Cisapride for Intestinal Constipation (Review)

Aboumarzouk OM, Agarwal T, Antakia R, Shariff U, Nelson RL

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 1
http://www.thecochranelibrary.com

Cisapride for Intestinal Constipation (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS

HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 14. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 15. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 16. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 17. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Analysis 1.1. Comparison 1 Primary Outcome, Outcome 1 Global Improvement of symptoms. . . . . . . . . 33
Analysis 1.2. Comparison 1 Primary Outcome, Outcome 2 Global Improvement of symptoms. . . . . . . . . 34
Analysis 2.1. Comparison 2 Secondary Outcomes, Outcome 1 Abdominal Pain: Visual Analogue Scale. . . . . . 34
Analysis 2.2. Comparison 2 Secondary Outcomes, Outcome 2 Stool Freqeuncy: Number of Stools passed per week. . 35
Analysis 2.3. Comparison 2 Secondary Outcomes, Outcome 3 Stool Frequency: Visual Analogue scale. . . . . . 36
Analysis 2.4. Comparison 2 Secondary Outcomes, Outcome 4 Stool Frequency: Passage of daily stools. . . . . . 36
Analysis 2.5. Comparison 2 Secondary Outcomes, Outcome 5 Stool Consistency: Visual Analogue Scale. . . . . 37
Analysis 2.6. Comparison 2 Secondary Outcomes, Outcome 6 Stool Consistency: Passage of normal stools. . . . . 37
Analysis 2.7. Comparison 2 Secondary Outcomes, Outcome 7 Bloating: Visual Analogue Scale. . . . . . . . . 38
Analysis 2.8. Comparison 2 Secondary Outcomes, Outcome 8 Bloating: Patients with persistent bloating. . . . . 38
Analysis 2.9. Comparison 2 Secondary Outcomes, Outcome 9 Feeling of incomplete evacuation: Visual Analogue Scale. 39
Analysis 2.10. Comparison 2 Secondary Outcomes, Outcome 10 Total Gastrointestinal Transit time. . . . . . . 39
Analysis 2.11. Comparison 2 Secondary Outcomes, Outcome 11 Difficulty of stool passage: Visual Analogue Scale. . 40
Analysis 3.1. Comparison 3 Side effects, Outcome 1 Side effects. . . . . . . . . . . . . . . . . . . 41
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Cisapride for Intestinal Constipation (Review) i
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INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Cisapride for Intestinal Constipation (Review) ii

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Cisapride for Intestinal Constipation

Omar M Aboumarzouk1 , Trisha Agarwal2 , Ramez Antakia3 , Umar Shariff4 , Richard L Nelson5
1 Urology Department, Cym Taf NHS Trust, Merthyr Tydfil, UK. 2Northern General Hospital, Sheffield, Northhampton, UK. 3General

& Colorectal Surgery, Doctors Accomodation, Block A, Sheffield Teaching Hospitals NHS Foundation Trust, South Yorkshire, UK.
4
General and Colorectal Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. 5 Department of General Surgery,
Northern General Hospital, Sheffield, UK

Contact address: Omar M Aboumarzouk, Urology Department, Cym Taf NHS Trust, Merthyr Tydfil, Wales, UK.
aboumarzouk@gmail.com. drbigo31262@gmail.com.

Editorial group: Cochrane Colorectal Cancer Group.

Publication status and date: New, published in Issue 1, 2011.
Review content assessed as up-to-date: 4 September 2010.

Citation: Aboumarzouk OM, Agarwal T, Antakia R, Shariff U, Nelson RL. Cisapride for Intestinal Constipation. Cochrane Database
of Systematic Reviews 2011, Issue 1. Art. No.: CD007780. DOI: 10.1002/14651858.CD007780.pub2.

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Cisapride is a propulsive agent, withdrawn from most of the world’s health institutes because of its recorded fatalities in addition to
serious side effects such as severe arrhythmias. However it is widely available in third world countries and can be easily purchased
through the Internet. We did a systematic review to assess its efficacy and safety in relieving constipation.
Objectives
The primary objective is to assess Cisapride’s role and safety as a prokinetic drug in the management of constipation and constipation
predominant Irritable bowel syndrome (C-IBS).
The secondary objective is to assess Cisapride’s efficacy in improving symptoms of constipation and IBS.
Search methods
Cochrane methodology was followed to find available RCTs that assessed the efficacy of cisapride.
Electronic databases searched November 2009:
Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library 2009 issue 4
MEDLINE (from 1966)
EMBASE (from 1980)
Selection criteria
All RCTs comparing cisapride to placebo or to active comparators were included. We included patients of all ages who had functional
constipation or C-IBS.
Data collection and analysis
Eight RCTs were included, comparing cisapride to a placebo on patients with constipation or C-IBS. The studies were pooled and
analysed and a combined effect was calculated using meta-analysis.
Cisapride for Intestinal Constipation (Review) 1
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Main results

8 trials included in the review for a total 424 patients who were randomised to Cisapride or placebo, of which 157 were children and
284 were female. Intervention duration was 8 to 12 weeks. Dosage of Cisapride in the adult and children trials were 5mg TDS and
0.2mg/kg/dose TDS respectively.

Cisapride showed significant benefit in investigators’ assessment of clinical improvement (OR: 0.45, P=0.03), likelihood of passing
daily stools (OR: 0.22, P<0.001), passage of normal stools (OR: 0.06, P<0.001) and total gastrointestinal transit time (MD: -19.47,
P<0.00001). However Cisapride showed no benefit in global improvement of symptoms (MD: 0.11, P=0.99), abdominal pain (MD:
1.94, P=0.56), stool frequency: weekly (MD: 3.36, P=0.11), visual analogue scale (MD: -0.23, P=0.66), stool consistency (MD: 0.32,
P=0.50), bloating (MD: 3.93, P=0.44), persistent bloating(OR: 1.11, P=0.83), ‘feeling of incomplete evacuation’ (MD: -3.80, P=0.08),
straining (MD -0.95, p=0.19).

Authors’ conclusions

No clear benefit can be demonstrated with cisapride. We do not feel that cisapride can be justifiably used for chronic constipation or
irritable bowel disease given its side effects of arrhythmia and associated 175 recorded deaths.

PLAIN LANGUAGE SUMMARY

No clear evidence that Cisapride relieves symptoms related to constipation or irritable bowel disease.

Cisapride has been used as a prokinetic to treat constipation, but was found to have some serious side effects and was directly associated
with fatalities from those side effects. Though it has been removed from the market and has not been used in most of the world’s
health institutes, it can still be prescribed in certain situations and is easily purchased through dealers on the Internet. We conducted a
systematic review to assess whether or not cisapride actually relieves constipation and controls the symptoms of irritable bowel disease,
in addition to looking at whether or not these effects are worth its use compared to the risk of cisapride’s dangerous side effects. Through
a detailed look at the literature, we found no clear evidence to suggest that cisapride has a role in controlling symptoms related to
constipation or IBS and believe its not worth the risk of its possibly fatal arrhythmia side effects.

