IBS treatment.
Annaházi A, Róka R, Rosztóczy A, Wittmann T. Role of anti-
spasmodics in the treatment of irritable bowel syndrome. World
J Gastroenterol 2014; 20(20): 6031-6043 Available from: URL:
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Submit a Manuscript: http://www.wjgnet.com/esps/
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DOI: 10.3748/wjg.v20.i20.6031
World J Gastroenterol 2014 May 28; 20(20): 6031-6043
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
© 2014 Baishideng Publishing Group Inc. All rights reserved.
http://www.wjgnet.com/1007-9327/full/v20/i20/6031.htm DOI:
http://dx.doi.org/10.3748/wjg.v20.i20.6031
INTRODUCTION
Irritable bowel syndrome (IBS) is a chronic gastrointes-
tinal (GI) disorder affecting a significant proportion of
the global population, with a calculated prevalence of
approximately 11.2%[1]. IBS has a large impact on health-
related quality of life, resulting in reduced work produc-
tivity, elevated absenteeism and increased health care use
and costs[2,3]. IBS can also seriously impair the patient-
doctor relationship[4], because ineffective symptom con-
trol can diminish clinicians’ credibility and prompt the
patient to seek further opinions[5]. IBS has a long course
and high relapse rates, with more than half of IBS pa-
tients reporting the same symptom profile after 1 and
7 years and a further 25% having persistent minor IBS
symptoms[6]. Regarding the long term persistence of IBS,
effective long-term therapies are of great economic im-
portance in both Eastern and Western countries; howev-
er, drug trials have revealed an extremely high relapse rate
in this disease[7]. Despite intensive research aiming to nd
new therapeutic pathways, the present possibilities have
mostly focused on symptom suppression, and only a few
drugs have been found to be more effective than placebo
over the long term.
A heterogeneous group of drugs called “antispas-
modics” or “spasmolytics” such as direct smooth muscle
relaxants (e.g., papaverine, mebeverine, peppermint oil),
anticholinergic agents (e.g., butylscopolamine, hyoscine,
cimetropium bromide, pirenzepine) and calcium channel
blockers (e.g., alverine citrate, otilonium bromide, pinave-
rium bromide), have been used in therapy for IBS for
decades. The aim of these drugs is to reduce defecation
symptoms by increasing colonic transit time, improving
stool consistency and reducing stool frequency. The phar-
macological action of these agents is not always clear,
and the mechanisms are often mixed. Nevertheless, meta-
analyses performed on studies comparing antispasmodics
to placebo or other treatments have uniformly conrmed
the positive effects of these drugs, and their side effect
proles have been excellent[8]. Recent adverse reactions,
such as severe constipation, ischemic colitis and possible
deaths[9], have led to the transient withdrawal of alos-
etron, a 5-HT3 receptor antagonist, and fatal ventricular
arrhythmias caused the retraction of the mixed 5-HT3
antagonist/5-HT4 agonist cisapride in many countries,
thus highlighting antispasmodics as attractive and reliable
therapeutic options.
The accurate diagnosis of IBS has been a major pit-
fall in designing clinical trials in the past because a precise
denition has been lacking. After the proposal of previ-
ous diagnostic criteria by Manning et al[10] and later by
Drossmann et al[11], the Rome criteria were developed,
emphasizing the importance of a positive diagnosis
based on symptoms. Currently, the diagnostic criteria for
IBS based on the Rome Ⅲ system are recurrent abdomi-
nal pain or discomfort for at least 3 d per month over
the previous 3 mo, associated with two or more of the
following: improvement with defecation; and onset as-
sociated with a change in frequency of stool; and onset
associated with a change in form (appearance) of stool[12].
These criteria must be fulfilled for the previous 3 mo,
with symptom onset at least 6 mo prior to diagnosis. De-
pending on the predominant bowel symptom, IBS can
be classied as IBS with constipation (IBS-C, 20%-30%
of patients), IBS with diarrhea (IBS-D, 20%-30% of
patients) or IBS with “mixed” constipation and diarrhea
(IBS-M, up to 45% of patients)[13].
In this review, we aimed to collect and summarize
the available data on the efcacy and safety of modern
antispasmodics in the treatment of IBS, focusing on
placebo-controlled clinical trials using valid patient selec-
tion criteria.
PATHOPHYSIOLOGY OF IBS
Profound research over the last few decades has revealed
a multifactorial pathogenesis. Preceding enteric infections,
altered colonic or small intestinal bacterial ora, increased
gut permeability and immune activation may play a role in
the development of the disease[14-16]. Signals from the GI
tract are processed in the brain, which in turn can inu-
ence GI motility, secretion and immune function[17]. This
brain-gut axis is essential for the healthy regulation of
the GI system, and its structural or functional alteration
can lead to the development of disorders such as IBS[18].
