Gordon 2013

EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL
Evid.-Based Child Health 8:1: 57109 (2013)

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ebch.1893
Osmotic and stimulant laxatives for the management of

childhood constipation (Review)
Gordon M, Naidoo K, Akobeng AK, Thomas AG
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 7
http://www.thecochranelibrary.com
Osmotic and stimulant laxatives for the management of childhood constipation (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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Figure 3.
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Figure 4.
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Figure 5.
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Figure 6.
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ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
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REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 PEG versus Placebo, Outcome 1 Frequency of defecation. . . . . . . . . . . .
Analysis 1.2. Comparison 1 PEG versus Placebo, Outcome 2 Serious adverse events.
. . . . . . . . . . .
Analysis 2.1. Comparison 2 PEG versus Lactulose, Outcome 1 Frequency of defecation. . . . . . . . . . .
Analysis 2.2. Comparison 2 PEG versus Lactulose, Outcome 2 Need for additional therapies. . . . . . . . .
Analysis 2.3. Comparison 2 PEG versus Lactulose, Outcome 3 Need for additional therapies (sensitivity analysis). .
Analysis 2.4. Comparison 2 PEG versus Lactulose, Outcome 4 Adverse events. . . . . . . . . . . . . .
Analysis 3.1. Comparison 3 PEG versus Milk of Magnesia, Outcome 1 Frequency of defecation. . . . . . . .
Analysis 3.2. Comparison 3 PEG versus Milk of Magnesia, Outcome 2 Frequency of defecation (sensitivity analysis).
Analysis 4.1. Comparison 4 Paraffin versus Lactulose, Outcome 1 Frequency of defecation. . . . . . . . . .
Analysis 5.1. Comparison 5 PEG versus Enema, Outcome 1 Frequency of defecation. . . . . . . . . . . .
Analysis 5.2. Comparison 5 PEG versus Enema, Outcome 2 Successful disimpaction. . . . . . . . . . . .
Analysis 6.1. Comparison 6 Lactulose versus Lactitol, Outcome 1 Frequency of defecation. . . . . . . . . .
Analysis 7.1. Comparison 7 PEG versus Paraffin, Outcome 1 Frequency of defecation. . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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58

[Intervention Review]
Osmotic and stimulant laxatives for the management of

childhood constipation
Morris Gordon1,2 , Khimara Naidoo3 , Anthony K Akobeng1 , Adrian G Thomas1
1 Royal Manchester Childrens Hospital, Manchester, UK. 2 Faculty of Health and Social Care, University of Salford, Salford, UK. 3 Guys
and St Thomas NHS Foundation Trust, London, UK

Contact address: Adrian G Thomas, Royal Manchester Childrens Hospital, Oxford Road, Manchester, M13 9WL, UK.
[email protected].
Editorial group: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group.
Publication status and date: New, published in Issue 7, 2012.
Review content assessed as up-to-date: 7 May 2012.
Citation: Gordon M, Naidoo K, Akobeng AK, Thomas AG. Osmotic and stimulant laxatives for the management of childhood
constipation. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD009118. DOI: 10.1002/14651858.CD009118.pub2.
ABSTRACT
Background
Constipation within childhood is an extremely common problem. Despite the widespread use of osmotic and stimulant laxatives by
health professionals to manage constipation in children, there has been a long standing paucity of high quality evidence to support this
practice.
Objectives
We set out to evaluate the efficacy and safety of osmotic and stimulant laxatives used to treat functional childhood constipation.
Search methods
The search (inception to May 7, 2012) was standardised and not limited by language and included electronic searching (MEDLINE,
EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders
Group Specialized Trials Register), reference searching of all included studies, personal contacts and drug companies.
Selection criteria
Randomised controlled trials (RCTs) which compared osmotic or stimulant laxatives with either placebo or another intervention, with
patients aged 0 to 18 years old were considered for inclusion. The primary outcome was frequency of defecation. Secondary endpoints
included faecal incontinence, disimpaction, need for additional therapies and adverse events.
Data collection and analysis
Relevant papers were identified and the authors independently assessed the eligibility of trials. Methodological quality was assessed
using the Cochrane risk of bias tool.The Cochrane RevMan software was used for analyses. Patients with final missing outcomes were
assumed to have relapsed. For continuous outcomes we calculated a mean difference (MD) and 95% confidence interval (CI) using a
fixed-effect model. For dichotomous outcomes we calculated an odds ratio (OR) and 95% confidence intervals (95% CI) using a fixedeffect model. The chi square and I2 statistics were used to assess statistical heterogeneity. A random-effects model was used in situations
of unexplained heterogeneity
59