BACKGROUND
Description of the condition
Constipation is a worldwide common ailment that can affect both
the healthy individuals as well as those with various predisposing
illnesses. It affects all age groups with a prevalence within the
general population as high as 17.1% in Europe, 15.3% in Oceania,
and a range between 1.9-27.2% in North America leaving many
patients seeking medical and non medical methods to treat the
condition (Peppas 2008; Higgins 2004). With an estimate of 5-
30% of children diagnosed with constipation and nearly a third
developing chronicity (NICE 2010).
It is estimated that around 2.5 million physician visits per year are
due to constipation (Sonnenberg 1989). Constipation can have a
large economical burden with a total health care cost of $2752 per
patient treated in the United States (Peppas 2008). In addition to
having a negative effect on the quality of life and health which
Cisapride for Intestinal Constipation (Review)
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can lead to loss of work and productivity, constipation may also
correlate with psychological and psychiatric symptoms (Dennison
2005; Donald 1985).
There has been an array of different definitions of constipation,
which generally surround the same symptoms of hard dry stool,
which is difficult to pass, a feeling of being bloated, painful bowel
movements, and a reduced frequency of bowel motion. General
Practitioners or Family Physicians tend to focus on the infrequence
of bowel movements while patients focus on different complaints
such as a sense of fullness or incomplete evacuation, hard stools,
and straining while defecating (Altabas 2003; Sandler 1987). Al-
though the symptoms in children are comparable to adults, chil-
dren complain less, however symptoms include Painful defeca-
tion, infrequent bowel activity, foul smelling wind and stools, ex-
cessive flatulence, irregular stool texture, passing occasional enor-
mous stools or frequent small pellets, withholding or straining to
stop passage of stools, soiling or overflow, abdominal pain, disten-
2
sion or discomfort, poor appetite, lack of energy, unhappy, angry
or irritable mood and general malaise (NICE 2010).
The first reported set of criteria to aid the diagnosis of consti-
pation was in 1978, to differentiate between constipation due to
structural disorders of the gut and functional disorders (Manning
1978). In 1991 in an international consensus, the Rome I Criteria
was produced to develop criterion for all gastrointestinal disorders
(Banerjee 2005). It has been recently further developed to a more
elaborate framework for establishing a diagnosis of constipation,
the Rome III criteria is now becoming a more widely accepted and
useful tool (Drossman 2006; Longstreth 2006). Specifically, cate-
gory C of the Rome III Criteria is described for functional bowel
disorders including constipation which presumes the absence of a
structural or biochemical explanation (Drossman 2006).
Rome III criteria for functional constipation, which must be ful-
filled for the last 3 months with symptom onset at least 6 months
prior to diagnosis (RomeIII 2006):
The presence of 2 or more of the following:
· Straining during at least 25% of defecations
· Lumpy or hard stools at least 25% of defecations
· Sensation of incomplete evacuation at least 25% of defecations
· Sensation of anorectal obstruction/blockage at least 25% of
defecations
· Manual maneuvers to facilitate at least 25% of defecations
(e.g., digital evacuation, support of the pelvic floor)
· Fewer than three defecations per week
Loose stools rarely present without the use of laxatives
Insufficient criteria of Irritable Bowel Syndrome
Stool consistency is determined by colonic transit and the absorp-
tion of water from the contents in the colon. The frequency of
defecation is dependent on rectal filling, rectal sensation, sociali-
sation and motivational behaviours (Azpiroz 2002).
While NICE has laid out a complete guidance to diagnosing and
managing children afflicted with idiopathic constipation (NICE
2010). A step laddered approach first leading to the diagnosis of
constipation (2 or more findings from Table 1), then by method of
exclusion of underlying causes (Table 2 and Table 3) the diagnosis
of idiopathic constipation is reached.
Though the pathophysiology behind functional constipation still
remains unclear and there has been no single cause found for func-
tional bowel disorders, recent studies have found a role in the al-
terations of serotonin (5-HT) signalling in gastrointestinal disor-
ders (Crowell 2004). Enterochromaffin cells synthesize and store
the majority of 5-HT, while EC and 5-HT receptors are found
throughout the gastrointestinal tract (Gershon 1999). A study by
Miwa et al found that patients who had constipation predomi-
nantly irritable bowel syndrome (IBS) had a significantly higher
mucosal 5-HT concentration than patients with diarrhoea pre-
dominantly IBS and normal controls (Miwa 2001). Furthermore,
many intestinal and extra-intestinal disorders with an abnormal
5-HT are reported as comorbid conditions in patients with func-
tional bowel disorders (Crowell 2004).
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The 5-HT receptors help mediate reflexes controlling GI motil-
ity and secretion as well as playing a direct role in modulating
motility and transit (Crowell 2004; Tally 1992). Stimulation of
EC cells induce the release of 5-HT within the mucosal crypts
and initiates the peristaltic reflex which is largely responsible for
bolus movement from proximal parts of the gastrointestinal tract
to distal parts (Crowell 2004).
Studies have therefore been conducted on 5-HT receptor ago-
nists and antagonists to evaluate their roles in gastrointestinal
transit times. These studies suggest that 5-HT receptor antago-
nists slow intestinal transit while 5-HT receptor agonists accel-
erate gastrointestinal transit times (Crowell 2004). To this end,
prokinetic agents, which are substances that stimulate gastroin-
testinal motor activity, have been used in the management of pa-
tients with gastrointestinal hypomotility and slow/prolonged tran-
sit times (Georgiadis 2000).
Prokinetics are classified into three categories according to their
mechanism of action:
1. Agents that increase the release of stimulating neurotrans-
mitters, e.g. 5-HT receptor agonists.
2. Agents that inhibit the action of inhibitory neurotransmitters,
e.g. opioid antagonists and antidopaminergic agents.
3. Agents that act as agonists on gastrointestinal hormone
receptors, e.g. motilin receptor agonists and somatostatin agonists.
Description of the intervention
Cisapride (Prepulsid), (Online Websites I), has been widely used
for constipation in patients of all ages, even in 1999 the European
Society of Paediatric Gastroenterology, Hepatology, and Nutrition
recommended that Cisapride be used as a first line drug and that
the potential benefits far outweigh the potential risks (Vandenplas
1999).
However in 2000, Cisapride was removed from the UK and USA
markets due to severe adverse events (Breckenridge 2000; Henney
2000; FDA 2000). Through prolonged blockage of the hERG
channel, which is the main channel responsible for the repolariza-
tion phase of cardiac action potentials, Cisapride prolongs the QT
intervals on ECGs and can lead to potentially fatal arrhythmias
such as Tosades de Pointes (Toga 2007). The results of a paper by
Hennessy et al, revealed that Cisapride is associated with a double
to a triple increase risk of hospitalisation for ventricular arrhyth-
mias and sudden cardiac death and a nearly eight fold increased risk
in the initial prescription period (first month) (Hennessy 2008).
Since its regular use in 1993, there have been 175 reported deaths
from cardiac arrhythmias or sudden deaths directly due to Cis-
apride; in addition, there have also been 386 reported cases of se-
rious ventricular arrhythmias (Augood 2008).
However, patients can still get Cisapride on an investigational lim-
ited access programme directly from the pharmaceutical company,
but must meet specific criteria (Lal 2002):
1. patients must have failed all standard therapeutic modalities
3
2. undergo appropriate diagnostic evaluation, including radio-
logic examination or endoscopy
3. baseline screening tests must be performed to screen for
contraindicated risk factors
4. the patient must be under the care of a gastroenterologist by
consultation, if the prescribing physician is not a gastroenterologist
5. institutional review board approval, completion of a Form
FDA 1572, and signed informed consent are necessary
How the intervention might work
A unique prokinetic which can be administered to hypomotility
disorders in the upper and lower gastrointestinal tract with equally
good results is Cisapride. It was first introduced in 1993 and used
principally because of its lack of antidopaminergic or choliner-
gic side effects, which has limited the use of other prokinetics
(Georgiadis 2000). Cisapride is a substituted piperidinyl benza-
mide and exerts its actions as a 5-HT receptor agonist, through
which, stimulating the release of acetylcholine from the postsynap-
tic nerve endings of the myenteric plexus (Georgiadis 2000). Due
to its actions on these receptors its affects can be demonstrated
throughout the whole gastrointestinal tract as 5-HT receptors are
widely spread throughout the gastrointestinal tract (Georgiadis
2000). Cisapride has been used in management of patients with
gastro oesophageal reflux disease, gastroparesis, IBS, chronic and
acute pseudo obstruction, and chronic idiopathic constipation.
In functional constipation and constipation predominately IBS,
Cisapride has shown that it considerably reduces the transit times
both in the small and large bowel in healthy adults as well as
patients with motility disorders (Georgiadis 2000). Studies have
also shown that transit times have been considerably reduced in the
caecum and ascending colon in patients with chronic idiopathic
constipation with the use of Cisapride (Robertson 1993).
Why it is important to do this review
There are numerous online pharmaceutical web sites that sell and
distribute Cisapride with no predefined criteria (Online Websites
II). The only requirement is to have a postal address and a valid
credit card (Online Websites II). Unlike the doctor prescribed
medication, these web sites do not warn of all the side effects
of Cisapride, which was the reason for its removal in the first
place (Henney 2000). Patients world wide can access these sites
and order the medication without any medical advice. With the
increasing use of the Internet, more and more patients can find
out in detail about constipation and its management modalities.
With these online stores, that are normally not regulated and are
border less, Cisapride can be distributed anywhere in the world
and guarantee Cisapride’s delivery directly to the customer’s door
(Online Websites II). One web site goes as far as to guarantee
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delivery and gives a notice that if the drug is seized by customs
that they will reship a new order (Online Websites II).
In addition, cisapride is also freely available in countries that do not
have strict regulations on pharmaceutical companies (Ambanatu
2007). In India there were 7 separate pharmaceutical companies
that sold Cisapride (Ambanatu 2007), while its freely sold in other
third world countries in Africa, the MiddleEast, and Asia (Online
Websites II; Ambanatu 2007). While restriction have been placed
on its use in France and Germany in which patients should have
failed in all the standard therapeutic modalities and have under-
gone an appropriate diagnostic evaluation before cisapride can be
prescribed (Ambanatu 2007).
To this end, an assessment of its efficacy must be made to provide
patients as well as clinicians, with a basis to weigh whether or not
its benefits outweigh its risks.
OBJECTIVES
The primary objective is to assess and evaluate the efficacy and
safety of Cisapride as a prokinetic drug in the management of
functional constipation and C-IBS.
The secondary objective is to assess and evaluate Cisapride’s ef-
ficacy in improvement of abdominal pain, distension, stool fre-
quency, bloating, ’sense of incomplete evacuation’, difficultly of
passing stools/straining and bowel transit time.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised controlled trials comparing Cisapride to placebo or
active comparators for treatment of constipation were considered
for inclusion.
Types of participants
Participants are patients (Children and Adults) with functional
constipation or constipation predominant IBS.
Patients with constipation due to secondary causes (e.g. mechani-
cal obstruction, endocrine/ metabolic disorders, neurological con-
ditions, musculo-skeletal disorder, psychological conditions, preg-
nancy, pharmacological agents) were excluded.
4
Types of interventions
Patients received Cisapride were compared to others receiving a
placebo, other medical therapies (laxatives), diet modification (fi-
bre), psychosocial intervention, any combination of therapies, or
untreated control groups.
Types of outcome measures
Primary outcomes
The primary outcome is global improvement of symptoms and
improvement of overall complaints caused by constipation.
Secondary outcomes
Secondary outcomes are improvement in abdominal pain, disten-
sion, stool frequency, and bowel transit time
Search methods for identification of studies
Electronic searches
We searched the following electronic databases November 2009:
Cochrane Central Register of Controlled Trials (CENTRAL) on
The Cochrane Library 2009 issue 4, MEDLINE (1966- present),
EMBASE (1980 - present), the Internet (Google Scholar) and the
Group Specialised Register.
The following search strategy were used to identify relevant ran-
domised trials:
#1 constipation OR chronic constipation OR colonic inertia OR
gastrointestinal motility OR colonic motility OR intestinal dys-
motility OR functional colonic diseases
#2 Cisapride OR Prepulsid Or Propulsid
#3 Randomized Control Trials
#3 #1 AND #2
#4 #1 AND #2 AND #3
Searching other resources
Referencing searching:
The references of all identified studies were inspected for more
trials.
Data collection and analysis
Selection of studies
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Two authors (OMA and RLN) independently assessed relevant
abstracts and titles identified by literature search against the pre-
defined inclusion criteria. Any disagreement among the authors
was resolved by consensus.
Data extraction and management
Four authors (OMA, US, RA, and TA) independently extracted
data from the included studies using a predetermined data extrac-
tion form. Any disagreements were resolved by consensus or by
consultation with a third party (RLN). We tried contacting the
authors of the primary studies for clarification of data and addi-
tional information.
Assessment of risk of bias in included studies
The Five authors (OMA, US, RA, TA and RLN) assessed the risk
of bias as described in the Cochrane Handbook for Systematic
Reviews of Interventions.
The following factors were examined:
1) Sequence generation (i.e. was the allocation sequence ade-
quately generated?);
2) Allocation sequence concealment (i.e. was allocation adequately
concealed?);
3) Blinding (i.e. was knowledge of the allocated intervention ad-
equately prevented during the study?);
4) Incomplete outcome data (i.e. were incomplete outcome data
adequately addressed?);
5) Selective outcome reporting (i.e. are reports of the study free of
suggestion of selective outcome reporting?); and
6) Other potential sources of bias (i.e. was the study apparently
free of other problems that could put it at a high risk of bias?).
A judgement of ’Yes’ indicates low risk of bias, ’No’ indicates high
risk of bias, and ’Unclear’ indicates unclear or unknown risk of
bias.
Measures of treatment effect
Review Manager Analyses (RevMan 5.0.15) was used to analyse
data. Analyses were performed using the intention to treat princi-
ple. Data from individual trials were combined for meta-analysis
when the interventions and controls are similar. Dichotomous
data were calculated as Odds ration (OR) with 95% confidence
intervals (95% CI). The weighed mean difference (WMD) with
95% CI was calculated for continuous outcomes.
Unit of analysis issues
In addition to simple parallel group designs, variations such as
cluster-randomisation and cross-over trials were analysed.
5
Dealing with missing data
The authors/researchers of papers with Missing data (studies, out-
comes, summary data, individuals, or study level characteristics)
were contacted for request of the missing data.
If request for missing data failed, the potential impact of missing
data on the findings of the review are addressed in the discussion
section.
Assessment of heterogeneity
A fixed effects model was used unless statistically significant het-
erogeneity was identified between the studies. A random effects
model was applied upon significant heterogeneity. A chi-square
test was used to assess heterogeneity (a P value of 0.10 will be
regarded as statistically significant). Upon statistically significant
heterogeneity, the included studies were examined for sources of
both clinical and methodological heterogeneity.
Assessment of reporting biases
The possibility of a publication bias was investigated through the
construction of funnel plots (trial effects versus trial size).
Data synthesis
A fixed effects model was used unless statistically significant het-
erogeneity exists between the studies. A random effects model was
employed if heterogeneity exists.
Subgroup analysis and investigation of heterogeneity
We investigated the following potential sources of heterogeneity
using sub-group analyses or meta-regression:
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1. Intervention - different types/ class of antibiotic agent and dif-
ferent control;
2. Different dosages of antibiotic agent;
3. Different duration of treatment;
4. Different length of follow-up period.
Sensitivity analysis
Sensitivity analyses were conducted based on the following:
a. only including patients whose outcome is known (i.e. number
of patients who completed the study used as denominator);
b. random effects versus fixed effects models; and
c. study quality.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Results of the search
The article selection process is displayed in Figure 1. A total of
478 articles were found in the literature search. Of these articles
447, were excluded through screening of the Titles and/or Ab-
stracts which did not meet the inclusion criteria. Thirty one ar-
ticles’ manuscripts were reviewed of which 8 were included (see
table of characteristics of Included Studies) and 23 were excluded
(see table of characteristics of Excluded Studies).
6
 Figure 1.