Therefore, psychological factors and chronic stress can
also be involved in triggering symptoms[19], in associa-
tion with alterations in the activity of specific brain re-
gions[20,21]. Nevertheless, abnormal intestinal motility and
visceral hypersensitivity remain key factors in the patho-
genesis of the disease[22]. The origin of visceral hypersen-
sitivity seems to be complex. Intraluminal factors, such
as serine-proteases, can increase colonic permeability in
IBS-D patients by activating protease-activated recep-
tor-2, resulting in visceral hypersensitivity[23]. Increased
colonic permeability in IBS-D patients has been corre-
lated with stool frequency, which also suggests a role in
symptom generation[24]. Luminal cysteine-proteases have
been shown to increase colonic permeability through the
degradation of tight junction proteins, resulting in vis-
ceral hypersensitivity in IBS-C patients, possibly through
local microinammation[25]. Colonic mucosal immune ac-
tivation, which is characterized by mast cell, intraepithe-
lial lymphocyte and lamina propria lymphocyte counts,
was found to be significantly higher in IBS-D than in
healthy controls[26]. This immune activation was similar
to inactive inflammatory bowel disease. Mast cells have
been implicated in the development of IBS: the number
of degranulating mast cells in colonic mucosa and their
spontaneous release of trypsin and histamine were mark-
edly increased in IBS patients compared with controls[27].
Furthermore, mast cells in close proximity to nerve end-
Annaházi A
et al
. Antispasmodics in irritable bowel syndrome
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ings have been significantly correlated with the severity
and frequency of abdominal pain/discomfort in IBS
patients. Enterochromafn cells can also play important
roles in the development of visceral hypersensitivity by
producing and releasing serotonin, which activates 5-HT3
receptors located on afferent sensory neurons[28]. Fur-
thermore, the activation of 5-HT4 receptors on sensory
afferent neurons triggers the peristaltic reflex, whereas
5-HT4 receptors on colonic smooth muscle mediate re-
laxation[29,30]. Motility disturbances in IBS patients have
been well known for decades. Baseline muscular tone was
found to be higher in IBS-D and IBS-M but not in IBS-C
compared with healthy individuals[31]. Further abnor-
malities in colonic motility patterns are characterized by
hyperreactivity - namely, a prolonged increase in colonic
motor activity after meals, an exaggerated increase in mo-
tor activity in response to stressors or cholecystokinin
(CCK) and increased motor activity in response to bal-
loon distention[32]. Stress alone can be an important factor
in the pathogenesis of motility disturbances, as suggested
by long-duration restraint in rats having been shown to
induce rapid, dramatic changes in small bowel motility,
with gradually increasing differences in colonic motility
as measured by electromyography[33]. Colonic motility
changes were still present 60 h after such restraint stress,
suggesting that these persistent alterations could form the
basis of the development of functional disorders. In a
study measuring electromyographic activity in the left co-
lon with an intraluminal probe, a large increase in short-
spike bursts was induced by stress (via the cold pressor
test) in IBS-C patients but not in controls or in chroni-
cally constipated patients, and this difference remained
significant for 2 h after the stress episode (Figure 1)[34].
Ingestion of a standard meal has provoked the increase
of aboral migrating long spike bursts in control subjects,
but this propulsive motor effect was largely depressed
in IBS-C patients[35]. In a subsequent study, repetitive
distention of the distal sigmoid colon below the sensory
threshold in IBS patients induced exaggerated colonic
motility[36]. Small bowel motility was also impaired, as the
repetitive distention inhibited motility of the small intes-
tine in healthy subjects, whereas no such effect was ob-
served in IBS patients[36]. Specic patterns of small bowel
motor activity have also been described in IBS patients,
such as ileal propulsive waves and clusters of jejunal
pressure activity, which have usually been associated with
abdominal cramping and pain[37]. Visceral hypersensitivity
by itself is not painful, but it can lead to abdominal pain
in IBS patients by the effect of an intense stimulus, such
as an exaggerated colonic contraction[38]. However, a clear
connection between visceral hypersensitivity and motility
disturbances could not been established, and these two
factors have usually been considered independent, both
requiring effective treatment[31].
VOLTAGE-GATED CALCIUM CHANNELS
Voltage-gated calcium channels are ion channels mediat-
ing calcium influx in response to membrane depolar-
ization, and they regulate intracellular processes, such
as contraction, secretion, neurotransmission and gene
expression, in a variety of cells[ 39]. Calcium-channels
are traditionally classified by their current properties
and pharmacology[40]. The L (long-lasting)-type calcium
channel is a large-conductance channel that produces
long-lasting current at strong depolarizations, and it is
generally inhibited by dihydropyridine (DHP) deriva-
tives[41]. L-type currents are most important for muscle
and endocrine cells, in which they mediate contraction
and secretion[39]. In neurons and cardiac pacemaker cells,
L-type currents can also be found to activate at lower
voltages. N (neuronal)-type currents are also long-lasting,
but they require strongly negative potentials for the com-
plete removal of inactivation and strong depolarizations
for activation, and they are not blocked by DHP[ 41]. In
Purkinje cells, three further channels have been identi-
Number of SSBs/15 min Number of SSBs/60 min
Number of SSBs/15 min
180
160
140
120
100
80
60
40
20
0
15 30 45 60 min
1 2 3 4 5 6
Stress Meal
t
/h
c
c
c
c
c
c
ac
ac
ac
c
ac
a
700
600
500
400
300
200
100
0
0 1 2 3 4 5 6
t
/h
Meal
c
c
ac
ac
A B
Stress
Figure 1 The number of short spike bursts measured by colonic intraluminal electromyography[34]. The values were calculated over the period of 15 (A) and
60 min (B). Each group included 8 patients. The 6-h screening session consisted of three 2-h periods: a control period; a period of stress (during which a cold pressor
test was performed for 15 min); and a post-prandial period (patients ingested a 800 kcal meal). SSBs: Short spike bursts. aP < 0.05 vs normal controls; cP < 0.05 vs
chronic constipation patients.