Main results
Eighteen RCTs (1643 patients) were included in the review. Nine studies were judged to be at high risk of bias due to lack of blinding,
incomplete outcome data and selective reporting. Meta-analysis of two studies (101 patients) comparing polyethylene glycol (PEG)
with placebo showed a significantly increased number of stools per week with PEG (MD 2.61 stools per week, 95% CI 1.15 to 4.08).
Common adverse events in the placebo-controlled studies included flatulence, abdominal pain, nausea, diarrhoea and headache. Metaanalysis of 4 studies with 338 participants comparing PEG with lactulose showed significantly greater stools per week with PEG (MD
0.95 stools per week, 95% CI 0.46 to 1.44), although follow up was short. Patients who received PEG were significantly less likely to
require additional laxative therapies. Eighteen per cent of PEG patients required additional therapies compared to 30% of lactulose
patients (OR 0.49, 95% CI 0.27 to 0.89). No serious adverse events were reported with either agent. Common adverse events in
these studies included diarrhoea, abdominal pain, nausea, vomiting and pruritis ani. Meta-analysis of 3 studies with 211 participants
comparing PEG with milk of magnesia showed that the stools/wk was significantly greater with PEG (MD 0.69 stools per week, 95%
CI 0.48 to 0.89). However, the magnitude of this difference is quite small and may not be clinically significant. One child was noted
to be allergic to PEG, but there were no other serious adverse events reported. Meta-analysis of 2 studies with 287 patients comparing
liquid paraffin (mineral oil) with lactulose revealed a relatively large statistically significant difference in the number of stools per week
favouring paraffin (MD 4.94 stools per week, 95% CI 4.28 to 5.61). No serious adverse events were reported. Adverse events included
abdominal pain, distention and watery stools. No statistically significant differences in the number of stools per week were found
between PEG and enemas (1 study, 90 patients, MD 1.00, 95% CI -1.58 to 3.58), dietary fibre mix and lactulose (1 study, 125 patients,
P = 0.481), senna and lactulose (1 study, 21 patients, P > 0.05), lactitol and lactulose (1 study, 51 patients, MD -0.80, 95% CI -2.63
to 1.03), and PEG and liquid paraffin (1 study, 158 patients, MD 0.70, 95% CI -0.38 to 1.78).
Authors conclusions
The pooled analyses suggest that PEG preparations may be superior to placebo, lactulose and milk of magnesia for childhood constipation. GRADE analyses indicated that the overall quality of the evidence for the primary outcome (number of stools per week) was
low or very low due to sparse data, inconsistency (heterogeneity), and high risk of bias in the studies in the pooled analyses. Thus, the
results of the pooled analyses should be interpreted with caution because of quality and methodological concerns, as well as clinical
heterogeneity, and short follow up. However, PEG appears safe and well tolerated. There is also evidence suggesting the efficacy of liquid
paraffin (mineral oil), which was also well tolerated.There is no evidence to demonstrate the superiority of lactulose when compared to
the other agents studied, although there is a lack of placebo controlled studies. Further research is needed to investigate the long term
use of PEG for childhood constipation, as well as the role of liquid paraffin.
PLAIN LANGUAGE SUMMARY

Laxatives for the management of childhood constipation
Constipation within childhood is an extremely common problem. Despite the widespread use of laxatives by health professionals to
manage constipation in children, there has been a long standing lack of evidence to support this practice.This review included eighteen
studies with a total of 1643 patients that compared nine different agents to either placebo (inactive medications) or each other. The
results of this review suggest that polyethylene glycol preparations may increase the frequency of bowel motions in constipated children.
Polyethylene glycol was generally safe, with lower rates of minor side effects compared to other agents. Common side effects included
flatulence, abdominal pain, nausea, diarrhoea and headache. There was also some evidence that liquid paraffin (mineral oil) increased
the frequency of bowel motions in constipated children and was also safe. Common side effects with liquid paraffin included abdominal
pain, distention and watery stools. There was no evidence to suggest that lactulose is superior to the other agents studied, although
there were no trials comparing it to placebo. The results of the review should be interpreted with caution due to methodological quality
and statistical issues in the included studies. In addition, these studies were relatively short in duration and so it is difficult to assess
the long term effectiveness of these agents for the treatment of childhood constipation. Long term effectiveness is important, given the
often chronic nature of this problem in children.
60
PEG versus placebo
Control
Relative effect
(95% CI)
101
(2 studies)
No of Participants
(studies)

low1,2
Quality of the evidence

(GRADE)
Comments
Sparse data (101 patients)

Inconsistency (moderate statistical heterogeneity I2 = 58%)
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval;
The mean number of

bowel movements in the
PEG group was on average 2.61 higher per week
(95% CI 1.15 to 4.08)
Corresponding risk
Assumed risk
Illustrative comparative risks* (95% CI)
Frequency of defecation The mean number of

(mean number of bowel bowel movements ranged
movements per week)
across the placebo
groups from 1.6 to 2.4
per week
Outcomes
Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation

Settings: outpatient
Intervention: PEG versus placebo
PEG versus placebo for the management of childhood constipation
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
61

BACKGROUND
Description of the condition

Constipation within childhood is an extremely common problem
(Van den Berg 2006), representing the chief complaint in 3% of
visits to general paediatric clinics and as many as 30% of visits to
paediatric gastroenterologists (Partin 1992). The term functional
constipation is used when no underlying organic cause can be
identified for the symptoms. Creating a workable diagnostic classification for functional constipation has proven difficult. Criteria
vary, but are mostly based on a variety of symptoms, including
decreased frequency of bowel movements, faecal incontinence and
a change in consistency of stools (Pijpers 2008).
A team of paediatricians met in 1997 in Rome to standardize the
diagnostic criteria for various functional gastroenterological disorders in children. The first paediatric Rome II criteria were published in 1999 (Rasquin-Weber 1999) and were updated during
the Rome III process in 2006, producing guidance for functional
constipation for neonates, toddlers and children (Hyman 2006;
Rasquin 2006).
To diagnose constipation using the Rome III criteria, at least two
of the symptoms below must be present for at least one month
in infants and children up to age four and at least two months in
children over four, with insufficient criteria for the diagnosis of
irritable bowel syndrome:
Two or fewer defecations per week;
At least one episode per week of incontinence after the
acquisition of toileting skills;
History of retentive posturing or excessive voluntary stool
retention (over 4 years) or excessive stool retention (under 4
years);
History of painful or hard bowel movements;
Presence of a large faecal mass in the rectum; and
History of large diameter stools which may obstruct the
toilet.
Effective management of childhood functional constipation depends on securing a therapeutic alliance with the parents, particularly through the first years when children cannot accurately report
symptoms. Clinicians depend on the reports and interpretations
of the parents, who know their child best, and their own training
and experience to differentiate between health and illness (Hyman
2006).
be dissolved in water and are therefore relatively easy to administer to young children. Stimulant laxatives, such as Senna and
Bisacodyl, come in a variety of forms, including tablets, liquids,
and suppositories.
How the intervention might work