Cisapride for Intestinal Constipation (Review) 7

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Included studies
Eight randomised control trials met the inclusion criteria (see ta-
ble of characteristics of Included Studies). All of the randomised
control trials compared the effects of cisapride to placebo in pa-
tients with chronic constipation (Farup 1998; Halabi 1999; Odeka
1997a; Nurko 2000; Staiano 1991; Van Outryve 1991; Verheyen
1987; Ziegenhagen 2004) The trials excluded with underlying
pathological causes of constipation.
Four studies were carried out in adults, with three of them inves-
tigating 18-75 years old adults (Farup 1998; Van Outryve 1991;
Ziegenhagen 2004) and one study including patients ranging up
to 90 years old (Verheyen 1987). Four trials studied children
(Halabi 1999; Odeka 1997a; Nurko 2000; Staiano 1991) with the
youngest included child being 1.5 years (Staiano 1991). The adult
trials tended to have a predominance of women, approximately 4:
1 whereas the trials in children were more gender matched.
In three of the adult trials the dosage of cisapride used was 5mg
TDS which was increased after 4 weeks if there was no improve-
ment to 10mg TDS (Farup 1998; Van Outryve 1991; Ziegenhagen
2004). The fourth trial compared both 5mg TDS and 10mg
TDS dosages to placebo (Verheyen 1987). The Children trials
used slightly different doses, 0.2mg/kg/dose TDS (Staiano 1991;
Odeka 1997a), 0.3mg/kg/dose QDS (Halabi 1999) and 0.2mg/
kg/dose increased to 0.3mg/kg/dose TDS if no improvement af-
ter 8 weeks (Nurko 2000). The intervention was carried out and
assessed after 12 weeks in all trials except for one (Halabi 1999)
where the trial ended after 8 weeks.
Figure 2. Methodological quality graph: review authors’ judgements about each methodological quality
item presented as percentages across all included studies.
Cisapride for Intestinal Constipation (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Excluded studies
Twenty four manuscripts were excluded from the final analysis (see
table of characteristics of Excluded Studies). Nine were found not
to be randomised control trials (Benini 1991; Bhatnagar 2000;
Cucchiara 1996; Loening-Baucke 1996; Müller-Lissner 1986;
Nurko 1996; Odeka 1997; Puntis 2000; Zou 1998) Four studies
included patients with underlying pathological disorders (Geders
1995; Hernandez 1988; Jost 1994; Staiano 1996). Four studies
looked at patients that did not fit the inclusion criteria of consti-
pation predominant IBS (Evans 1997; Lu 2003; Müller-Lissner
1987; Veysey 2001). Three of the trials did not compare cisapride
with placebo (Altabas 2003; Ni 2001; Lu 2003). Krevsky 1989 did
not examine any of the parameters of the primary and secondary
outcomes and Müller-Lissner 1995 only looked at the effect of ta-
pering and withdrawal effects of cisapride. Unfortunately Odeka
1997 only reported results on the graphs leaving gaps in the data.
The author was contacted but this proved unsuccessful and hence
the study was excluded. Schütze 1997 was initially included but
when analysing his data it was found that there were no reported
standard deviations. Several attempts were made to contact the
authors but were unsuccessful and the study was eventually ex-
cluded.
Risk of bias in included studies
See ’Characteristics of included studies’; Figure 2; Figure 3.
8
 Figure 3. Methodological quality summary: review authors’ judgements about each methodological quality
item for each included study.

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Allocation
The methods for allocation concealment and sequence generation
is unclear in all eight trials.
Blinding
All eight studies have described themselves as double-blinded tri-
als.
Incomplete outcome data
All the eight trials had clearly reported element of drop out rates
and whether these were included or excluded from the final data
analysis. Drop out rates were reasonably low ranging from 1 to
2 (Nurko 2000; Verheyen 1987) to a maximum of 19% (Odeka
1997a). In most cases patient withdrawal was due to loss of fol-
low up. When patients withdrew to side effects or insufficient re-
sponse, they tended to be matched in both cisapride and placebo
intervention groups (Farup 1998; Ziegenhagen 2004). Only three
trials included the candidates who dropped out in their final data
analysis (Verheyen 1987;Odeka 1997a; Ziegenhagen 2004), this
did not affect their final outcomes.
Selective reporting
There were no selective reporting in any of the eight trials, how-
ever, we believe that the variation of the assessments between the
Figure 4. Forest plot of comparison: 1 Primary Outcome, outcome: 1.1 Global Improvement of symptoms.
Three trials looked at the investigator assessment of clinical im-
provement (Nurko 2000; Van Outryve 1991; Verheyen 1987),
(Figure 5), with the outcome defined as those who did not im-
prove clinically. Since there was no significant heterogeneity be-
tween the trials (p=0.50), a fixed effects model was used There
was a significant trend to favour cisapride, with the odds of no
clinical improvement only half as large in cisapride patients than
in control patients (Odds ratio 0.45, 95% CI 0.22 to 0.91, p=
0.03).
Cisapride for Intestinal Constipation (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
studies, and the exclusion of other vital assessment parameters,
such as gastrointestinal transit times, might pose a potential risk
of selective reporting.
Other potential sources of bias
The unclarity of the sequence generation and the allocation con-
cealment can be a source of bias which can affect the final results.
Effects of interventions
The included studies have used different outcome measures to
assess their primary and secondary outcomes. The outcomes were
group and analysed accordingly.
Primary Outcome: Global Improvement of Symptoms
Two trials assessed Global improvement of symptoms using the
visual analogue scale (VAS), allowing combined analysis of the
mean difference between improvements seen with cisapride com-
pared to the control (Farup 1998, Ziegenhagen 2004) (Figure 4).
There was significant heterogeneity to the studies (P<0.001) and
hence a random effects model was used. This heterogeneity may
be partly explained by the fact that Ziegenhagen 2004 reported
his outcomes on an ‘intention to treat’ basis. Otherwise the studies
have a similar baseline population group. The analysis indicated
no evidence of a significant effect of cisapride compared to control
(Mean difference -0.11, 95% CI -12.07 to 11.85, p=0.99).
10
 Figure 5. Forest plot of comparison: 1 Primary Outcome, outcome: 1.2 Global Improvement of symptoms.

Secondary outcomes
Abdominal Pain
Three trials compared the VAS of abdominal pain and these
were used in a pooled analysis (Farup 1998; Van Outryve 1991;
Ziegenhagen 2004), (Figure 6). There was significant heterogene-
ity between the studies (P<0.001) and therefore a random effects
model was used. There was no significant difference between the
cisapride and control groups with regard to abdominal pain (Mean
Difference -1.94, 95% CI -8.50 to 4.62, P=0.56).

Figure 6. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.1 Abdominal Pain: Visual
Analogue Scale.

Stool Frequency
Four studies conducted in children reported their stool frequency
in terms of number stools passed per week (Halabi 1999; Nurko
2000; Odeka 1997; Staiano 1991) (Figure 7). There was signifi-
cant heterogeneity between the studies (P<0.001) and therefore a
random effects model was used. The reason for this heterogeneity
is uncertain since all studies are completed in children with similar
baseline characteristics. A meta-analysis indicated no statistically
significant difference between the two groups (Mean Difference
2.36, 95% CI -0.57 to 5.29, P=0.11).

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 7. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.2 Stool Freqeuncy: Number of
Stools passed per week.

Ziegenhagen 2004 and Farup 1998 looked at changes in stool

frequency with the VAS (Figure 8). The data does not indicate any
trends towards cisapride or the control (Mean difference -0.23,
95% CI -1.23 to 0.77, p=0.66).

Figure 8. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.3 Stool Frequency: Visual
Analogue scale.

Two studies looked at the number of patients who began to pass

daily stools (Van Outryve 1991; Verheyen 1987) (Figure 9). There
was no evidence of heterogeneity between the two studies. A fixed-
effects analysis indicated that the likelihood of passing daily stools
was significantly increased for cisapride patients, with the odds of
passing daily stools only a fifth of those for placebo (Odds Ratio
0.22, 95% CI 0.09 to 0.51, P<0.001).

Figure 9. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.4 Stool Frequency: Passage of
daily stools.

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Stool Consistency
Farup 1998 and Ziegenhagen 2004 examined stool consistency
using a visual analogue scale (Figure 10). There was no significant
heterogeneity between the two studies (p=0.33). A fixed-effects
analysis suggested no evidence of a difference is VAS scores between
the two treatments (Mean difference 0.32, 95% CI -0.61 to 1.26,
P=0.50).

Figure 10. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.5 Stool Consistency: Visual
Analogue Scale.

Only one study (Van Outryve 1991) examined the passage of nor-
mal stools, with the outcome defined as there being no improve-
ment in stool consistency (Figure 11). This study showed a signif-
icant benefit of cisapride relative to the control group. The odds
of no improvement in the cisapride group were less than a tenth
of those in the control group (Odds ratio 0.06, 95% CI 0.02 to
0.25, P<0.001).

Figure 11. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.6 Stool Consistency: Passage of
normal stools.

Bloating
Farup 1998 and Ziegenhagen 2004 examined bloating using vi-
sual analogue scale (Figure 12). There was significant heterogene-
ity between these two studies (p<0.001) and so a random-effects
analysis was performed. This suggested no difference in bloating
between the two groups (Mean difference 3.93, 95% CI -5.96 to
13.83, p=0.44).

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 12. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.7 Bloating: Visual Analogue Scale.

Only Van Outryve 1991 used persistent bloating as an outcome

(Figure 13). The study found no evidence of a difference between
cisapride and placebo in terms of this outcome (Odds ratio 1.11,
95% CI 0.42 to 2.95, p=0.83).

Figure 13. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.8 Bloating: Patients with
persistent bloating.

Feeling of incomplete evacuation

Two studies (Farup 1998; Ziegenhagen 2004) measured improve-
ments in ‘feeling of incomplete evacuation’ on visual analogue scale
(Figure 14). A random-effects analysis indicated a slight sugges-
tion of a benefit if cisapride, although this result was not signifi-
cant at the 5% significance level. Patients on cisapride had scores
that were, on average around 4 units lower than control patients
(mean difference -3.80, 95% CI -8.01 to 0.41, P=0.08).

Figure 14. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.9 Feeling of incomplete
evacuation: Visual Analogue Scale.

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Total Gastrointestinal Transit time
All three randomised control trials in children measured total gas-
trointestinal transit time (TGTT) with cisapride compared to con-
trol (Figure 15). Two studies (Nurko 2000; Staiano 1991) used
radio-opaque markers and measured TGTT as the time for 80%
of markers to be eliminated. Halabi 1999 used carmine as a marker
and measured the time between ingestion and appearance in the
stool. There was no significant heterogeneity between the studies.
A fixed-effects analysis indicate a significantly shorter transit time
with cisapride with patients passing stools 19hrs quicker (mean
difference -19.47, 95% CI -22.04 to -16.89, P<0.00001.)

Figure 15. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.10 Total Gastrointestinal Transit
time.

Difficulty of stool passage (Straining)

Farup 1998 and Ziegenhagen 2004 examined difficulty of stool
passage (straining) using visual analogue scale (Figure 16). A fixed-
effects analysis was performed. This suggested no difference in ’dif-
ficulty of stool passage’ between the two groups ( Mean Difference
-0.95, 95% CI -2.36 to 0.46, P=0.19)

Figure 16. Forest plot of comparison: 2 Secondary Outcomes, outcome: 2.11 Difficulty of stool passage:
Visual Analogue Scale.