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IBS
Normal controls
Chronic constipation
Annaházi A
et al
. Antispasmodics in irritable bowel syndrome
the doses used in clinical practice would not reach this
concentration in humans. They concluded that alverine
citrate should be considered a true spasmolytic, because
it suppresses the duration of spontaneous contractions
of the gut, preventing local ischemia and reectoric pain
in the colonic wall evoked by “spasms”. In addition, it
has also been noted that alverine can increase calcium
inux during action potentials by inhibiting the inactiva-
tion of calcium channels, but it reduces the sensitivity of
contractile proteins to calcium, consequently suppressing
the evoked muscular activity. Stress-induced colonic mo-
tility changes are an important factor in the pathogenesis
of IBS; therefore, the clinical effects of alverine and the
antifoaming agent, simethicone were tested in a rat model
of colonic hypersensitivity induced by acute restraint
stress[45]. Treatment with simethicone (200 mg/kg po)
or alverine citrate (10 mg/kg po) reduced stress-induced
increases in colonic permeability and hypersensitivity to
distension, but lower doses were ineffective[45]. However,
the combination of inactive doses of simethicone (100
mg/kg) with low doses of alverine (7 mg/kg) completely
abolished the effects of stress, suggesting a synergistic
action.
Clinical trials: Clinical studies on alverine citrate in IBS
have been scarce (Table 1). In a randomized, placebo-
controlled, double-blind clinical trial conducted in three
British centers, after a 2-wk screening period, IBS pa-
tients selected according to the modified Rome criteria
received 12 wk of treatment with 120 mg alverine citrate
three times daily[46]. The patients completed diary cards
about abdominal pain or discomfort, bloating, bowel
movements, stool consistency, and general well-being;
furthermore, the severity and frequency of abdominal
pain, bloating, nausea and early satiety were assessed at
study visits four times during treatment. Although ab-
dominal pain, bloating and general well-being were all
slightly more improved in the alverine-treated group than
in the placebo group, when comparing the rst diary card
to the third, the difference was not statistically signicant.
This nding might be explained by the placebo effect be-
ing exceptionally high, sometimes reaching almost 70%,
which would require a study with a much great number
of participants to detect a possible positive effect of al-
verine. Regarding safety, no serious adverse events were
reported in the study, and more patients experienced ad-
verse events in the placebo group (48.1%) than in the al-
verine-treated group (39.6%). Using the well-known spas-
molytic properties of alverine, a randomized, placebo-
controlled trial showed that pretreatment of patients over
5 d with 60 mg alverine citrate plus 300 mg simethicone
three times daily reduced intubation time during colo-
noscopy by 19%; nonetheless, it did not affect scores for
pain, spasm, difculty or cleanliness[47]. The combination
of alverine with simethicone was also tested in a double-
blind, placebo-controlled, randomized trial conducted
in 17 sites in Hungary and Poland[48]. A total of 412 IBS
patients meeting the Rome Ⅲ criteria received a combi-
ed. P-type currents are blocked by low concentrations
of ω-agatoxin, whereas the Q-type is only responsive to
high concentrations. Residual currents, which were resis-
tant to all known calcium-blockers at the time of their
discovery, were called R (resistant)-type. The last group
of voltage-gated calcium channels, the T (transient)-type,
is characterized by a small and transient conductance ac-
tivated upon weak depolarizations[41]. These currents are
responsible for modulation of the action potential and
for the performance of pacemaker activities.
The medical use of calcium antagonists started in the
1980s with DHP-type antagonists, which block L-type
channels, in the treatment of hypertension by exploiting
their properties as vasodilators[40]. Because a Ca2+ increase
in smooth muscle is required for contraction, calcium
antagonists induce relaxation of blood vessels, followed
by a consequent reduction in blood pressure. Further,
relaxation of the coronary arteries increases coronary
ow, acting against angina pectoris. Calcium antagonists
have no effect on skeletal muscles; however, they slightly
inuence cardiac muscle by decreasing pacemaker activity
and conduction. Based on the well-known gastrointesti-
nal motility impairments in IBS, calcium antagonists used
for cardiovascular conditions appeared to be potential
options for relieving symptoms by relaxing the colonic
smooth muscles. Therefore, in the late 1980s, nicardipine
was proposed for the treatment of irritable bowel syn-
drome, based on its spasmolytic properties[42]. Nonethe-
less, cardiovascular side effects have seriously limited the
application of such calcium antagonists, thereby inspiring
researchers to identify substances that act selectively on
the gastrointestinal tract.