Osmotic laxatives are poorly absorbed in the gut. They act as hyperosmolar agents, increasing water content of stool and therefore
making stool softer and easier to pass, as well as increasing colonic
peristalsis. Stimulant laxatives act on the intestinal mucosa, increasing water and electrolyte secretion. They also stimulate peristaltic action.
Why it is important to do this review

Despite the widespread use of these medications by health professionals to manage constipation in children, there has been a
long standing paucity of high quality evidence to support this
practice. Previous efforts have been made to produce guidance on
this topic (Baker 1999; Anonymous 2006), most recently by the
National Institute for Health and Clinical Excellence in the UK
(Anonymous 2010).
In recent years, the widespread introduction of PEG to paediatric
practice has led to a resurgence in research on paediatric constipation. Some studies have suggested that polyethylene glycol has
greater efficacy when compared with placebo (Thomson 2007), as
well as when compared to lactulose (Voskujl 2004; Candy 2006).
A recently published Cochrane review investigated the specific
comparison of PEG versus lactulose (Lee-Robichaud 2010) in children and adults. There currently exists no other systematic review
using the Cochrane collaboration format for the use of osmotic
laxatives in children. A previous Cochrane review evaluating the
effect of stimulant laxatives on constipation in children found no
studies of sufficient quality to allow evaluation (Price 2001). An
up to date systematic review using the Cochrane Collaboration
format is indicated to summarise the current evidence on the use
of osmotic and stimulant laxatives for the management of constipation in children.
OBJECTIVES
Description of the intervention
Laxative therapies are often the mainstay of medical therapy used
in children suffering with functional constipation, alongside adjuvant therapies such as dietary and behavioural modification. Osmotic laxatives, such as lactulose, milk of magnesia and polyethylene glycol (PEG), are usually supplied as solutions or powders to
The primary objectives are to evaluate the efficacy and safety of

osmotic and stimulant laxatives used to treat functional childhood
constipation.
METHODS
62

Criteria for considering studies for this review
4. Cochrane Inflammatory Bowel Disease and Functional Bowel

Disorder Group Specialized Trials Register
Types of studies
The search strategy was not limited by language.

MEDLINE on PUBMED will be searched using the following
search strategy:
#1 Constipation
#2 Constipation [MeSH]
#3 faecal impaction OR impaction
#4 delayed bowel movement
#5 obstipation
#6 costiveness
#7 retention
#8 defecation
#9 bowel function*
#10 bowel habit*
#11 bowel movement*
#12 bowel symptom*
#13 bowel motility
#14 colon transit
#15 evacuation
#16 intestinal motility
#17 stool*
#18 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR
#9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16
OR #17
#19 Polyethylene glycol*
#20 macrogol*
#21 PEG
#22 polyethylene glycol 3350
#23 polyethylene glycol 4000
#24 Miralax OR Transipeg OR Movicol OR Forlax OR Idrolax
OR GoLytely OR PMF-100 OR Golitely OR Nulitely OR Fortans OR TriLyte OR Colyte OR lactulose OR disaccharide OR
Apo-Lactulose OR Chronulac OR lactitol OR sorbitol OR Generlac OR Cephulac OR Cholac OR Constilac OR Enulose OR
cilac OR Heptalac OR Actilax OR Duphalac OR Kristalose OR
milk of magnesia OR magnesium hydroxide OR Magnesium citrate OR citroma OR Osmoprep OR Visicol
#25 senna OR docusate sodium OR Sodium picosulphate OR
Bisacodyl OR Cascara OR casanthranol OR Buckthorn OR
senokot OR Aloe Vera OR aloin Phenolphthalein OR Dulcolax
#26 laxative*
#27 stimulant
#28 osmotic
#29 #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR
#26 OR #27 OR #28
#30 For
#31 Treat OR Treatment
#32 Therapy
#33 Efficacy
#34 management OR manage
Randomised controlled trials were considered for inclusion.

Types of participants
Patients aged 0 to 18 years with a diagnosis of functional constipation, with or without incontinence were considered for inclusion.
The diagnosis of constipation was patient self-reported, physician
diagnosed, or by consensus criteria (e.g. Rome III). Studies with
patients suffering from any underlying pathology, such as thyroid
abnormalities, Hirschsprungs disease or having undergone previous bowel surgery at study entry, were excluded.
Types of interventions
Studies comparing osmotic or stimulant laxatives with another intervention or placebo were considered for inclusion. All preparations and dosing regimes were considered. Studies using multiple
osmotic or stimulant laxative combinations or combinations of
both as their intervention were also considered for inclusion.
Types of outcome measures
Primary outcomes
The primary outcome measure was the frequency of defecation

(number of stools per week).
Secondary outcomes
Secondary outcomes included:

1) Faecal incontinence;
2) Disimpaction;
4) Need for additional therapies; and
5) Adverse events.
Search methods for identification of studies

Electronic searches
A. Electronic searching
The following electronic databases were searched for relevant studies:
1. MEDLINE (1966 to May 7, 2012; National Library of
Medicine, Bethesda, USA)
2. EMBASE (1984 to May 7, 2012; Elsevier Science, New York,
USA)
3. Cochrane Central Register of Controlled Trials
63

#35 #30 OR #31 OR #32 OR #33 OR #34
#36 Children OR child
#37 Child [MeSH]
#38 Paediatric
#39 Adolescent
#40 Infant
#41 Neonat*
#42 Toddler
#43 Pediatric
#44 Young
#45 Childhood
#46 #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR
#43 OR #44 OR #45
#47 #18 AND #29 AND #35 AND #46
Similar search strategies, but modified appropriately, and using the
above keywords were used to search the other electronic databases
listed above.
There is some evidence that data from abstracts can be inconsistent
with data in published articles (Pitkin 1999), therefore abstract
publications were not included in this review.
Searching other resources
B. Reference searching
The references of all identified studies were inspected for more
trials.
C. Personal contacts
Leaders in the field were contacted to try to identify other studies.
D. Drug companies
The manufacturers of osmotic and stimulant laxative agents were
contacted for additional data.
Data collection and analysis