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Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Side effects
Five of the eight studies reported side effects due to the medi-
cations given (Ziegenhagen 2004; Van Outryve 1991; Verheyen
1987; Halabi 1999; Nurko 2000). There was no significant het-
erogeneity between the studies, therefore a fixed-effect analysis was
performed (Figure 17). There was no significant difference be-
tween the cisapride and control groups (Odds Ratio 0.93, 95%
CI 0.36 to 2.35, P=0.87).
Figure 17. Forest plot of comparison: 3 Side effects, outcome: 3.1 Side effects.
DISCUSSION
We have found that there is no clear significant effect of cisapride
to control constipation or IBS symptoms compared to a placebo
in adults and children. Though there were some significant im-
provements from the investigators’ assessments (P=0.03) favour-
ing cisapride, in addition cisapride having a far less gastric empty-
ing times than the placebo (P<0.00001), cisapride did not show a
significant difference in controlling or improving the global symp-
toms or each individual symptoms.
The final analysis reveals that there was no significant improvement
of the global overall symptoms of patients on cisapride compared
to those who were taking a placebo (P=0.99), although investigator
assessments did favour the cisapride group to the placebo group
(P=0.03).
The analysis of the secondary outcomes showed that there was no
difference between cisapride and placebo with regards to abdom-
inal pain (P=0.56), stool frequency (P=0.11), stool consistency
(P=0.50), bloating (P=0.44), feeling of incomplete evacuation (P=
0.08), and straining or difficultly of stool passage (P=0.19). While
cisapride had a significantly shorter bowel transit time compared
to a placebo (P<0.00001).
Cisapride for Intestinal Constipation (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Though there was substantial heterogeneity between some of the
studies, a source could not be identified and remains unclear, es-
pecially as there was no clear clinical heterogeneity.
Five studies reported side effects, but there was no significant dif-
ferences between the cisapride and the placebo groups (P=0.87).
In total the cisapride group had 4 patients who developed wors-
ening abdominal pain/cramps while the placebo group had 7, in
addition, 2 patients in the cisapride group developed diarrhoea
and 3 had developed headaches, while 1 patient in the placebo
group developed a headache and none developed diarrhoea. None
of the studies reported any deaths or major side effects, however,
major side effects are usually not detected with small studies.
Cisapride has been pulled from markets around the world due
to its dangerous side effects such as prolonging the QT interval
and causing arrhythmias such as Tosades de Pointes which can be
fatal (Breckenridge 2000; Henney 2000; FDA 2000; Toga 2007).
In fact to date there have been 175 reported deaths due to side
effects of cisapride on the cardiovascular system, in addition to
386 reported cases of serious ventricular arrhythmias associated
with cisapride (Augood 2008; TPJ 2000). Initially the side ef-
fects were attributed to co-administration of other medications
which increased cisapride’s plasma levels by inhibiting its hep-
atic metabolism or to patients with significant risk factors such as
cardio-vascular disease and renal impairment (Georgiadis 2000).
Subsequent studies have found that, actually, the side effects and
16
deaths were directly related to cisapride, in fact it was found that
cisapride was associated with doubling to tripling the risk of hos-
pitalisation for ventricular arrhythmias, and an eightfold risk in
the initial prescription period (Hennessy 2008).
Even though cisapride has been stopped and pulled from most of
the worlds markets, it can still be purchased online and shipped to
your address anywhere in the world, even with free shipping and
handling (Online Websites II). There are approximately 63 million
people in just North America that meet the Rome II criteria for
constipation, with almost 2.5 million physician visits and almost
$2750 spent annually per patient, patients with severe constipation
are desperate to find a treatment or even a pill to alleviate their
symptoms (Sonnenberg 1989; Peppas 2008; Higgins 2004).
For years new methods come out claiming to treat constipation
and old ones die out, in fact in the early 20th century, chronic
constipation was thought to produce toxaemia and was the cause
of many diseases and illnesses (Ellis 2009). Surgeons at the time
would perform total colectomies on patients that had chronic con-
stipation, but was later abandoned for the use of paraffins orally
(Ellis 2009).
Cisapride has been pulled out of the market, however, patients can
still buy it from other sources. This review has found no evidence
to suggest that cisapride has or doesn’t have a role in treating or
alleviating symptoms of chronic constipation or Irritable Bowel
Syndrome. Eventhough the included studies in this review did not
yield any significant side effects, the evidence from other sources
is uncontroversial.
AUTHORS’ CONCLUSIONS
REFERENCES
References to studies included in this review
Farup 1998 {published data only}
Farup PG, Hovdenak N, Wetterhus S, Lange OJ, Hovde
O, Trondstad R. The symptomatic effect of cisapride in
patients with irritable bowel syndrome and constipation..
Scand J Gastroenterol. 1998;33(2):128–31.
Halabi 1999 {published data only}
Halabi IM. Cisapride in management of chronic pediatric
constipation.. J Pediatr Gastroenterol Nutr. 1999;28(2):
199–202.
Nurko 2000 {published data only}
Nurko S, Garcia-Aranda JA, Worona LB, Zlochisty O.
Cisapride for the treatment of constipation in children: A
double-blind study. J Pediatr. 2000;136(1):35–40.
Cisapride for Intestinal Constipation (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Implications for practice
We believe that cisapride lacks enough evidence to suggest it has a
role in the treatment of constipation or alleviating the symptoms of
IBS. This review yielded 8 RCTs, but also significant heterogeneity
was found between many of the sub-analyses, which leaves the
results with uncertainty and should be carefully interpreted.
Implications for research
Though the sample size was small and the negative findings might
signify a low statistical power which might be rectified with a larger
sample size, due to cisapride’s reported fatalities and serious side
effects we do not recommend further trials to be conducted on
this drug. However, potentially a study on cisapride’s side effects
can be conducted on patients who are buying cisapride from other
sources and who refuse to give it up. In addition a more uniformly
reporting of the outcomes will allow studies to be more pooled for
comparison. Also, focus should be more on symptom assessment of
pain and bloating and assessments of gastrointestinal transit times
and stool frequency, as well as global improvement of constipation
symptoms.
Due to lack of evidence, the results are inconclusive and normally
a suggestion of further RCTs for a thorough meta analysis would
be recommended but due to the serious and fatal side effects, it
would be potentially dangerous to conduct further research on
such a drug as cisapride.
ACKNOWLEDGEMENTS
Editorial office (Henning Keinke Andersen) of the Colorectal Can-
cer Group
Odeka 1997 Aug {published data only}
Odeka EB, Miller V. Use of cisapride in treatment of
idiopathic constipation in children.. J Pediatr Gastroenterol
Nutr. 1997;25(2):250.
Staiano 1991 {published data only}
Staiano A, Cucchiara S, Andreotti M, Minella R, Manzi
G. Effect of Cisapride on Chronic Idiopathic Consipation
in Children. Digestive Diseases and Sciences 1991;36(6):
733–736.
Van Outryve 1991 {published data only}
Van Outryve M, Milo R, Toussaint J, Van Eeghem P.
“Prokinetic” treatment of constipation-predominant
irritable bowel syndrome: a placebo-controlled study of
cisapride.. J Clin Gasroenterol 1991;13(1):49–57.
Verheyen 1987 {published data only}
Verheyen K, Vervaeke M, Demyttenaere P, Van Mierlo FJ.
17
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with placebo in the treatment of functional constipation.
A general-practice multicenter study. Current Therapeutic
Research - Clinical and Experimental 1987;41(6):978–85.
Ziegenhagen 2004 {published data only}
Ziegenhagen D, Kruis W. Cisapride treatment of
constipation-predominant irritable bowel syndrome is
not superior to placebo. Journal of Gastroenterology
and Hepatology 2004;19:744–749. [DOI: 10.1111/
j.1400-1746.2004.03384.x]
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Altabas 2003 {published data only}
Altabas K, Bilic A, Jurcic D, Dorosulic Z, et al.The Efficacy
of Cisapride vs. Placebo and Diet in patients with Chronic
Consitpation. Coll Antopol 2003;27(1):197–204.
Benini 1991 {published data only}
Benini I, Caliari S, Bardelli E, Pilati S, Bonfante F, Castellani
G, Sembenini C, Vantini I. Cisapride in severe chronic
constipation: a double blind study. [abstract]. Gut 1991;32
(Suppl. 5):A575.
Bhatnagar 2000 {published data only}
Bhatnagar SK. Cisapride for the treatment of constipation
in children.. Indian Pediatr 2000;37(8):917–8.
Cucchiara 1996 {published data only}
Cucchiara S. Cisapride therapy for gastrointestinal
disease.[see comment]. [Review] [90 refs]. Journal of
Pediatric Gastroenterology & Nutrition 1996;22(3):259–69.
Evans 1997 {published data only}
Evans PR, Bak YT, Kellow JE. Effects of oral cisapride
on small bowel motility in irritable bowel syndrome.
Alimentary Pharmacology & Therapeutics 1997;11(5):
837–44.
Geders 1995 {published data only}
Geders JM, Gaing A, Bauman WA, Korsten MA. The effect
of cisapride on segmental colonic transit time in patients
with spinal cord injury.. Am J Gastroenterol 1995;90(2):
285–9.
Hernandez 1988 {published data only}
Hernandez G, Troncoso G, Palencia C, Maldonado S.
Double-blind dose-response study of cisapride in the
treatment of chronic functional constipation. ADV. THER.
1988;5(5):121–7.
Jost 1994 {published data only}
Jost WH, Schimrigk K. The effect of cisapride on delayed
colonic transit time in patients with idiopathic Parkinson’s
disease.. Wien Klin Wochenschr 1994;106(21):673–6.
Krevsky 1989 {published data only}
Krevsky B, Maurer AH, Malmud LS, Fisher RS. Cisapride
accelerates colonic transit in constipated patients with
colonic inertia.. Am J Gastroenterol. 1989;84(8):882–7.
Liu 2002 {published data only}
Liu RS. Cisapride combined with bisacodyl and doxepin in
treating functional constipation. Chinese Journal of New
Drugs and Clinical Remedies 2002;21(1):26–7.
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Loening-Baucke 1996 {published data only}
Loening-Baucke V. Cisapride for children with intractable
constipation: an interim verdict!. J Pediatr Gastroenterol
Nutr. 1996;22(1):3–5.
Lu 2003 {published data only}
Lu D, Wu, T, Liu Y, Zhuang Z, Chen H, Li W, Wang C,
Chen Y. Clinical efficacy of different drugs on irritable
bowel syndrome. Chinese Journal of Gastroenterology 2003;8
(5):272–5.
Müller-Lissner 1986 {published data only}
Müller-Lissner S. Cisapride in chronic constipation and
laxative abuse [abstract]. Digestion 1986;34(2):158.
Müller-Lissner 1987 {published data only}
Müller-Lissner SA. Treatment of chronic constipation with
cisapride and placebo.. Gut 1987;28(8):1033–8.
Müller-Lissner 1995 {published data only}
Müller-Lissner SA. Cisapride in chronic idiopathic
constipation: can the colon be re-educated? Bavarian
Constipation Study Group.. Eur J Gastroenterol Hepatol.
1995;7(1):69–73.
Ni 2001 {published data only}
Ni YH, Lin CC, Chang SH, Yeung CY, Taiwan Pediatric
Constipation Study Group. Use of cisapride with
magnesium oxide in chronic pediatric constipation.. Acta
Paediatr Taiwan. 2001;42(6):345–9.
Nurko 1996 {published data only}
Nurko S, Garcia-Aranda JA, Guerrero VY, Worona LB.
Treatment of intractable constipation in children: experience
with cisapride. Journal of Pediatric Gastroenterology &
Nutrition 1996;22(1):38–44.
Odeka 1997 {published data only}
Odeka EB, Sagher F, Miller V, Doig C. Use of cisapride
in treatment of constipation in children.. J Pediatr
Gastroenterol Nutr. 1997;25(2):199–203.
Puntis 2000 {published data only}
Puntis J.W. Cisapride was effective in the short term for
constipation in children. Commentary. Evidence-Based
Medicine 2000;5(5):150.
Schütze 1997 {published data only}
Schütze K, Brandstätter G, Dragosics B, Judmaier G,
Hentschel E. Double-blind study of the effect of cisapride
on constipation and abdominal discomfort as components
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1997;11(2):387–94.
Staiano 1996 {published data only}
Staiano A, Del Giudice E, Simeone D, Miele E, Marino A.
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constipation.. Dig Dis Sci 1996;41(5):870–4.
Veysey 2001 {published data only}
Veysey MJ, Malcolm P, Mallet AI, Jenkins PJ, Besser
GM, Murphy GM, Dowling RH. Effects of cisapride
on gall bladder emptying, intestinal transit, and serum
deoxycholate: a prospective, randomised, double blind,
placebo controlled trial.. Gut 2001;49(6):828–34.
18
Zou 1998 {published data only}
Zou DW, Xu GM, Li ZS. Anorectal manometric
abnormalities and effect of cisapride on patients with
chronic idiopathic constipation. Chinese Journal of Digestion
1998;18:268–70.
Additional references
Altabas 2003
Altabas K, Bilic A, Jurcic D, Dorosulic Z, et al.The Efficacy
of Cisapride vs. Placebo and Diet in patients with Chronic
Consitpation. Coll Antopol 2003;27(1):197–204.
Ambanatu 2007
Ambanatu H. J. IS INDIA A DUMP YARD FOR
HAZARDOUS DRUGS? : A COMPARATIVE STUDY
OF REGULATION OF DRUGS IN INDIA AND
OTHER COUNTRIES. Commoncauseindia.org 2007. [:
http://www.commoncauseindia.org/nl/Jan–March–2008/
3.htm]
Augood 2008
Augood C, MacLennan S, Gilbert R, Logane S. Cisapride
treatment for gastro-oesophageal reflux in children.
Cochrane Database of Systematic Reviews 2008, Issue 4.
Azpiroz 2002
Azpiroz F, Enck P, Whitehead W. Anoreactal functional
testing: review of collective experience. Am. J. Gastroenterol
2002;97:232–240.
Banerjee 2005
Banerjee R, Choung O, Gupta R, et al.Rome I criteria are
more sensitive than Rome II for the diagnosis of irritable
bowel syndrome in Indian patients. Asian Institute of
Gastroenterology 2005;24:194–6.
Breckenridge 2000
Breckenridge A. Suspension of Cisapride (Prepulsid)
licences: Product withdrawal. Committee on Safety of
Medicines, London 2000.
Crowell 2004
Crowell M. Review: Role of serotonin in the
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Pharmacology 2004;141:1285–1293.
Dennison 2005
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Donald 1985
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FDA. Letter from FDA on Cisapride. http://
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SafetyAlertsforHumanMedicalProducts/ucm173074.htm.
Georgiadis 2000
Georgiadis G, Markantonis-Kyroudis S, Triantafillidis J.
Review: Prokinetic agents: current aspects with focus on
cisapride. Annals of Gastroenterology 2000;13(4):269–289.
Gershon 1999
Gershon M. Roles played by 5-hydrocytrptamine in the
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Halabi 1999
Halabi IM. Cisapride in management of chronic pediatric
constipation.. J Pediatr Gastroenterol Nutr. 1999;28(2):
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Hennessy 2008
Hennessy S, Leonard C, Newcomb C, Kimmel S, Bilker W.
Cisapride and ventricular arrhythmia. British Journal of
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Henney 2000
Henney J. Withdrawal of troglitazone and Cisapride. JAMA
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Higgins 2004
Higgins PD, Johanson JF. Epidemiology of constipation in
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Lal 2002
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Towards positive diagnosis of irritable bowel. Br Med J
1978;2:653–4.
Miwa 2001
Miwa J, Echizen H, Marsueda K, Umeda N. Paitents with
constipation-predominant irritable bowel syndrome (IBS)
may have elevated serotonin concentrations in colonic
mucosa as compared with diarrhoea-predominant patients
and subjects with normal bowel habits. Digestion 2001;63:
188–194.
Müller-Lissner 1987
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NICE 2010
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diagnosis and management of idiopathic childhood
constipation inprimary and secondary care. National
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Website based. Cisapride. Internet. [: http:/
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Peppas 2008
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Robertson 1993
Robertson C, Evans D, Ledingham S, Atkinson M.
Cisapride in the treatment of gastroesophageal reflux
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RomeIII 2006
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Sandler 1987
Sandler RS, Drossman DA. Bowel habits in young adults
not seeking health care. Dig Dis Sci 1987;32(8):841–5.
Sonnenberg 1989
Sonnenberg A, Koch TR. Physician visits in the United
States for constipation: 1958 to 1986. Dig Dis Sci 1989;34
(4):606–11.
Staiano 1991
Staiano A, Cucchiara S, Andreotti M, Minella R, Manzi
G. Effect of Cisapride on Chronic Idiopathic Consipation
in Children. Digestive Diseases and Sciences 1991;36(6):
733–736.
Tally 1992
Tally N. Review article: 5-hydroxytryptamine agonists and
antagonists in the modulation of gastrointestinal motility
and sensation: clinical implications. Aliment. Pharmacol
1992;6:273–289.
Toga 2007
Toga T, Kohmura Y, Kawatsu R. The 5-HT4 Agonists
Cisapride, Mosapride, and CJ-033466, a Novel Potent
Compound, Exhibit Different Human Ether-a-go-go-
related Gene (hERG)-Blocking Activities. Journal of
Pharmacological Science 2007;105:207–210.
TPJ 2000
TPJhttp://www.pharmj.com/Editorial/20000729/
clinical/cisapride.htmlhttp://www.pharmj.com/Editorial/
20000729/clinical/cisapride.html. Cisapride withdrawn
because of cardiac side effects. The Pharmaceutical
Journal 2000;265(7107):152. [: http://www.pharmj.com/
Editorial/20000729/clinical/cisapride.html]
Vandenplas 1999
Vandenplas Y, Belli D, Benatar A. The role of Cisapride
in the treatment of paediatric gastroesophageal reflux. J.
Pediatr. Gastoenterol. Nutr 1999;28:518–28.
Veysey 2001
Veysey MJ, Malcolm P, Mallet AI, Jenkins PJ, Besser
GM, Murphy GM, Dowling RH. Effects of cisapride
on gall bladder emptying, intestinal transit, and serum
deoxycholate: a prospective, randomised, double blind,
placebo controlled trial.. Gut 2001;49(6):828–34.
∗
Indicates the major publication for the study
20
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Farup 1998