MODERN ANTISPASMODICS WITHOUT
CARDIOVASCULAR SIDE EFFECTS
Alverine citrate
Experimental studies: Alverine citrate is an antispasmodic
drug that inhibits calcium uptake and modulates smooth
muscle activity. An experimental study on anesthetized cats
showed that alverine acts on vagal sensory endings of the
GI tract, where it decreases the responses of mechano-
receptors to mechanical and chemical stimuli[43]. Because
chemically induced responses and smooth muscle contrac-
tion are both calcium dependent, decreased chemical sen-
sitivity and smooth muscle relaxation can be explained
by reduced calcium influx. In addition, a calcium-inde-
pendent mechanism of action, such as selective 5-HT1A
receptor antagonism, might also be present, which has
been demonstrated in rats using a 5-HT agonist-induced
hypersensitivity model[44]. However, the picture is more
complex than rst thought - in guinea pig urinary bladder
preparations, the frequency of spontaneous contractions
in endogenously active smooth muscle was surprisingly
increased by low doses of alverine citrate, whereas con-
traction amplitude was decreased. Higher doses of the
drug could suppress both the frequency and amplitude
of contractions; nevertheless, the authors speculated that
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Annaházi A
et al
. Antispasmodics in irritable bowel syndrome
nation of 60 mg alverine citrate and 300 mg simethicone
or placebo three times per day for 4 wk. Combined alver-
ine citrate and simethicone treatment achieved a higher
reduction in abdominal pain and discomfort, as measured
using visual analog scale (VAS) scores, and significantly
more patients responded to therapy than to placebo, re-
gardless of stool pattern. A visible, but not statistically
significant, trend was also observed, showing greater
improvement in IBS life impact scores with combination
therapy than with placebo. No severe drug-related ad-
verse events were noted in the study, and the numbers of
adverse events were similar in both groups.
Mebeverine
Experimental studies: Mebeverine is a beta-phenyletyl-
amine derivative of reserpine, which has relatively specic
effects on smooth muscle cells without atropine-like side
effects in humans[49]. It directly blocks voltage-operated
sodium channels and inhibits intracellular calcium accu-
mulation[49,50]. It is three times more potent than papav-
erine in inhibiting the peristaltic reex of the guinea-pig
ileum[51], but further animal studies on its pharmacologi-
cal effect have been lacking.
Clinical trials: Mebeverine became treatment of inter-
Table 1 Characteristics and primary outcomes of randomized, double-blind, placebo controlled clinical trials in irritable bowel
syndrome patients
Ref. IBS
population
Selection
criteria
Treatment Dose Duration Outcome
Mitchell et al[46] All subtypes Modied
Rome
Alverine citrate vs
placebo
120 mg tid 12 wk No signicant difference compared to placebo
Wittmann
et al[48]
All subtypes Rome ⅢAlverine citrate + 60 mg tid + 4 wk Signicantly reduced abdominal pain and discomfort
compared to placebo
simethicone vs placebo 300 mg tid More therapy responders, regardless of stool pattern,
compared to placebo
Connel et al[52] All subtypes Mebeverine vs placebo 100 mg qid 12 wk Superior in controlling IBS symptoms compared to
placebo
Kruis et al[58] All subtypes Mebeverine vs placebo vs
Wheat bran
400 mg daily 16 wk No signicant difference compared to placebo
Enck et al[59] All subtypes Mebeverine vs placebo vs
Dietary ber
16 wk Therapy response rate lower than placebo
Everitt et al[61] All subtypes Rome ⅢMebeverine vs 135 mg tid 6 wk No signicant difference between drugs
methylcellulose vs
placebo with/without
cognitive behavioral
therapy web site
(assisted or not)
3 tbl. bid Signicantly increased enablement at 6 and 12 wk in
website group compared to no website group, signicantly
more participants scored their subjective assessment
of global relief as improved at 12 wk in website group
compared to no website group.
Baldi et al[69] Abdominal
pain
predominant
Otilonium bromide vs
placebo
40 mg tid No signicant difference in abdominal pain, bloating and
general well-being compared to placebo, but signicantly
reduced sigmoid motility
Battaglia et al[70] All subtypes Drossman Otilonium bromide vs
placebo
40 mg tid 15 wk Signicantly better compared to placebo in reduction of
abdominal pain frequency, global score improvement of
abdominal pain and discomfort, therapy responder rate,
reduced tenderness of the sigmoid colon, higher general
well-being and global judgement of investigators; superior
in improving severity of diarrhea/constipation, number of
evacuations and mucus in stool; more effective in treating
diarrhea, but not constipation
Clave et al[72] All subtypes Rome ⅡOtilonium bromide vs
placebo
40 mg tid 15 wk Reduced abdominal pain frequency and bloating and
improved stool frequency and patient global assessment
compared to placebo; lower symptom recurrence after
treatment
Awad et al[85] All subtypes Pinaverium bromide vs
placebo
50 mg tid Signicantly reduced post-prandial rectal spike amplitude
plus frequency and spontaneous recto-anal inhibitory
reex frequency compared to placebo
Chassany et al[98] All subtypes Rome ⅡPhloroglucinol +
trimethylphloroglucinol
vs placebo
62.2 mg + 80
mg tid
1 wk Signicantly higher relative decrease of pain intensity
and responder rate in the phloroglucinol plus
trimethylphloroglucinol group compared to placebo;
persisting treatment effect in a higher percent of patients
treated with phloroglucinol plus trimethylphloroglucinol
Cha et al[99] IBS-D Rome ⅢPhloroglucinol vs
placebo
80 mg tid 2 wk Signicantly improved subjects' global assessment and
decreased stool frequency
Characteristics and primary outcomes of randomized, double-blind, placebo controlled clinical trials in irritable bowel syndrome (IBS) patients with alver-
ine citrate, mebeverine, otilonium bromide, pinaverium bromide and phloroglucinol. IBS-D: IBS with diarrhea.