All identified abstracts and results from searches were reviewed by
two authors (MG and KN). If the reference appeared relevant, a
full copy of the study was obtained.
Selection of studies
Two authors (MG and KN), after reading the full texts, independently assessed the eligibility of all trials identified based on the inclusion criteria above. Disagreement among authors was discussed
and agreement reached by consensus.
Data extraction and management
A data extraction form was developed and piloted to extract information on relevant features and results of included studies. The
two reviewers separately extracted and recorded data on the predefined checklist.
Extracted data included the following items:
a. characteristics of patients: age, sex, duration of symptoms;
b. study methods, total number of patients originally assigned to

each treatment group;
c. intervention: preparations, dose, administration regime;
d. control: placebo, other drugs;
e. concurrent medications;
f. outcomes (time of assessment, length of follow up, frequency
of defecation, pain on defecation and/or straining, faecal incontinence, stool consistency, need for additional therapies, number and type of adverse events associated with treatment, adverse
events); and
g. withdrawals and reasons for withdrawals.
Assessment of risk of bias in included studies

The methodological quality of selected trials was assessed independently by two authors using the Cochrane risk of bias tool
(Higgins 2011a). Factors assessed included:
1. sequence generation (i.e. was the allocation sequence
adequately generated?);
2. allocation sequence concealment (i.e. was allocation
adequately concealed?);
3. blinding (i.e. was knowledge of the allocated intervention
adequately 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. Disagreements was resolved by consensus. Study authors were
contacted for further information when insufficient information
was provided to determine the risk of bias.
We used the GRADE approach for rating the overall quality of
evidence for the primary outcome. Randomised trials start as high
quality evidence, but may be downgraded due to: (1) risk of bias,
(2) indirectness of evidence, (3) inconsistency (unexplained heterogeneity), (4) imprecision (sparse data), and (5) reporting bias
(publication bias). The overall quality of evidence for each outcome was determined after considering each of these elements, and
categorized as high quality (i.e. further research is very unlikely to
change our confidence in the estimate of effect); moderate quality
(i.e. further research is likely to have an important impact on our
confidence in the estimate of effect and may change the estimate);
low quality (i.e. further research is very likely to have an important
impact on our confidence in the estimate of effect and is likely to
change the estimate); or very low quality (i.e. we are very uncertain
about the estimate) (Guyatt 2008; Schnemann 2011).
Measures of treatment effect
64

The primary outcome, frequency of defecation, was assessed using
the mean difference (MD) with 95% confidence intervals (CI).
The secondary outcomes were assessed by calculating the odds
ratio (OR) and 95% CI.
Dealing with missing data
The authors of included studies were contacted to supply any
missing data.
Assessment of heterogeneity
Heterogeneity among trial results was assessed by inspection of
graphical presentations and by calculating the chi square test of
heterogeneity (a P value of 0.10 was regarded as statistically significant). We also used the I2 statistic to quantity the effect of
heterogeneity (Higgins 2003). A random-effects model was used
in situations of unexplained heterogeneity. We aimed to further
investigate potential sources of heterogeneity.
Assessment of reporting biases
If an appropriate number of studies was found, we aimed to investigate the possibility of a publication bias through the construction
of funnel plots (trial effects versus trial size).
Data synthesis
For outcomes that were sufficiently homogenous, meta-analysis
was carried out using a fixed-effect model. A random-effects model
was used in situations of unexplained heterogeneity.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses were to be carried out to further study the
effects of a number of variables on the outcomes including:
a. whether patients were being inducted in to remission from
constipation or whether this was a study of maintenance therapy;
b. the effect of length of therapy / follow up; and
c. specifically what, if any agents, were initially allowed in the
protocol to clear any impaction (such as enemas).
Sensitivity analysis
Sensitivity analyses was 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; and
b. random-effects versus fixed-effect models.
We also planned to consider the effect of:
c. allocation concealment;
d. type of agent;
e. dose of agent; and
f. concurrent medications.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
See:Characteristics of included studies; Characteristics of excluded
studies.
The database searches on May 7, 2012, identified 1568 records.
No further studies were identified through other sources. After
duplicates were removed, 1135 records were screened for inclusion (see Study flow diagram Figure 1). Of these, we identified 36
potentially relevant studies for full text review. Eighteen studies
were excluded for various reasons. Six studies were not randomised
controlled trials (Moulies 1961; Sonheimer 1982; Tolia 1988;
Loening-Baucke 2002; Loening-Baucke 2004; Shevtsov 2005)
four studies had no comparison group (Hejl 1990; Youssef 2002;
Dupont 2006; Hardikar 2007), two studies concerned adult patients (Ferguson 1999; Corazziari 1996) two were not research
articles (Clayden 1978; Kinservik 2004), one study was of children with soiling (Berg 1983), one study was of children with
faecal impaction without a diagnosis of functional constipation
(Miller 2012); one study was of children with underlying bowel
pathology (Kazak 1999) and one study was an abstract publication
(Quitadamo 2010).
65

Figure 1. Study flow diagram.
66

Eighteen studies were identified which satisfied the inclusion criteria and were included in the review. Two compared PEG with
placebo (Thomson 2007; Nurko 2008), five compared PEG with
lactulose (Gremse 2002; Voskujl 2004; Dupont 2005; Candy
2006; Wang 2007), three compared PEG with milk of magnesia (magnesium oxide) (Loening-Baucke 2006, Gomes 2011,
Ratanamongkol 2009), two compared liquid paraffin with lactulose (Urganci 2005; Farahmand 2007) two compared liquid paraffin with PEG (Tolia 1993; Rafati 2011), one compared PEG with
enemas (Bekkali 2009), one compared a dietary fibre mix with
lactulose (Kokke 2008), one lactulose with senna (Perkin 1977)
and one lactitol with lactulose (Pitzalis 1995).
The total number of participants in the included trials was 1,643.