Methods Randomized, placebo-controlled, double-blinded trial

Participants 70 patients between 18 and 75 years with constipation predominant IBS

Diagnosis was based on Rome criteria.
Inclusion criteria was patients with continuous or recurrent symptoms for more than
6 months, with symptoms at least three times a week, and without favourable or long
lasting effect of precious therapies
Patients with diarrhoea or alternating stool patterns without constipation, or doubtful
compliance, proven or clinically suspected disorders that might interfere with the evalua-
tion of symptoms, significant abnormalities in blood chemistry or haematology, previous
GI surgery(except for cholecystectomy and appendectomy), pregnancy or lactation, or
patients receiving drugs with effects on GI motility, or placed on a fibre rich diet during
the past 2 moths, or receiving other drug therapy for IBS or constipation (except laxatives
as needed)

Interventions 12 weeks of either 5mg TDS of cisapride or placebo.

After 4 weeks if there is no improvement of symptoms the dose is doubled to 10mg
TDS. The dose is continued till the end of treatment
Laxatives were given if there was no stools passed for 3 or more consecutive days

Outcomes Assessment of the global improvement by using the visual analogue scale (0 best; 100
worst) was done at each follow up visit. Also other parameters included the patients score
for each of the IBS symptoms and on general well being. Also the investigators global
evaluation of the effect and safety of the treatment
Patients were followed up at 4, 8, and 12 weeks

Notes The diagnosis of IBS should have been made before the age of 50 years
8 patients dropped out of the study because of either adverse events, insufficient response,
lost of follow up, or pregnancy plans (5 in the cisapride group and 3 in the placebo
group)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear No mention of how the allocation sequence

was generated.

Allocation concealment? Unclear No mention of allocation concealment.

Blinding? Yes This was a double blinded study.

All outcomes

Cisapride for Intestinal Constipation (Review) 21

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Farup 1998 (Continued)

Incomplete outcome data addressed? Yes Incomplete data was addressed and did not
All outcomes affect the final outcomes

Free of selective reporting? Yes There were no indications of selective re-

porting.

Free of other bias? No The unclarity of the sequence generation

and the allocation concealment is a source
of bias
The investigators’ opinions of the overall
effectiveness can be considered a source of
bias

Halabi 1999

Methods Randomized, placebo-controlled, double-blinded trial

Participants 64 patients (37 males and 27 females), between 4 and 18 years with chronic constipation
Inclusion criteria: symptoms, pain, difficulty in defecation, or three of fewer bowel
movements per week; minimum duration of symptoms of 3 months; absence of history
of small or large bowel organic disease; and adequate documentation and good patient
compliance

Interventions 8 weeks of either 0.3mg/kg QDS of cisapride or placebo in syrup form

Outcomes Stool frequency measurements were performed weekly. Gastrointestinal transit time was
measure at the start and finish of the treatment
Follow up was after every week.

Notes There were initially 69 patients which met the inclusion criteria but 5 were dropped out
due to inability for follow up, their data was not included in the study

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear No mention of how the allocation sequence

was generated.

Allocation concealment? Unclear No mention of allocation concealment.

Blinding? Yes This was a double blinded study.

All outcomes

Incomplete outcome data addressed? Yes The Authors addressed any incomplete
All outcomes data.

Cisapride for Intestinal Constipation (Review) 22

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Halabi 1999 (Continued)

Free of selective reporting? Yes There were no indications of selective re-

porting.

Free of other bias? No The unclarity of the sequence generation

and the allocation concealment is a source
of bias

Nurko 2000

Methods Randomized, placebo-controlled, double-blinded trial

Participants 36 patients (24 males and 12 females), between 2 and 16 years with chronic constipation
Patients with constipation (fewer than 3 bowel movements per week), chronic consti-
pation (lasting a minimum of 6 months), and spontaneous bowel movements (BMs
occurring more than 48 hours after the administration of laxatives) were considered
All patients with underlying causes of constipation were excluded

Interventions 12 weeks of either 0.2mg/kg/dose TDS of cisapride or placebo in suspension form

Follow up after 8 weeks; if not improvement the dose was increased to 0.3mg/kg/dose
TDS
if bowels were not open for 48 hours then senokot was given, if not open after 2 days
with senokot then daily enemas were added to the regime. Once bowels were opened
then senokot and if enemas were given, were stopped

Outcomes the parameters measured were spontaneous bowel movements per week, fecal soiling
episodes per day, laxatives doses per week, laxatives usage, encopresis, and overall clinical
response to treatment. Clinical response was defined as more than 3 SBMs per week,
with no fecal soiling, and no use of other laxatives for at least 2 weeks. failure was defined
as 2 episodes of fecal impaction requiring disimpaction with enemas or anaesthesia or
not fulfilling the above criteria for response after 12 weeks of therapy
Patients were asked to keep a diary of the above parameters and were followed up at 2,
4, 8, and 12 weeks

Notes one patient dropped out due to worsening constipation (in the placebo group)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear No mention of how the allocation sequence

was generated.

Allocation concealment? Unclear No mention of allocation concealment.

Blinding? Yes This was a double blinded study.

All outcomes

Cisapride for Intestinal Constipation (Review) 23

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Nurko 2000 (Continued)

Incomplete outcome data addressed? Yes Incomplete data was addressed and did not
All outcomes affect the final outcomes

Free of selective reporting? Yes There were no indications of selective re-

porting.

Free of other bias? No The unclarity of the sequence generation

and the allocation concealment is a source
of bias

Odeka 1997 Aug

Methods Randomized, placebo-controlled, double-blinded trial

Participants 37 patients (17 males, 20 females), between 2 and 16 years with chronic constipation for
>3 months, absence of organic disease of small or large bowel, adequate record keeping
and willingness to comply with treatment

Interventions 8 weeks of either 0.2mg/kg/dose TDS of cisapride or placebo.

Outcomes Parameters of assessment were stool frequency and total gastrointestinal time
Stool frequency was reported as mean +- SD
Total gastrointestinal time was reported on a graph with no written data. Attempts were
made to contact the author with no success

Notes 7 patient dropped out due to lack of effect (3 in the cisapride group and 4 in the placebo
group)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear No mention of how the allocation sequence

was generated.

Allocation concealment? Unclear No mention of allocation concealment.

Blinding? Yes This was a double blinded study.

All outcomes

Incomplete outcome data addressed? Yes Incomplete data was addressed and did not
All outcomes affect the final outcomes

Free of selective reporting? Yes There were no indications of selective re-

porting.

Cisapride for Intestinal Constipation (Review) 24

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Odeka 1997 Aug (Continued)

Free of other bias? No The unclarity of the sequence generation

and the allocation concealment is a source
of bias

Staiano 1991

Methods Randomized, placebo-controlled, double-blinded trial

Participants 20 children (11 boys and 9 girls), between 1.5 and 9.5 years with chronic constipation
Symptoms of constipation should be at least for 6 months.
Exclusion criteria: all secondary causes of constipation, patients with Hypothyroidism,
hyperparathyroidism, spinal and anal anomalies, and mental retardation

Interventions 12 weeks of either 0.2mg/kg TDS of cisapride or placebo.

Patients were reviewed after 4, 8, 12 weeks. Laxatives or suppositories were continued if
used prior

Outcomes Parameters of assessment were the stool frequency, total gastrointestinal transit time, and
anorectal motility
Results were reported as mean +- SD data.

Notes 3 patients were dropped out due to lack of compliance. (1 in the cisapride group and 2
in the placebo group)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear No mention of how the allocation sequence

was generated.