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Annaházi A
et al
. Antispasmodics in irritable bowel syndrome
est for IBS in the 1960s. In an early study by Connell[52],
iv mebeverine decreased all sigmoid colonic motility,
especially in hyperactive subjects, and it had less or no
effect in hypoactive subjects. In a subsequent part of the
study, mebeverine was superior to placebo at each time
point over 12 wk of treatment in IBS patients in terms
of symptom improvement and general well-being. Using
prolonged ambulant manometry in 12 IBS patients and
6 healthy controls, compared to a placebo period, mebe-
verine had no significant effects on interdigestive small
bowel motor parameters in controls; in contrast, a higher
phase 2 motility index was observed in both IBS-D and
IBS-C patients, and phase 3 motility was also affected[53].
These alterations in small bowel motile activity by mebe-
verine suggest possible spasmolytic and prokinetic effects
in IBS patients.
Regarding symptom control in IBS, non-placebo-
controlled studies have shown positive results. Signicant
improvement was observed after 6 wk of treatment
with both the plain and sustained-release forms of me-
beverine, with a minimal number of adverse events[54].
When comparing pinaverium bromide to mebeverine
in 91 IBS-D patients, the improvements in global well-
being were similar in the two groups, the daily defecation
frequencies were markedly decreased, and stool consis-
tencies became well formed in both groups, while no
signicant side effects were observed[55]. In a clinical trial
comparing the effects of ramosteron, a 5-HT3 recep-
tor antagonist, to those of mebeverine in patients with
IBS-D, both treatments were equally effective in reducing
abdominal pain/discomfort and urgency and improving
the stool form score and stool frequency compared to
baselines[56].
However, when the effects of mebeverine have been
compared to placebo and not compared to another drug
or measured by self-control, the results have been con-
troversial. A recent systematic review, including eight
randomized trials, revealed that clinical improvement and
relief of abdominal pain by mebeverine treatment were
not statistically signicant compared to placebo[57-59]. No
differences were found in the effectiveness of 200 and
135 mg mebeverine doses. Tolerability was excellent,
without signicant adverse effects. Similarly, no positive
effects of mebeverine over placebo were seen in an ex-
ploratory study performed in 135 IBS patients fullling
the Rome Ⅲ criteria who were recruited from general
practice, when mebeverine, methylcellulose and placebo
were compared, with or without the combination of a
cognitive behavioral therapy-based self-management web
site (with or without additional telephone and e-mail sup-
port)[60,61]. Disappointingly, the use of the web site also
did not improve IBS symptom severity scores or quality
of life scores signicantly over the “no web site” group;
nevertheless, there was a visible trend toward continued
improvement in the self-management group (particularly
those with telephone support) throughout the study,
while the “no web site” group and the medication groups
seemed to lose their therapeutic gains from weeks 6 to
12. However, in a study performed in London, personal
sessions of cognitive behavioral therapy were benecial
in addition to mebeverine, and the effects persisted for
up to six months after therapy, both in terms of symp-
tom relief and improvement in social and work disabil-
ity[62]. Depression and anxiety predict poor outcomes in
mebeverine-treated IBS patients, and in cases of patients
with unhelpful coping behaviors (e.g., avoidance), the
combination of mebeverine with cognitive-behavioral
therapy could be useful[63].
Otilonium bromide
Experimental studies: Otilonium bromide is weakly
absorbable from the GI tract due to its quaternal ammo-
nium structure; thus, it is almost completely excreted in
the feces[64]. In experimental studies, it accumulated in the
walls of the GI tract after oral administration, with mini-
mal systemic absorption[65]. Its effects are rather complex,
consisting mainly of L-type calcium-channel blockade,
but binding to muscarinic M1, M2, M4 and M5 receptors
has also been observed[66]. Antagonism of M3-coupled
calcium signals in human colonic crypt cells suggested an
anti-secretory action in IBS-D patients[67]. Additionally,
by antagonism of tachykinin NK-2 receptors, otilonium
not only causes spasmolysis but also reduces peripheral
sensory afferent transmission to the central nervous
system[64]. These effects suggest that otilonium could be
effective in reducing both of the main symptoms of IBS:
spasms and abdominal pain.
Clinical trials: In a small study of 15 IBS patients, one
week of treatment with otilonium bromide signicantly
increased the pain threshold of IBS patients to anorectal
distension, while thresholds for rst sensation and stool
remained unchanged[68]. In a multicenter, double-blind,
placebo-controlled trial with 72 IBS patients in Italy,
treatment with 40 mg otilonium bromide three times
daily significantly decreased abdominal pain and bloat-
ing, improved well-being and global assessment, while
it markedly increased the pain threshold during sigmoid
distension. Nevertheless, these results did not differ
from those of the placebo group[69]. However, otilonium
signicantly reduced sigmoid motility during distension,
whereas placebo did not, suggesting the need for larger
studies, a different setup or more accurate patient selec-
tion. Seven years later, the results of a larger trial were
published in Italy, including 375 IBS patients selected by
the Drossman criteria, when a 2-wk placebo run-in peri-
od was included to exclude patients with low compliance
or with quickly resolving symptoms[70]. After randomiza-
tion, the patients received 40 mg otilonium bromide or
placebo three times daily for 15 wk, and their symptoms
were assessed at weeks 5, 10 and 15. Abdominal pain
frequency was reduced in both of the groups, with a
statistically significant difference in favor of otilonium
after 10 and 15 wk of treatment. The global score im-
provements in abdominal pain and discomfort were sig-
nicantly greater in the otilonium group throughout the
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whole study. Therapy was successful in signicantly more
patients treated with otilonium than in those treated with
placebo. Defecation disturbances improved similarly in
both groups. Tenderness of the sigmoid colon, general
well-being and global judgements by the investigators all
differentially improved in the otilonium-treated group.