The age range varied from 6 months up to 16 years. The duration
of the studies varied from 2 weeks to 12 months. The specific
criteria for a diagnosis of constipation also varied between studies,
as did the minimum length of symptoms. All studies excluded
children with organic causes for their pathology (see characteristics
of included studies).
Risk of bias in included studies

The risk of bias analysis for the included studies is summarised in
Figure 2 and Figure 3.
Figure 2. Methodological quality graph: review authors judgements about each methodological quality
item presented as percentages across all included studies.
67

Figure 3. Methodological quality summary: review authors judgements about each methodological quality
item for each included study.
68
Allocation
In five of the included studies, the method of random allocation of
participants to intervention groups was described and was judged
as adequate (Tolia 1993; Loening-Baucke 2006; Thomson 2007;
Kokke 2008; Ratanamongkol 2009). These studies were rated as
low risk for sequence generation. For one study (Candy 2006), the
sponsor gave a response to a request for more details and confirmed
adequate sequence generation. This study was rated as low risk
for sequence generation. Allocation was described as random in
the 12 remaining studies, although the method of randomisation
was not described. These studies were rated as unclear risk for
sequence generation. Allocation concealment was rated as low risk
in five studies (Perkin 1977; Loening-Baucke 2006; Thomson
2007; Kokke 2008; Ratanamongkol 2009) and as unclear risk in
the other studies.
Blinding
Methods for blinding were described and judged to be adequate
in six studies. These studies were rated as low risk for blinding (Voskujl 2004; Dupont 2005; Candy 2006; Thomson 2007;
Kokke 2008; Nurko 2008). In five studies, the use of blinding
was reported but not described clearly. These studies were rated as
unclear risk for blinding (Perkin 1977; Pitzalis 1995; Wang 2007;
Ratanamongkol 2009; Rafati 2011). The remaining seven studies
were described as open label and were rated as high risk for blinding (Tolia 1993; Gremse 2002; Urganci 2005; Loening-Baucke
2006; Farahmand 2007; Bekkali 2009; Gomes 2011).
Incomplete outcome data

Two studies were judged to be of high risk of bias (Gomes 2011,
Rafati 2011). The outcome data was judged as to have been addressed adequately in all the remaining studies.
Selective reporting
In five studies, no details were given of adverse events given and
therefore they were judged to be at risk of bias (Pitzalis 1995;
Gremse 2002; Bekkali 2009; Gomes 2011; Rafati 2011). The remaining thirteen studies were not clearly free of selective reporting. In these studies there was not enough information available
to make a judgement and so they were rated as unclear.
Other potential sources of bias

One study stated that they were supported by a pharmaceutical
company, but details of the extent of involvement were unclear.
Two studies were sponsored by pharmaceutical companies, but
confirmation was received by the authors that industry had no
involvement (Thomson 2007; Nurko 2008). Most of the remaining studies did not mention sources of funding and had no other
potential sources of bias.
Figure 3 shows the review authors judgements about each methodological quality item for each included study.
Effects of interventions
See: Summary of findings for the main comparison PEG
versus placebo for the management of childhood constipation;
Summary of findings 2 PEG versus lactulose for the management
of childhood constipation; Summary of findings 3 PEG versus
milk of magnesia (MOM) for the management of childhood
constipation; Summary of findings 4 Liquid paraffin (mineral
oil) versus lactulose for the management of childhood constipation
In the analyses, we used as the denominator the total number of
patients randomised. In all analyses, the frequency of defecation
was measured as stools per week.
PEG versus Placebo

The published results for the two studies concerning 101 patients
were inadequate to allow pooling for meta-analysis. The authors
were contacted and directed us to the study sponsors who supplied
unpublished data to allow analysis for outcomes at 2 weeks. One
of the studies (Nurko 2008) used multiple dosing regimens, but
data were obtained for the dose of 0.8 g/kg.
Efficacy
Frequency of defecation
Heterogeneity was noted to be moderate (P = 0.12, I2 = 58%)
and using a random-effects model, the mean difference (MD) was
2.61 stools per week (95% CI, 1.15 to 4.08), favouring PEG,
see Analysis 1.1 and Figure 4. The GRADE analysis indicated
that the overall quality of the evidence for the primary outcome
(frequency of defecation) was low due to sparse data (101 patients)
and inconsistency (statistical heterogeneity I2 = 58%) in the pooled
analysis (See Summary of findings for the main comparison).
69

Figure 4. Forest plot of comparison: 1 PEG versus Placebo, outcome: 1.1 Frequency of defecation.
Episodes of faecal incontinence

At 2 weeks, both studies reported higher rates of faecal incontinence in the PEG group. As there was some discrepancy in baseline data between groups in one study (Nurko 2008) and the difference before and after treatment was not reported, meta-analysis
for this outcome was not completed.
Safety
Serious adverse events were not reported in the PEG groups in
either study, but were seen in the placebo groups (8% of placebo
patients experienced a serious adverse event). However, there was
no statistically significant difference in the incidence of serious
adverse events (OR 0.17, 95% CI 0.02 to 1.48). Minor adverse
events were common and included flatulence, abdominal pain,
nausea, diarrhoea and headache. However, data were not reported
to allow meta-analysis. The studies both stated that no difference
in the incidence of adverse events appeared to exist between the
groups.
PEG versus Lactulose
One of the five studies (Wang 2007) did not report data that could
be used for meta-analysis. The authors were contacted, but no
response was received and so the remaining 4 studies including
328 patients were analysed. One study separated results for babies
and toddlers (Dupont 2005). Using the method described in the
Cochrane handbook (Higgins 2011b) the mean and standard deviation for the entire sample were calculated.
Efficacy
Heterogeneity was noted to be high (P = 0.02, I2 = 70%) and
using a random-effects model a statistically significant difference in
favour of PEG was seen, with a MD of 1.09 stools per week (95%
CI, 0.02 to 2.17), see Analysis 2.1 and Figure 5. The GRADE
analysis indicated that the overall quality of the evidence for the
primary outcome (frequency of defecation) was very low due to
sparse data (328 patients), inconsistency (statistical heterogeneity
I2 = 70%), and a high risk of bias (i.e. lack of blinding and selective
reporting) in one study in the pooled analysis (See Summary of
findings 2).
Figure 5. Forest plot of comparison: 2 PEG versus Lactulose, outcome: 2.1 Frequency of defecation.
Need for additional therapies