Allocation concealment? Unclear No mention of allocation concealment.

Blinding? Yes This was a double blinded study.

All outcomes

Incomplete outcome data addressed? Yes The Authors addressed any incomplete
All outcomes data.

Free of selective reporting? Yes There were no indications of selective re-

porting.

Free of other bias? No The unclarity of the sequence generation

and the allocation concealment is a source
of bias

Cisapride for Intestinal Constipation (Review) 25

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Van Outryve 1991

Methods Randomized, placebo-controlled, double-blinded trial

Participants 69 patients (15 males and 54 females), between 17 and 75 years with constipation
predominant IBS
Criteria for diagnosis was non menstrual abdominal pain and constipation-associated or
not with flatulence or abdominal distension-and absence of an organic, metabolic, or
overt psychic etiology
Inclusion criteria: Constipation was defined as low defecation frequency or the passage
of hard stools for at least 6 months. IBS must be diagnosed before the age of 50 years,
abdominal pain and flatulence or distension had occurred at least three times a week
and had been severe enough to interfere with the normal activities, and if none of the
previous therapies had yielded a lasting favourable result
Exclusion: diarrhoea, abdominal pain without constipation, painless constipation, preg-
nancy and lactation, alcoholism, heavy smoking (more than 40 cigarettes per day), termi-
nal disease, severe cardiovascular, pulmonary, nephrologic, neurologic, or psychiatric dis-
orders, a history of GI surgery, except for cholecystectomy and appendicectomy, proved
or clinically suspected deficiency of the gallbladder, biliary duct (cholelithiasis), pan-
crease (pancreatitis), liver or thyroid gland, diverticulitis, Crohn’s disease Uncerative col-
itis, amyloidosis, Schonlein Henoch purpura, ileus with severe adherences, prophyria,
malignant disorders, severe dehydration, or gynaecological disorders, and patients who
had been put on a fibre rich diet within the 2 months preceding

Interventions 12 weeks of either 5mg cisapride or placebo to be taken TDS, 15 minutes before each
main meal
If by 4 weeks the symptoms improved the dose was unaltered. If abdominal pain had
worsened the dose was halved (2.5mg TDS) and if complaints had not improved the
dose was doubled (10mg TDS)
The dose selected after 4 weeks was continued throughout the trial

Outcomes Symptoms and stool patterns were assessed at 4, 8, and 12 weeks

The severity and frequency were noted of abdominal pain, distention, flatulence, defe-
cation urge, feeling of incomplete evacuation, eructation, pyrosis, postprandial nausea,
postprandial fullness, nervousness, anxiety, tension, and depression. Severity was rated
3 (severe), 2 (moderate), 1 (mild) or 0 (absent) and frequency was rated 3 (nearly con-
tinuously), 2 (every day), 1 (occasionally) or 0 (never)
The number of days on which a stool was passed, rather than the total number of stools
was used as an efficacy parameter
Assessments were made of the effect of treatment on abdominal pain, constipation, and
flatulence or distention, a Visual Analogue Scale (VAS 0=absent, 100=as bad as possible)

Notes 9 patients dropped out due to diarrhoea, disappearance of complaints, inefficacy, in-
sufficient/lack of improvement, and vacationing. (4 in the cisapride group and 5 in the
placebo group)

Risk of bias

Item Authors’ judgement Description

Cisapride for Intestinal Constipation (Review) 26

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Van Outryve 1991 (Continued)

Adequate sequence generation? Unclear No mention of how the allocation sequence

was generated.

Allocation concealment? Unclear No mention of allocation concealment.

Blinding? Yes This was a double blinded study.

All outcomes

Incomplete outcome data addressed? Yes The Authors addressed any incomplete
All outcomes data.

Free of selective reporting? Yes There were no indications of selective re-

porting.

Free of other bias? No The unclarity of the sequence generation

and the allocation concealment is a source
of bias

Verheyen 1987

Methods Randomized, placebo-controlled, double-blinded trial

Participants 46 patients (12 men and 34 females), between 17 and 90 years with chronic functional
constipation
Patients were considered to be constipated when they had opened their bowels 10 times
or less over an initial 21 day period preceding the double blind treatment. if more than
10 stools were passed they were included if at least 90% of their stools were of hard or
very hard consistency
Reasons for exclusion: organic cause of constipation, lower abdominal pain prevailing
with constipation, pregnancy, lactating mothers, patients who were confined to bed or
had an extremely low degree of physical activity

Interventions 12 weeks of either 5mg cisapride or 10mg cisapride or placebo to be taken TDS, 30
minutes before meals
patients were allowed laxatives when constipation episode was perceived as intractable.
Patients were told not to change their diet or life style during the study period and to
continue using fibre or bulk-forming agents if they had done so before the start of the
study

Outcomes Patients were assessed after 4, 8, and 12 weeks.

Patients were asked to complete a 10cm visual analogue scale (VAS) ranging from ’could
not be worse’ to ’stools completely normal’ indicating their perception of the constipa-
tion. Every 4 weeks the patient and investigator gave a global evaluation of the treat-
ment: deterioration (constipation worse than before the study), poor (no substantial im-
provement), good (frequency or consistency of stools markedly improved), and excellent
(virtually normalization of stools)
Parameters assessed were stool frequency and consistency, ease of passage and need of
laxatives.Scoring of the stool consistency was by a 4 point scale: very hard (0), hard (1),

Cisapride for Intestinal Constipation (Review) 27

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Verheyen 1987 (Continued)

normal (2), watery (3); ease of defecation was scored by 3 point scale: very difficult (0),
difficult (1), easy (2)

Notes 2 patients dropped out due to adverse events and meteorism. (1 in the cisapride group;
no mention in which group, and 1 in the placebo group)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear No mention of how the allocation sequence

was generated.

Allocation concealment? Unclear No mention of allocation concealment.

Blinding? Yes This was a double blinded study.

All outcomes

Incomplete outcome data addressed? Yes The Authors addressed any incomplete
All outcomes data.

Free of selective reporting? Yes There were no indications of selective re-

porting.

Free of other bias? No The unclarity of the sequence generation

and the allocation concealment is a source
of bias
The investigators’ opinions of the global
evaluation for the treatment can be consid-
ered a source of bias

Ziegenhagen 2004

Methods Randomized, placebo-controlled, double-blinded trial

Participants 82 patients (18 males and 64 females), between 18 and 75 years with constipation variant
of IBS
Diagnosis was based on Rome I criteria.
Reasons for exclusions: alternating stool pattern (diarrhoea/constipation), pregnancy
or lactation, alcoholism, heavy smoking (>2 packets/day), severe concurrent disorders
including AIDS and neuro-psychiatric diseases, previous gastrointestinal surgery besides
cholecystectomy and appendectomy, significant abnormalities in blood chemistry or
imaging examinations, patient on a fibre-rich diet in the previous 2 months, weight loss
>5 kg in the last 6 months

Interventions 12 weeks of either 5mg of Cisapride or identical-looking placebos, to be taken TDS 15

min before each meal
After 4 weeks patients scored their symptoms using a visual analogue scale (0 best; 100

Cisapride for Intestinal Constipation (Review) 28

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ziegenhagen 2004 (Continued)

worst); if VAS >10mm --> treatment continued and if VAS <10mm --> the dose was
doubled to 2 tablets TDS
The Dose selected after the first 4 weeks is the dose continued throughout the study

Outcomes Symptom assessment by patients and investigators during the follow-ups after 4, 8, and
12 weeks
Using VAS scoring (0 best; 100 worst) of global rating of bowel disease and assessment of
secondary parameters using VAS (0 worst 100 best); abdominal pain, bloating, frequency
of stool passage, consistency of stools, difficulty of stool passage, need to defecate (have
to but cannot), feeling of incomplete eventuation

Notes 12 patients dropped out due to insufficient effect, withdrawal of consent, and loss to
follow-up. (6 in the cisapride group and 6 in the placebo group)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear No mention of how the allocation sequence

was generated.

Allocation concealment? Unclear No mention of allocation concealment.

Blinding? Yes This was a double blinded study.

All outcomes

Incomplete outcome data addressed? Yes Incomplete data was addressed and did not
All outcomes affect the final outcomes

Free of selective reporting? Yes There were no indications of selective re-

porting.

Free of other bias? No The unclarity of the sequence generation

and the allocation concealment is a source
of bias
The investigators’ opinions of the assess-
ment of the patient’s symptoms can be con-
sidered a source of bias

Characteristics of excluded studies [ordered by study ID]

Cisapride for Intestinal Constipation (Review) 29

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Study Reason for exclusion

Altabas 2003 Patients included in the study were encouraged to use/take a fibre-rich diet throughout the study period.
Hence no way of knowing whether or not the results are due to the fibre rich diet or the drugs themselves

Benini 1991 Abstract for British society of Gastroenerology

Not a RCT

Bhatnagar 2000 Comment on an article

Not a RCT

Cucchiara 1996 Review of Cisapride on the U&LGIT

Not a RCT

Evans 1997 Study on patients with constipation IBS, diarrhoea IBS and healthy individuals

Geders 1995 Study on patients with spinal cord injury

Hernandez 1988 Study included patients who had simple, environment induced constipation, idiopathic megacolon or
mega-rectum, dolicho-colon, and patients with constipation due to addictive purgation, diabetes, or due to
dopamine agonists in Parkinson therapy, no differentiation was made between them (they were grouped as
one result)

Jost 1994 Study on patients with Parkinson’s disease

Krevsky 1989 This study was aimed at determining the effect of cisapride on the colonic transit time by using colonic
transit scintigraphy and imaging on patients with constipation
No other parameters were measured.

Liu 2002 Study on the effect of cisapride combined with bisacodyl and doxepin in treating functional constipation

Loening-Baucke 1996 Editorial Comment on cisapride and constipation

Not a RCT

Lu 2003 Study on the drug treatment of IBS.

Müller-Lissner 1986 Abstract for international cisapride investigator’s meeting

Not a RCT

Müller-Lissner 1987 This study was aimed at determining the effect of cisapride on laxative consumption in patients with
idiopathic painless constipation and chronic laxative intake

Müller-Lissner 1995 This article studied the tapering and withdrawal of cisapride treatment on patients with chronic constipation.
2 groups, the first took cisapride for 24 weeks at 20mg BD, while the other was given cisapride for 6 weeks
at 20mg then reduced to 10mg BD for 6 weeks, then completely withdrawn for 12 weeks of F/U. there was
improvement of symptoms in both groups, but symptoms slowly/gradually worsened in the second group.
There was no baseline input to compare to.
The data was mainly on the withdrawal effect of cisapride.