Extended analysis of the data from this study with dif-
ferent analysis forms 3 years later revealed that otilonium
had therapeutic gains over placebo not only in terms of
pain intensity, pain frequency and meteorism but also
regarding the severity of diarrhea/constipation, the num-
ber of evacuations and the presence of mucus in stool[71].
When sorting patients according to stool habits, otilo-
nium was more effective than placebo in treating diarrhea
but was only as effective as placebo in managing consti-
pation.
Otilonium bromide in irritable bowel syndrome (OBIS)
was a recent international clinical trial in which patients
diagnosed according to the Rome Ⅱ criteria received
40 mg otilonium bromide three times a day or placebo
over 15 wk after randomization[72,73]. Otilonium bromide
effectively reduced abdominal pain frequency and bloat-
ing, while improving stool frequency and patients’ global
assessments, compared to placebo. The prominent
outcome of this study was the efcacy of otilonium in
dramatically reducing abdominal pain frequency from
more than half of the days to less than one day per
week, compared to the persistent 1-3 episodes in the
placebo group. Otilonium had no signicant effects on
pain severity, stool consistency or mucus in the stool.
During the 10-wk follow-up period after nishing treat-
ment, the likelihood of symptom recurrence was signi-
cantly higher in the placebo group than in the otilonium
group. This nding might be explained by the elongated
persistence of otilonium in the colonic wall due to its
lipophilic properties. No serious adverse events occurred
in the study, and only three adverse events, consisting of
dry mouth or nausea, were judged by the investigator to
be related to otilonium’s side effects.
When compared to other spasmolytics in a meta-anal-
ysis, otilonium bromide performed outstandingly among
12 different antispasmodics in terms of IBS symptom
control[74]. In a double-blind, randomized, active-con-
trolled trial conducted in China of IBS patients selected
according to the Rome Ⅱ criteria, the results conrmed
the similar, but not superior, efcacy of otilonium to that
of mebeverine in the management of the frequency and
intensity of abdominal pain, and abdominal bloating, at-
ulence and satisfactory stool frequency were all improved
similarly by both therapies[75]. The most common side
effects of dry mouth and nausea/dizziness - recorded in
previous studies as well-might have been caused by pe-
ripheral and central muscarinic antagonism, respectively,
and could be explained by the known ability of otilonium
to bind to muscarinic receptors[66].
Pinaverium bromide
Experimental studies: Pinaverium bromide is also a
quaternary ammonium derivate that is poorly absorbed,
with pronounced pharmacological effects in the gastro-
intestinal tract instead of the cardiovascular system[76].
It has a low absorption rate from the GI tract, corrobo-
rated by hepato-biliary excretion[64]. It has been shown
that its effects are very similar to those of the established
L-type calcium-channel blockers (nitrendipine, diltia-
zem, D600); that is, it reduces the plateau phase of slow
waves, thereby inhibiting calcium influx and preventing
consequent contractions[77]. Pinaverium has been shown
to inhibit the contractile response in dog and rat colonic
smooth muscle preparations to acetylcholine, the neu-
rotransmitter of cholinergic intrinsic nerves[77,78]. Simi-
larly, in colonic smooth muscle cells isolated from normal
or inamed human colons, pinaverium bromide inhibits
contraction induced by different agonists (CCK 8, car-
bachol or KCl)[79]. In inamed colonic cells, pinaverium
exerts more pronounced inhibition than the non-GI-
selective L-type calcium channel blockers nicardipine and
diltiazem. This effect of pinaverium on colonic smooth
muscle cells is mediated mainly by the inhibition of cal-
cium influx through L-type calcium channels, thereby
inhibiting contractions induced by acetylcholine or KCl
in rat preparations[80]. Stress plays an important role in the
pathogenesis of IBS; therefore, colonic smooth muscle
preparations from cold restraint-stressed rats have also
been examined, revealing that the hypermotility observed
after stress is mostly related to increased calcium inux
into the cells[80]. This observation supports the use of pi-
naverium in IBS, in which pathological colonic hypermo-
tility must be suppressed. Furthermore, in rats chronically
tted with intraparietal electrodes in the proximal colon,
pinaverium bromide has been found to have no effect
on colonic long spike bursts in the fasting state, but it in-
hibits increases in colonic spike burst frequency induced
by a meal or by CCK-8[81]. However, it loses its effects in
capsaicin-pretreated animals, showing the participation
of sensory afferent neurons in the mechanism of action,
which might also explain the efcacy of pinaverium bro-
mide in treating the two main features of IBS: motility
disorders and gut hypersensitivity.