Using a fixed-effect model, there was a statistically significant result
favouring PEG. For the 3 studies (254 patients) that reported this
outcome (Voskujl 2004; Dupont 2005; Candy 2006), 18% of
PEG patients required additional therapy compared to 30% of
lactulose patients, (OR 0.49, 95% CI 0.27 to 0.89), see Analysis
2.2. When a sensitivity analysis using a random-effects model was

calculated the results were no longer statistically significant (OR
0.51, 95% CI 0.19 to 1.38), see Analysis 2.3.
Safety
Serious adverse events were only reported in one study (Candy
70

2006) and this was a chest infection in a patient in the PEG group,
thought to be unrelated to therapy. Minor adverse events were
seen in most studies, but were not reported in one study (Gremse
2002). Common adverse events included diarrhoea, abdominal
pain, nausea, vomiting and pruritis ani. For the 2 studies (154
patients) that reported data allowing meta-analysis (Dupont 2005;
Candy 2006), there was no statistically significant difference in the
proportion of patients who experienced at least one adverse event.
Twenty-four per cent of PEG patients experienced at least one
adverse event compared to 37% of lactulose patients (OR 0.37,
95% CI 0.14 to 1.03), see Analysis 2.4.
study and lack of blinding, incomplete outcome data and selective

reporting in the other study) in two studies in the pooled analysis
(See Summary of findings 3).
Safety
A serious adverse event of allergy to PEG was reported in one
patient (Loening-Baucke 2006). Minor adverse events data were
not reported to allow meta-analysis. One study (Ratanamongkol
2009) noted a statistically significant difference in proportion of
patients experiencing diarrhoea. Twenty-eight per cent of patients
in the milk of magnesia group experienced diarrhoea compared to
4% of PEG patients (P = 0.002). The final study (Gomes 2011)
did not explicitly report adverse event data.
PEG versus Milk of Magnesia

Three studies (211 participants) compared PEG to milk of magnesia. One study (Loening-Baucke 2006) reported outcomes at
1 month and 12 months. However, data for outcomes at 4
weeks were used for meta-analysis. Another study (Ratanamongkol
2009) reported median and interquartile ranges for results and
these were used to estimate the mean and standard deviation.
Efficacy
favouring PEG. The MD was 0.69 stools per week (95% CI, 0.48
to 0.89), see Analysis 3.1. There was no evidence of heterogeneity
in the pooled analysis (P = 0.87, I2 = 0%). The GRADE analysis
indicated that the overall quality of the evidence for the primary
outcome (frequency of defecation) was low due to sparse data
(211 patients) and a high risk of bias (i.e. lack of blinding in one
Liquid Paraffin versus Lactulose

Two studies (Urganci 2005; Farahmand 2007) (287 participants)
compared liquid paraffin to lactulose. These studies reported outcomes at 8 weeks.
Efficacy
favouring paraffin. The MD was 4.94 stools per week (95% CI
4.28 to 5.61) see Analysis 4.1 and Figure 6. There was no evidence
of heterogeneity in the pooled analysis (P = 0.45, I2 = 0%). The
GRADE analysis indicated that the overall quality of the evidence
for the primary outcome (frequency of defecation) was low due
to sparse data (287 patients) and a high risk of bias (i.e. lack of
blinding in both studies) in two studies in the pooled analysis (See
Summary of findings 4).
Figure 6. Forest plot of comparison: 4 Paraffin versus Lactulose, outcome: 4.1 Frequency of defecation.
Safety
No serious adverse events were reported in either study. Minor adverse events such as abdominal pain, distention and watery stools
were reported with both agents, but data were not presented in a
manor to allow meta-analysis.
PEG versus Enemas
One study (Bekkali 2009) compared PEG to enemas (90 participants), This study reported outcomes at 4 weeks.
Efficacy
There was no statistically significant difference in the frequency of
defecation between PEG and enema groups. The MD was 1.00
stools per week (95% CI -1.58 to 3.58).
71

Succesful disimpaction
Successful disimpaction was reported in 80% of enema patients
compared to 68% of PEG patients. However, the difference was
not statistically significant (OR 0.52, 95% CI 0.20 to 1.37).
Safety
Adverse event data were not explicitly reported within this study,
although the authors reported significantly higher rates of faecal
incontinence and watery stools with PEG.
Dietary fibre mix versus Lactulose

One study (Kokke 2008) compared dietary fibre with lactulose
(125 participants). This study reported outcomes at 8 weeks.
Efficacy
Kokke 2008 reported that there was no statistically significant
difference in the frequency of defecation between the two agents
at eight weeks (mean 7 stools per week in the fibre group versus 6
stools per week in the lactulose group; P = 0.481).
Safety
The authors reported no serious or significant adverse effects.
There were three cases of diarrhoea (one in the fibre mixture group
and two in the lactulose group).
Senna versus Lactulose

One crossover study (Perkin 1977) compared senna with lactulose
(21 participants),
Efficacy
Passage of stool
There was no statistically significant difference between the two
agents in the number of patients passing stools of any kind each
day.
Safety
No serious or significant adverse effects were reported in the 2
study groups. Minor adverse events such as colic or diarrhoea, were
more commonly seen in the senna group.
Lactitol versus Lactulose