Cisapride for Intestinal Constipation (Review) 30

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Ni 2001 This study was between MgO and Cisapride combined with MgO. No real way to measure effect of Cisapride
itself on the patient’s with constipation

Nurko 1996 This study is an Open study

Not a RCT

Odeka 1997 Not a RCT

Puntis 2000 Commentary

Not a RCT

Schütze 1997 The author uses patients appropriate to the inclusion criteria. However no Standard Deviations were included
in the provided data. Therefore the data could not be used in the final meta-analysis
Several attempts were made to contact the authors in various Austrian hospitals but they were unable to be
traced

Staiano 1996 Study on patients with Severe Brain Damage

Veysey 2001 Study was on healthy individuals and patients with acromegaly and the study focus was on UGI physiology

Zou 1998 Not a RCT

Cisapride for Intestinal Constipation (Review) 31

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Primary Outcome

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Global Improvement of 2 132 Mean Difference (IV, Random, 95% CI) -0.11 [-12.07, 11.
symptoms 85]
2 Global Improvement of 3 151 Odds Ratio (M-H, Fixed, 95% CI) 0.45 [0.22, 0.91]
symptoms

Comparison 2. Secondary Outcomes

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Abdominal Pain: Visual 3 201 Mean Difference (IV, Random, 95% CI) -1.94 [-8.50, 4.62]
Analogue Scale
2 Stool Freqeuncy: Number of 4 154 Mean Difference (IV, Random, 95% CI) 2.36 [-0.57, 5.29]
Stools passed per week
3 Stool Frequency: Visual 2 132 Mean Difference (IV, Fixed, 95% CI) -0.23 [-1.23, 0.77]
Analogue scale
4 Stool Frequency: Passage of daily 2 115 Odds Ratio (M-H, Fixed, 95% CI) 0.22 [0.09, 0.51]
stools
5 Stool Consistency: Visual 2 132 Mean Difference (IV, Fixed, 95% CI) 0.32 [-0.61, 1.26]
Analogue Scale
6 Stool Consistency: Passage of 1 69 Odds Ratio (M-H, Fixed, 95% CI) 0.06 [0.02, 0.25]
normal stools
7 Bloating: Visual Analogue Scale 2 132 Mean Difference (IV, Random, 95% CI) 3.93 [-5.96, 13.83]
8 Bloating: Patients with persistent 1 69 Odds Ratio (M-H, Fixed, 95% CI) 1.11 [0.42, 2.95]
bloating
9 Feeling of incomplete 2 132 Mean Difference (IV, Random, 95% CI) -3.80 [-8.01, 0.41]
evacuation: Visual Analogue
Scale
10 Total Gastrointestinal Transit 3 117 Mean Difference (IV, Fixed, 95% CI) -19.47 [-22.04, -16.
time 89]
11 Difficulty of stool passage: 2 132 Mean Difference (IV, Fixed, 95% CI) -0.95 [-2.36, 0.46]
Visual Analogue Scale

Cisapride for Intestinal Constipation (Review) 32

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 3. Side effects

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Side effects 5 297 Odds Ratio (M-H, Fixed, 95% CI) 0.93 [0.36, 2.35]

Analysis 1.1. Comparison 1 Primary Outcome, Outcome 1 Global Improvement of symptoms.

Review: Cisapride for Intestinal Constipation

Comparison: 1 Primary Outcome

Outcome: 1 Global Improvement of symptoms

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Farup 1998 28 47 (5) 34 41 (3.8) 49.9 % 6.00 [ 3.75, 8.25 ]

Ziegenhagen 2004 34 35.6 (4.2) 36 41.8 (4.43) 50.1 % -6.20 [ -8.22, -4.18 ]

Total (95% CI) 62 70 100.0 % -0.11 [ -12.07, 11.85 ]

Heterogeneity: Tau2 = 73.23; Chi2 = 62.50, df = 1 (P<0.00001); I2 =98%
Test for overall effect: Z = 0.02 (P = 0.99)

-100 -50 0 50 100

Favours experimental Favours control

Cisapride for Intestinal Constipation (Review) 33

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.2. Comparison 1 Primary Outcome, Outcome 2 Global Improvement of symptoms.

Review: Cisapride for Intestinal Constipation

Comparison: 1 Primary Outcome

Outcome: 2 Global Improvement of symptoms

Study or subgroup Experimental Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Nurko 2000 5/17 11/19 32.9 % 0.30 [ 0.08, 1.21 ]

Van Outryve 1991 7/36 13/33 49.1 % 0.37 [ 0.13, 1.09 ]

Verheyen 1987 7/30 4/16 18.0 % 0.91 [ 0.22, 3.75 ]

Total (95% CI) 83 68 100.0 % 0.45 [ 0.22, 0.91 ]

Total events: 19 (Experimental), 28 (Control)
Heterogeneity: Chi2 = 1.40, df = 2 (P = 0.50); I2 =0.0%
Test for overall effect: Z = 2.21 (P = 0.027)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours experimental Favours control

Analysis 2.1. Comparison 2 Secondary Outcomes, Outcome 1 Abdominal Pain: Visual Analogue Scale.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 1 Abdominal Pain: Visual Analogue Scale

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Farup 1998 28 32 (4.9) 34 27 (3.8) 32.8 % 5.00 [ 2.78, 7.22 ]

Van Outryve 1991 36 1 (0.2) 33 1.5 (0.2) 34.1 % -0.50 [ -0.59, -0.41 ]

Ziegenhagen 2004 34 30.5 (4.4) 36 40.8 (4.09) 33.1 % -10.30 [ -12.29, -8.31 ]

Total (95% CI) 98 103 100.0 % -1.94 [ -8.50, 4.62 ]

Heterogeneity: Tau2 = 32.84; Chi2 = 116.40, df = 2 (P<0.00001); I2 =98%
Test for overall effect: Z = 0.58 (P = 0.56)

-100 -50 0 50 100

Favours experimental Favours control

Cisapride for Intestinal Constipation (Review) 34

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.2. Comparison 2 Secondary Outcomes, Outcome 2 Stool Freqeuncy: Number of Stools passed
per week.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 2 Stool Freqeuncy: Number of Stools passed per week

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Halabi 1999 32 6.75 (0.92) 32 1.31 (0.93) 25.3 % 5.44 [ 4.99, 5.89 ]

Nurko 2000 17 4.1 (1.1) 19 2.2 (0.6) 25.2 % 1.90 [ 1.31, 2.49 ]

Odeka 1997 Aug 18 1.02 (0.1) 19 1.23 (0.99) 25.3 % -0.21 [ -0.66, 0.24 ]

Staiano 1991 9 5.1 (1.9) 8 2.8 (0.8) 24.1 % 2.30 [ 0.94, 3.66 ]

Total (95% CI) 76 78 100.0 % 2.36 [ -0.57, 5.29 ]

Heterogeneity: Tau2 = 8.79; Chi2 = 306.24, df = 3 (P<0.00001); I2 =99%
Test for overall effect: Z = 1.58 (P = 0.11)

-100 -50 0 50 100

Favours experimental Favours control

Cisapride for Intestinal Constipation (Review) 35

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.3. Comparison 2 Secondary Outcomes, Outcome 3 Stool Frequency: Visual Analogue scale.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 3 Stool Frequency: Visual Analogue scale

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Farup 1998 28 59 (4.5) 34 58 (2.7) 27.8 % 1.00 [ -0.90, 2.90 ]

Ziegenhagen 2004 34 52.5 (2.63) 36 53.2 (2.38) 72.2 % -0.70 [ -1.88, 0.48 ]

Total (95% CI) 62 70 100.0 % -0.23 [ -1.23, 0.77 ]

Heterogeneity: Chi2 = 2.23, df = 1 (P = 0.14); I2 =55%
Test for overall effect: Z = 0.45 (P = 0.66)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours experimental Favours control

Analysis 2.4. Comparison 2 Secondary Outcomes, Outcome 4 Stool Frequency: Passage of daily stools.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 4 Stool Frequency: Passage of daily stools

Study or subgroup Experimental Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Van Outryve 1991 9/30 9/16 34.8 % 0.33 [ 0.09, 1.17 ]

Verheyen 1987 17/36 28/33 65.2 % 0.16 [ 0.05, 0.51 ]

Total (95% CI) 66 49 100.0 % 0.22 [ 0.09, 0.51 ]

Total events: 26 (Experimental), 37 (Control)
Heterogeneity: Chi2 = 0.71, df = 1 (P = 0.40); I2 =0.0%
Test for overall effect: Z = 3.53 (P = 0.00042)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours experimental Favours control

Cisapride for Intestinal Constipation (Review) 36

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.5. Comparison 2 Secondary Outcomes, Outcome 5 Stool Consistency: Visual Analogue Scale.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 5 Stool Consistency: Visual Analogue Scale

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Farup 1998 28 62 (3.9) 34 61 (2.3) 32.4 % 1.00 [ -0.64, 2.64 ]

Ziegenhagen 2004 34 53.8 (2.37) 36 53.8 (2.47) 67.6 % 0.0 [ -1.13, 1.13 ]

Total (95% CI) 62 70 100.0 % 0.32 [ -0.61, 1.26 ]

Heterogeneity: Chi2 = 0.97, df = 1 (P = 0.33); I2 =0.0%
Test for overall effect: Z = 0.68 (P = 0.50)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours experimental Favours control

Analysis 2.6. Comparison 2 Secondary Outcomes, Outcome 6 Stool Consistency: Passage of normal stools.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 6 Stool Consistency: Passage of normal stools

Study or subgroup Experimental Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Van Outryve 1991 14/36 30/33 100.0 % 0.06 [ 0.02, 0.25 ]

Total (95% CI) 36 33 100.0 % 0.06 [ 0.02, 0.25 ]

Total events: 14 (Experimental), 30 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 3.96 (P = 0.000075)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours experimental Favours control

Cisapride for Intestinal Constipation (Review) 37

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.7. Comparison 2 Secondary Outcomes, Outcome 7 Bloating: Visual Analogue Scale.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 7 Bloating: Visual Analogue Scale

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Farup 1998 28 48 (5.2) 34 39 (4.4) 49.8 % 9.00 [ 6.57, 11.43 ]

Ziegenhagen 2004 34 42.4 (4.47) 36 43.5 (4.69) 50.2 % -1.10 [ -3.25, 1.05 ]

Total (95% CI) 62 70 100.0 % 3.93 [ -5.96, 13.83 ]

Heterogeneity: Tau2 = 49.64; Chi2 = 37.31, df = 1 (P<0.00001); I2 =97%
Test for overall effect: Z = 0.78 (P = 0.44)

-100 -50 0 50 100

Favours experimental Favours control

Analysis 2.8. Comparison 2 Secondary Outcomes, Outcome 8 Bloating: Patients with persistent bloating.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 8 Bloating: Patients with persistent bloating

Study or subgroup Experimental Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Van Outryve 1991 14/36 12/33 100.0 % 1.11 [ 0.42, 2.95 ]

Total (95% CI) 36 33 100.0 % 1.11 [ 0.42, 2.95 ]

Total events: 14 (Experimental), 12 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.22 (P = 0.83)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours experimental Favours control

Cisapride for Intestinal Constipation (Review) 38

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.9. Comparison 2 Secondary Outcomes, Outcome 9 Feeling of incomplete evacuation: Visual
Analogue Scale.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 9 Feeling of incomplete evacuation: Visual Analogue Scale

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Farup 1998 28 52 (5.2) 34 58 (4.3) 48.9 % -6.00 [ -8.41, -3.59 ]

Ziegenhagen 2004 34 39.7 (4.3) 36 41.4 (4.43) 51.1 % -1.70 [ -3.75, 0.35 ]

Total (95% CI) 62 70 100.0 % -3.80 [ -8.01, 0.41 ]

Heterogeneity: Tau2 = 7.95; Chi2 = 7.12, df = 1 (P = 0.01); I2 =86%
Test for overall effect: Z = 1.77 (P = 0.077)

-100 -50 0 50 100

Favours experimental Favours control

Analysis 2.10. Comparison 2 Secondary Outcomes, Outcome 10 Total Gastrointestinal Transit time.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 10 Total Gastrointestinal Transit time

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Halabi 1999 32 23.38 (7.49) 32 43 (3.1) 84.2 % -19.62 [ -22.43, -16.81 ]

Nurko 2000 17 77 (11.1) 19 95.4 (9.8) 14.0 % -18.40 [ -25.27, -11.53 ]

Staiano 1991 9 57.2 (20.2) 8 77.8 (20.3) 1.8 % -20.60 [ -39.89, -1.31 ]

Total (95% CI) 58 59 100.0 % -19.47 [ -22.04, -16.89 ]

Heterogeneity: Chi2 = 0.12, df = 2 (P = 0.94); I2 =0.0%
Test for overall effect: Z = 14.81 (P < 0.00001)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours experimental Favours control

Cisapride for Intestinal Constipation (Review) 39

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.11. Comparison 2 Secondary Outcomes, Outcome 11 Difficulty of stool passage: Visual
Analogue Scale.

Review: Cisapride for Intestinal Constipation

Comparison: 2 Secondary Outcomes

Outcome: 11 Difficulty of stool passage: Visual Analogue Scale

Mean Mean
Study or subgroup Experimental Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Farup 1998 28 55.5 (5.4) 34 56 (3.7) 35.7 % -0.50 [ -2.86, 1.86 ]

Ziegenhagen 2004 34 41.2 (3.44) 36 42.4 (4.04) 64.3 % -1.20 [ -2.95, 0.55 ]

Total (95% CI) 62 70 100.0 % -0.95 [ -2.36, 0.46 ]

Heterogeneity: Chi2 = 0.22, df = 1 (P = 0.64); I2 =0.0%
Test for overall effect: Z = 1.32 (P = 0.19)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours experimental Favours control

Cisapride for Intestinal Constipation (Review) 40

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 3.1. Comparison 3 Side effects, Outcome 1 Side effects.