Clinical trials: Pinaverium bromide has been used for
managing functional bowel disorders for decades, with
double-blind studies performed as early as 1977[82]. Its
effects on colonic smooth muscle have been well es-
tablished by animal experiments; however, intensive
research has only started to characterize its mechanism
of modifying GI motility in humans. In an early pilot
study performed in 12 IBS patients, colonic motility was
detected by surface electromyography over a 2-h fasting
period and a 2-h postprandial period following a stan-
dard meal, before and after 10 d of treatment with 50
mg pinaverium bromide three times daily[83]. The leading
symptoms, such as abdominal pain, bloating and altered
bowel habits, started to ameliorate on day 4 of treat-
ment. Abnormal colonic motility patterns (viz., increased
frequency and amplitude of contraction, arrhythmia in
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motoric activity), which were particularly pronounced
post-prandially, diminished after 10 d of treatment. In
a continuation of this pilot study, the authors studied
22 IBS patients and 7 healthy controls[84]. The healthy
controls received no treatment but served as controls for
electromyographic measurements. The study protocol
was as previously described, except for the length of
pinaverium bromide therapy, which was extended to 14
d. The results showed increased fasting and postprandial
colonic motility parameters in IBS patients compared to
controls, which was effectively reduced by 14 d of pi-
naverium bromide therapy. Abdominal pain and bloating
were also signicantly improved by treatment. Stool fre-
quency was normalized by pinaverium bromide therapy
in both diarrheic and constipated IBS patients. The ef-
fects of pinaverium bromide on intestinal motility were
afrmed by a further randomized, double-blind, placebo-
controlled trial on IBS patients[85]. Pinaverium bromide
was administered in a 50 mg dose (po, tid), and myoelec-
trical and mechanical activities of the rectum and the
internal anal sphincter were recorded before treatment, in
the fasting state and at 2 h post-prandially. Post-prandial
rectal spike amplitude and frequency, as well as the fre-
quency of the spontaneous recto-anal inhibitory reflex,
were signicantly decreased after treatment with pinave-
rium bromide. Pinaverium bromide was also able to
change colonic transit and colonic responses to food in
IBS patients, as demonstrated by a technique using orally
ingested radiopaque markers visible on plain abdominal
X-rays[86]. Benecial effects of pinaverium bromide treat-
ment were also demonstrated by an open trial, in which
61 treated IBS patients experienced signicantly reduced
abdominal pain, improved stool consistency, reduced
defecation straining and urgency, and decreased mucus
in stool, with good drug tolerance and few side effects[87].
The clinical efficacy of pinaverium bromide was also
evaluated using a statistical technique new to the field-
namely, by employing polar vectors on data from a phase
Ⅳ clinical trial with 1677 Rome Ⅲ IBS patients receiving
pinaverium bromide combined with simethicone[88]. The
results showed amelioration of stool frequency and con-
sistency in IBS-C, IBS-D and IBS-M patients; further-
more, the intensity of abdominal pain and bloating was
also signicantly reduced.
When comparing pinaverium to otilonium bromide
in IBS, both treatments were similarly useful in reduc-
ing the intensity of pain and in regulating bowel move-
ments, but otilonium was superior to pinaverium in terms
of decreasing pain frequency[89]. The side effects were
similar in the two groups. The use of pinaverium has
generally been considered safe; however, the drug is not
licensed for use in pregnant women. In a letter reporting
ten involuntary cases of pregnant women taking pinave-
rium bromide due to dispensing errors, nine individuals
delivered healthy babies, while the tenth experienced a
spontaneous abortion 1 week after the ingestion of pi-
naverium[90]. Several women complained of abdominal
pain and constipation in parallel with pinaverium use.
Phloroglucinol
Experimental studies: Phloroglucinol is a phenol deriva-
tive with non-specic antispasmodic properties, together
with its methylated form trimethylphloroglucinol. The
mechanism of action is most likely based on the direct
inhibition of the voltage-dependent calcium channels
of smooth muscle; however, the modulation of prosta-
glandin or nitric oxide release has also been suggested[91].
Although it has long been used in clinical practice as an
antispasmodic for painful urogenital and gastrointestinal
conditions, in an early study on anesthetized rats, phloro-
glucinol was found to be inactive toward the contraction
of the duodenum, ileum and colon[92]. Similarly, in anes-
thetized dogs, phloroglucinol plus trimethyl-phloroglucin-
ol failed to antagonize acetylcholine-induced contraction
of the colon[93].
Clinical trials: In parallel with animal studies, phloroglu-
cinol plus trimethyl-phloroglucinol had no clear effects
in humans on ascending and sigmoid colon hypermotility
evoked by neostigmine[94]. However, in 20 IBS patients, iv
phloroglucinol effectively reduced postprandial rectosig-
moid motility increases after a test meal, compared to pla-
cebo[95]. In another study of IBS patients, phloroglucinol
inhibited phasic contractions provoked by intrarectally
injected glycerol, but it did not modify colonic tone[96]. In
an open-label study of 100 IBS patients selected accord-
ing to the Rome Ⅱ criteria, po 50 mg phloroglucinol was
administered three times daily for two months[97]. The 68
patients who completed the study reported significant
improvement in abdominal pain, frequency of stools per
day, urgency, passage of mucus per the rectum, sense of
incomplete defecation and bloating. Nevertheless, strain-
ing was unchanged. Further, a multicenter, randomized,
double-blind, placebo-controlled trial examined the ef-
fects of phloroglucinol/trimethylphloroglucinol (62.2
mg P plus 80 mg TMP three times daily) or placebo for
7 d in 307 IBS patients diagnosed using the Rome Ⅱ
criteria[98]. The relative decrease in pain intensity and the
responder rate were signicantly higher in the P/TMP-
treated group, compared to the placebo-treated group.