One study (Pitzalis 1995) compared lactitol to lactulose (51 participants), This study reported outcomes at 30 days.
Efficacy
There was no statistically significant difference in the frequency
of defecation between the two agents. The MD was -0.80 stools
per week (95% CI -2.63 to 1.03).
Safety
Adverse events were not reported.
PEG versus Liquid paraffin
Two studies (196 participants) compared PEG to liquid paraffin
(Tolia 1993; Rafati 2011). The studies had varying lengths of
follow up (2 days versus assessments at 7 to 120 days). The two
studies were not pooled for meta-analysis because the primary
outcomes were not similar enough to allow pooling.
Efficacy
Rafati 2011 found no statistically significant difference in the frequency of defecation between PEG and liquid paraffin. The MD
was 0.70 stools per week (95% CI -0.38 to 1.78). Tolia 1993
reported on the frequency of bowel movements after treatment
(scored as > 5, 1 to 5 or none). The authors reported that PEG
patients had more frequent bowel movements after treatment than
liquid paraffin patients (P < 0.005).
Safety
No serious adverse events were reported. Tolia 1993 reported significantly more vomiting in the PEG group compared to liquid
paraffin (P < 0.005)..
Subgroup and sensitivity analyses
GIven the heterogenous nature of the included studies, further
subgroup or sensitivity analyses were not completed.
Publication Bias
Publication bias was not investigated as there were not enough
studies to construct a reliable funnel plot.
72
PEG versus lactulose
Control
Relative effect
(95% CI)
328
(4 studies)
No of Participants
(studies)

very low1,2,3

(GRADE)
Comments

Inconsistency (high statistical heterogeneity I2 = 70%; P = 0.02)
High risk of bias in one study in pooled analysis due to lack of blinding and selective reporting

The mean number of

(95% CI 0.02 to 2.17)
Corresponding risk
Assumed risk

movements per week)
across the lactulose
per week
Outcomes

Intervention: PEG versus lactulose
PEG versus lactulose for the management of childhood constipation
A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
73
Control
Relative effect
(95% CI)
211
(3 studies)
No of Participants
(studies)

low1,2

(GRADE)
Comments

High risk of bias in two studies in pooled analysis due to lack of blinding in one study and lack of blinding, incomplete outcome data
and selective reporting in the other study

The mean number of

(95% CI 0.48 to 0.89)
Corresponding risk
Assumed risk

movements per week)
across the MOM groups
from 4.3 to 9.7 per week
Outcomes

Intervention: PEG versus MOM
PEG versus milk of magnesia (MOM) for the management of childhood constipation
74
Control
Relative effect
(95% CI)
287
(2 studies)
No of Participants
(studies)

low1,2

(GRADE)
Comments

High risk of bias in two studies in pooled analysis due to lack of blinding in both studies

The mean number of

(95% CI 4.28 to 5.61)
Corresponding risk
Assumed risk

movements per week)
across the lactulose
per week
Outcomes

Intervention: Liquid paraffin (mineral oil) versus lactulose
Liquid paraffin (mineral oil) versus lactulose for the management of childhood constipation
75

DISCUSSION
Summary of main results
Lactulose was the most studied agent. Despite the many agents that
it was compared to, no trial found superiority of lactulose in terms
of efficacy. All but one trial found lactulose was inferior to other
agents. Although, it is worth noting that there were no studies
comparing lactulose with placebo. In addition, the occurrence of
minor adverse events, such abdominal cramps and flatus, were
more common in the lactulose groups.
PEG was also frequently studied, with trials comparing its efficacy
for constipation with lactulose, milk of magnesia and placebo. All
the results showed a statistically significant benefit favouring PEG.
However, the effect size was modest in these analyses, particularly
for the pooled analysis of PEG versus milk of magnesia. Although
PEG was superior to milk of magnesia the magnitude of this difference is quite small and may not be clinically significant. With
the exception of 1 case of allergy to PEG, no significant adverse
events were associated with the use of PEG and the limited evidence reported suggests that minor adverse events occur with a
similar or reduced frequency. There was one study that found that
PEG was of similar efficacy to rectal enemas for treating faecal
impaction.
The largest treatment effect seen within this review, in terms of
the frequency of defecation (i.e. number of stools per week), was
seen with liquid paraffin (mineral oil) when compared to lactulose.
While a number of case reports have been made that raise safety
concerns about liquid paraffin in terms of the risk of aspiration
pneumonia (Zanetti 2007), no cases of this or any serious adverse
events were noted in the trials in this review.
Overall completeness and applicability of

evidence
While there are a large number of studies included in this review,
it is clear that these studies are extremely heterogenous, with nine
different study agents and a variety of specific treatment regimens
reported. As such, despite the common nature of the problem,
it is difficult to draw particularly strong conclusions for any of
the investigated agents. The scope of this study was osmotic and
stimulant laxatives, but the vast majority of studies investigated
osmotic laxatives.
If we consider PEG, while this was the most studied agent in 10
different trials, with a total of 1161 participants, these studies compared PEG to 5 different agents, as well as its use for constipation
or faecal impaction. In addition, there was wide variation in study
length and the time at which outcomes were assessed. Clearly,
given the modest effect sizes and small sample sizes, coupled with
these variations in treatment protocols (time of outcome assessment, use of additional therapies, specific form of interventional
laxative used), the ability to use these findings to inform clinical
practice is modest at best. These factors have certainly contributed
to the statistical evidence of heterogeneity in intervention effects

observed in meta-analyses comparing PEG to placebo or lactulose.
As constipation is a chronic problem, outcomes really need to be
assessed in the medium to long term. However, only one study
assessed outcomes beyond three months and half of the studies
measured outcomes at 1 month or less. If management of chronic
constipation is considered in terms of induction (disimpaction)
and maintenance of remission, the limitation in the application
of these results becomes apparent. It is difficult to comment on
the ability of PEG or lactulose to maintain a childs normal bowel
habits over the long term, when the studies have such short follow
up periods. In addition, outcomes such as frequency of defecation
are inherently limited in relation to the realities of clinical practice.
While there may be a statistically significant increase in rates of
defecation between study groups, this does not give any information as to whether the patient or their parents feel that there has
been a functional improvement.