Review: Cisapride for Intestinal Constipation

Comparison: 3 Side effects

Outcome: 1 Side effects

Study or subgroup Experimental Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Halabi 1999 3/32 0/32 4.9 % 7.71 [ 0.38, 155.64 ]

Nurko 2000 1/17 1/19 9.7 % 1.13 [ 0.06, 19.50 ]

Van Outryve 1991 0/36 1/33 16.8 % 0.30 [ 0.01, 7.54 ]

Verheyen 1987 3/30 3/16 38.4 % 0.48 [ 0.09, 2.72 ]

Ziegenhagen 2004 2/40 3/42 30.3 % 0.68 [ 0.11, 4.33 ]

Total (95% CI) 155 142 100.0 % 0.93 [ 0.36, 2.35 ]

Total events: 9 (Experimental), 8 (Control)
Heterogeneity: Chi2 = 3.06, df = 4 (P = 0.55); I2 =0.0%
Test for overall effect: Z = 0.16 (P = 0.87)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours experimental Favours control

ADDITIONAL TABLES
Table 1. History-taking to diagnose constipation

Key components Potential findings in a child younger than Potential findings in a child/young
..................................... 1 year person older than 1 year
................................................................. .................................................................
.. .....................................

Stool patterns -Fewer than three complete stools per week Fewer than three complete stools per week
(this does not -Overflow soiling (commonly very loose
apply to exclusively breast fed [no form], very smelly [smells more un-
babies after 6 weeks of age) pleasant than normal stools], stool passed
-Hard large stool without sensation. Can also be thick and
-’Rabbit droppings‘ sticky or dry and flaky.)
-‘Rabbit droppings= (type 1, see
-Large, infrequent stools that can block the
toilet

Symptoms associated with defecation -Distress on stooling -Poor appetite that improves with passage
-Bleeding associated with hard stool of large stool
- Straining

Cisapride for Intestinal Constipation (Review) 41

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. History-taking to diagnose constipation (Continued)

-Waxing and waning of abdominal pain

with passage of stool
-Evidence of retentive posturing: typical
straight legged, tiptoed, back arching pos-
ture
-Straining
-Anal pain

History -Previous episode(s) of constipation -Previous episode(s) of constipation

-Previous or current anal fissure -Previous or current anal fissure
-Painful bowel movements and bleeding as-
sociated with hard stools

Table 2. History-taking to diagnose idiopathic constipation

Key components
......................................
Findings and diagnostic clues that indicate ‘Red flag’ findings and diagnostic clues that
idiopathic constipation indicate an underlying disorder or condi-
................................................................. tion: not idiopathic constipation
............... .................................................................
................

Timing of onset of constipation and poten- In a child younger than 1 year:
tial precipitating factors
Reported from birth or first few weeks of
Starts after a few weeks of life life
Obvious precipitating factors coinciding
with the start of symptoms: fissure, change
of diet, infections
In a child/young person older than 1
year:
Starts after a few weeks of life Obvious pre-
cipitating factors coinciding with the start
of symptoms: fissure, change of diet, tim-
ing of potty/toilet training and acute event
such as infections, moving house, starting
nursery/school, fears and phobias, major
change in family, taking medicines

Passage of meconium Normal (within 48 hours after birth [in Failure to pass meconium/delay (more than
term baby]) 48 hours after birth [in term baby])

Stool patterns ‘Ribbon stools= (more likely in a child

younger than 1 year)

Growth and general well being
In a child younger than 1 year: No ?red flag‘, but see ?amber flag‘ below.
Generally well, weight and height within
normal limits
In a child/young person older than 1 year:
Generally well, weight and height within
normal limits, fit and active

Cisapride for Intestinal Constipation (Review) 42

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. History-taking to diagnose idiopathic constipation (Continued)

Symptoms in legs /locomotor development No neurological problems in legs (such as Previously unknown or undiagnosed weak-
falling over in a child/young person older ness in legs, locomotor delay
than 1 year), normal locomotor develop-
ment

Abdomen Abdominal distension with vomiting

Diet and fluid intake In a child younger than 1 year:

Changes in infant formula, weaning, insuf-
ficient fluid intake
In a child/young person older than 1
year:
History of poor diet and/or insufficient
fluid Intake

’Amber flag’, possible idiopathic constipa-

tion
Growth and general well being: Faltering
growth
Personal/familial/social factors: Disclosure
or evidence that raises concerns over possi-
bility of child maltreatment

Table 3. Physical examination to diagnose idiopathic constipation

Key components
......................................
Findings and diagnostic clues that indicate ’Red flag’ findings and diagnostic clues that
idiopathic constipation indicate an underlying disorder or condi-
................................................................. tion: not idiopathic constipation
.. .................................................................
..................................

Inspection of perianal area: appearance, po- Normal appearance of anus and surround- Abnormal appearance/position/patency of
sition, patency, etc ing area anus: fistulae, bruising, multiple fissures,
tight or patulous anus, anterior placed
anus, absent anal wink

Abdominal examination Soft abdomen. Flat or distension that can Gross abdominal distension
be explained because of age or overweight
child

Spine/lumbosacral region/gluteal examina- Normal appearance of the skin and Abnormal: asymmetry or flattening of the
tion anatomical structures of lumbosacral/ gluteal muscles, evidence of sacral agene-
gluteal regions sis, discoloured skin, naevi or sinus, hairy
patch, lipoma, central pit (dimple that you
can‘t see the bottom of ), scoliosis

Cisapride for Intestinal Constipation (Review) 43

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 3. Physical examination to diagnose idiopathic constipation (Continued)

Lower limb neuromuscular examination Normal gait. Normal tone and strength in Deformity in lower limbs such as
including tone and strength lower limbs talipes
Abnormal neuromuscular signs
unexplained by any existing
condition, such as cerebral
palsy

Lower limb neuromuscular examination: Reflexes present and of normal amplitude Abnormal reflexes
reflexes (perform only if =red flags‘ in his-
tory or physical examination suggest new
onset neurological impairment)

APPENDICES
Appendix 1. Medline Search strategy 19.11.08
289 hits:
16 11 and 14 and 15 289 Advanced DISPLAY
15 (enterokinetic* agent* or prokinetic* substance* or Cisapride* or prepulsid*).mp. or propulsid*.tw. [mp=title, original title, abstract,
name of substance word, subject heading word] 1830 Advanced DISPLAY
14 13 or 12 31173 Advanced DISPLAY
13 exp Constipation/ 8159 Advanced DISPLAY
12 (constipation or Chronic constipation or colon* inerti* or gastrointestinal* motility or colonic motility or intestinal* dysmotil-
ity*).mp. or functional* colonic* disease*.tw. [mp=title, original title, abstract, name of substance word, subject heading word] 31173
Advanced DISPLAY
11 10 and 9 1945888 Advanced DISPLAY
10 humans.sh. 10785221 Advanced DISPLAY
9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 2376391 Advanced DISPLAY
8 groups.ab. 885980 Advanced DISPLAY
7 trial.ab. 183698 Advanced DISPLAY
6 randomly.ab. 127995 Advanced DISPLAY
5 drug therapy.fs. 1313713 Advanced DISPLAY
4 placebo.ab. 110956 Advanced DISPLAY
3 randomized.ab. 176305 Advanced DISPLAY
2 controlled clinical trial.pt. 80624 Advanced DISPLAY
1 randomized controlled trial.pt. 268396 Advanced DISPLAY

Cisapride for Intestinal Constipation (Review) 44

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 2. Embase 24.11.08
210 hits:
27 24 or 26 210 Advanced DISPLAY
26 22 and 25 and 16 and 19 197 Advanced DISPLAY
25 (therapy* or drug* or treatment* or medicine*).tw. 2757151 Advanced DISPLAY
24 22 and 16 and 23 75 Advanced DISPLAY
23 Constipation/dt [Drug Therapy] 2943 Advanced DISPLAY
22 21 or 20 6006 Advanced DISPLAY
21 (enterokinetic* agent or prokinetic substance* or cisapride* or prepulsid*).mp. or propulsid*.ti,ab. [mp=title, abstract, subject
headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 6006 Advanced DISPLAY
20 exp cisapride/ 5926 Advanced DISPLAY
19 18 or 17 33898 Advanced DISPLAY
18 exp Constipation/ 26402 Advanced DISPLAY
17 (constipation or Chronic constipation or colon* inerti* or gastrointestinal* motility or colonic motility or intestinal* dysmotili*).mp.
or functional* colonic* diseas*.ti,ab. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device man-
ufacturer, drug manufacturer name] 33898 Advanced DISPLAY
16 11 not 15 2850708 Advanced DISPLAY
15 13 not 14 348956 Advanced DISPLAY
14 13 and 12 111609 Advanced DISPLAY
13 (animal* or nonhuman*).ti,ab. 460565 Advanced DISPLAY
12 “human*”.ti,ab. 1170599 Advanced DISPLAY
11 6 or 3 or 7 or 9 or 2 or 8 or 4 or 1 or 10 or 5 3027514 Advanced DISPLAY
10 (random* or cross* over* or factorial* or placebo* or volunteer*).ti,ab. 522954 Advanced DISPLAY
9 ((single* or double* or treble* or triple*) adj (blind* or mask*)).ti,ab. 91904 Advanced DISPLAY
8 single blind procedure/ 7817 Advanced DISPLAY
7 double blind procedure/ 70553 Advanced DISPLAY
6 phase 4 clinical trial/ 671 Advanced DISPLAY
5 phase 3 clinical trial/ 8277 Advanced DISPLAY
4 multicenter study/ 44217 Advanced DISPLAY
3 controlled study/ 2782142 Advanced DISPLAY
2 randomization/ 26318 Advanced DISPLAY
1 randomized controlled trial/ 163066 Advanced DISPLAY

Appendix 3. C.LIB 19.11.08

96 Clinical Trials:
#1 (constipation or chronic constipation or colonic inerti* or gastrointestinal* dysmotilit* or functional colonic diseas*) 2769 edit
delete
#2 Cisapride OR prepulsid or propulsid or enterokinetic agent OR prokinetic substance* 637 edit delete
#3 substi* piperidinyl 3 edit delete
#4 benzamid* 523 edit delete
#5 5-ht receptor 486 edit delete
#6 (#2 OR #3 OR #4 OR #5) 1625 edit delete
#7 (#1 AND #6) 126 edit delete

Cisapride for Intestinal Constipation (Review) 45

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
WHAT’S NEW
Last assessed as up-to-date: 4 September 2010.

Date Event Description

5 September 2009 Amended Included/Excluded studies added; Results of data extraction added

HISTORY
Protocol first published: Issue 2, 2009
Review first published: Issue 1, 2011

CONTRIBUTIONS OF AUTHORS
OMA and RLN assessed relevant abstracts and titles identified by the literature search.
OMA, TA, RA, US extracted the data from the included studies using a data extraction form.
OMA wrote the protocol, RLN edited it.
OMA and TA analysed the data and wrote the final review and RLN edited it.

DECLARATIONS OF INTEREST
None of the authors have any conflict of interest known.

SOURCES OF SUPPORT
Internal sources
• New Source of support, Not specified.

External sources
• New Source of support, Not specified.

Cisapride for Intestinal Constipation (Review) 46

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
INDEX TERMS

Medical Subject Headings (MeSH)

Arrhythmias, Cardiac [chemically induced]; Cisapride [adverse effects; ∗ therapeutic use]; Constipation [∗ drug therapy]; Gastrointestinal
Agents [adverse effects; ∗ therapeutic use]; Irritable Bowel Syndrome [drug therapy]; Randomized Controlled Trials as Topic

MeSH check words

Adult; Child; Female; Humans; Male

Cisapride for Intestinal Constipation (Review) 47

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.