Further, the treatment effect persisted up to the 7th day
in a higher percentage of patients treated with P/TMP
than in those treated with placebo. The frequency and
severity of adverse events did not differ between the two
treatment groups, and no adverse events were considered
sufficiently serious to stop treatment. Finally, according
to a preliminary report, 72 patients with D-IBS, based on
the ROME Ⅲ criteria, were involved in a double-blind,
placebo-controlled trial and were treated with placebo or
phloroglucinol (80 mg) three times daily for 14 d after a
1-wk run-in period[99]. Signicantly more patients report-
ed “moderate or more improvement” in Subjects Global
Assessment in the phloroglucinol group than in the pla-
cebo group over the 2-wk period of treatment and the
1-wk post-treatment period. Stool frequency decreased
significantly in the phloroglucinol group, compared to
the placebo group. Individual symptom scores and stool
P- Reviewers Bener A S- Editor Wen LL L- Editor Cant MR E- Editor Ma S
P- Reviewers Bener A S- Editor Song XX L- Editor Stewart GJ E- Editor Ma S
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. Antispasmodics in irritable bowel syndrome
consistency also improved signicantly, but they did not
differ from those of the placebo group. Regarding its
safety, a French epidemiologic study of phloroglucinol in
pregnancy did not nd evidence of a teratogenic risk in
humans[100].
FUTURE PERSPECTIVES: T-TYPE
CALCIUM CHANNELS
The low-voltage-activated or T-type Ca2+ channels (T-
channels) are a subclass of voltage-gated Ca2+ channels
named after their characteristic of being activated by
small depolarizations of the plasma membrane[101,102].
They can also generate neuronal spontaneous ring and
pacemaker activities, and they generally control excitabil-
ity[101,102]. In mammals, T-channels are encoded by three
pore-forming calcium-channel α1 subunit genes: CaV3.1,
CaV3.2 and CaV3.3. The CaV3.2 subtype is expressed
in the cell bodies and nerve endings of somatic afferent
bers, where it plays a role in regulating neuronal excit-
ability and modifying pain perception[103,104]. Knockout of
the CaV3.2 gene results in decreased mechanical, thermal
and chemical sensitivity in mice, compared to their wild-
type littermates[105], whereas systemic injections of mibe-
fradil, a T-channel antagonist, induces mechanical and
thermal antinociception in rats without affecting their
sensorimotor abilities[106]. Interestingly, ethosuximide, an
anti-epileptic and relatively selective T-channel blocker,
elicits near-complete reversal of mechanical allodynia/hy-
peralgesia in a rat model of painful peripheral neuropathy
induced by the chemotherapeutic agent paclitaxel, where-
as opiates and the NMDA receptor antagonist MK-801
are only slightly or not effective in this model[107]. Despite
the importance of T-channels in somatic pain percep-
tion, their roles in visceral perception and gastrointestinal
pathologies have not been well established. Recently,
an interesting study demonstrated the possible role of
T-channels in the pathophysiology of IBS[108]. IBS was
modeled in rats using intracolonic sodium butyrate injec-
tions, a method that induces colonic hypersensitivity by
reproducing the elevated colonic butyrate concentrations
found in a subset of IBS patients resulting from butyro-
genic enteric ora[109]. CaV3.2 knockdown treatment pre-
vented butyrate-induced hypersensitivity without modi-
fying colonic sensitivity in control rats, suggesting that
CaV3.2 channels do not significantly participate in co-
lonic sensitivity under healthy conditions[108]. Further, the
T-channel blocker mibefradil reversed butyrate-mediated
colonic hypersensitivity by both intrathecal and topical
routes. Similarly, intraperitoneal administration of other
T-channel antagonists, ethosuximide and NP078585,
produced robust antihyperalgesic effects[108]. T-channels
were up-regulated in the dorsal root ganglions (DRGs)
of butyrate-treated animals, and neuronal T-type current
density was also increased, emphasizing the participation
of T-channels in the mechanism of colonic hypersensitiv-
ity[108]. Based on these results, the antinociceptive effects
of TTA-A2, a state-dependent CaV3 blocker, were tested
recently in vitro in cell cultures and in mice DRGs, show-
ing that TTA-A2 potently inhibited recombinant and
native T-currents in sensory neurons expressing CaV3.2-
like T-type channels, consequently decreasing their excit-
ability[110]. Moreover, in the previously described rat IBS
model, systemic administration of TTA-A2 robustly
abolished butyrate-induced hypersensitivity and induced
a statistically significant dose-dependent antihyperalge-
sic effect[110]. These results demonstrate that T-channel
blockers are promising candidates for further research
into novel analgesics that could be potentially useful for
treating the characteristic symptoms of IBS, such as vis-
ceral pain and discomfort.
CONCLUSION
In conclusion, antispasmodics without cardiovascular ac-
tions, such as alverine citrate, mebeverine, otilonium bro-
mide, pinaverium bromide and phloroglucinol, are widely
used in therapy for IBS. Their effects are mostly based on
their spasmolytic properties via the inhibition of calcium
inux into smooth muscle cells. Further, otilonium could
have direct inhibitory effects on primary sensory affer-
ents, thus reducing hypersensitivity, which is a common
feature in IBS. Otilonium and pinaverium are quaternary
ammonium derivatives that are poorly absorbed from
the GI tract, therefore mainly acting locally. Clinical trials
with antispasmodics in IBS have sometimes been contro-
versial, which can be explained by the marked placebo ef-
fect in many cases. Nevertheless, the overall results have
generally been positive, showing that antispasmodics
are able to regulate GI motility disturbances, defecation
alterations and abdominal pain/discomfort, with excel-
lent safety proles. A new generation of calcium-channel
blockers acting on T-type calcium channels could rep-
resent a novel therapeutic pathway in the future for the
management of IBS.
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