There were no studies that were judged to be fully free of risk of
bias. While the majority of studies described themselves as randomised, only six studies provided enough detail to be judged as at
low risk of bias. The other studies were rated as unclear for random
sequencer. This was also the case for allocation concealment, again
with the majority of studies giving insufficient detail to be judged
as low risk of bias. Seven studies were open label (high risk of bias)
or reported insufficient information to be judged at low risk of
bias. Four studies were judged to be at high risk of bias for selective
reporting and two studies were judged to be at high risk of bias
due to selective reporting. This has to be considered when judging the conclusions of this review. Furthermore, GRADE analyses
indicated that the overall quality of the evidence for the primary
outcome (number of stools per week) was low or very low due to
sparse data, inconsistency (heterogeneity), and high risk of bias in
the studies in the pooled analyses. Thus, given these concerns the
results of the pooled analyses should be interpreted with caution.
AUTHORS CONCLUSIONS
Implications for practice
The evidence base suggests that PEG is moderately effective at
improving the frequency of defecation in children with chronic
constipation when compared to placebo and more effective than
other agents, such as lactulose, milk of magnesia or liquid paraffin
(mineral oil). It also appears to have a good safety profile, with
minor adverse events common, but less so than with these other
agents. The strength of this evidence is limited by sparse data, inconsistency (clinical and statistical heterogeneity) and a high risk
76

of bias in some studies included in the pooled analyses. It is also
difficult to comment on the use of PEG for the long term management of childhood constipation as most studies only measured
short term outcomes. While only two studies investigated liquid
paraffin in comparison with lactulose, they found a reasonable effect size supporting the use of liquid paraffin. There was no evidence found to suggest lactulose is more effective than the other
agents studied, but there was a lack of placebo controlled trials.
placebo.
Future research should be clear at the outset as to whether it seeks
to investigate the use of agents for the induction of remission from
severe constipation, or whether it will investigate maintenance of
normal bowel habits. Studies should be reported in sufficient detail
to allow the methodology to be assessed and replicated by other
researchers.
Implications for research

The evidence base for this extremely prevalent problem is small
and published papers are generally of sub optimal quality, as well
as having problems with methodological, statistical and clinical
heterogeneity. As such, the strength of our conclusions is extremely
limited and more research is needed. Key questions that need addressing include the safety of liquid paraffin, given its apparent effectiveness, but limited investigation. In particular, future research
should compare liquid paraffin with PEG. The role of PEG for
the long term management of chronic constipation also needs further investigation to allow research to better inform actual clinical practice. There is a lack of studies comparing lactulose with
ACKNOWLEDGEMENTS
Funding for the IBD/FBD Review Group (September 1, 2010 August 31, 2015) has been provided by the Canadian Institutes of
Health Research (CIHR) Knowledge Translation Branch (CON
- 105145) and the CIHR Institutes of Nutrition, Metabolism
and Diabetes (INMD); and Infection and Immunity (III) and the
Ontario Ministry of Health and Long Term Care (HLTC3968FL2010-2235).
Miss Ila Stewart has provided support for the IBD/FBD Review
Group through the Olive Stewart Fund.
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References to studies included in this review

Bekkali 2009 {published data only}
Bekkali NL, van den Berg MM, Dijkgraaf MG, van Wijk
MP, Bongers ME, Liem O, et al.Rectal fecal impaction
treatment in childhood constipation: enemas versus high
doses oral PEG. Pediatrics 2009;124(6):e110815.
Candy 2006 {published data only}
Candy DC, Edwards D, Geraint M. Treatment of faecal
impaction with polyethylene glycol plus electrolytes (PGE
+ E) followed by a double-blind comparison of PEG + E
versus lactulose as maintenance therapy. Journal of Pediatric
Gastroenterology and Nutrition 2006;43(1):6570.
Gremse 2002 {published data only}

Gremse DA, Hixon J, Crutchfield A. Comparison of
polyethylene glycol 3350 and lactulose for treatment of
chronic constipation in children. Clinical Pediatrics 2002;
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Kokke 2008 {published data only}
Kokke FT, Scholtens PA, Alles MS, Decates TS, Fiselier TJ,
Tolboom JJ, et al.A dietary fiber mixture versus lactulose
in the treatment of childhood constipation: a doubleblind randomized controlled trial. Journal of Pediatric
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Dupont C, Leluyer B, Maamri N, Morali A, Joye J, Fiorini
J, et al.Double-blind randomized evaluation of clinical and
biological tolerance of polyethylene glycol 4000 versus
lactulose in constipated children. Journal of Pediatric
Loening-Baucke 2006 {published data only}

Loening-Baucke V, Pashankar D. A randomized,
prospective, comparison study of polyethylene glycol 3350
without electrolytes and milk of magnesia for children with
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Farahmand F. A randomised trial of liquid paraffin versus
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in children. Acta Medica Iranica 2007;45:1838.
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Gomes PB, Duarte MA, Melo Mdo C. Comparison of
the effectiveness of polyethylene glycol 4000 without
electrolytes and magnesium hydroxide in the treatment
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Nurko S, Youssef NN, Sabri M, Langseder A, McGowan J,
Cleveland M, et al.PEG3350 in the treatment of childhood
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Pitzalis 1995 {published data only}
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Virgilii F, Gasparri R, Calvani L, Bonamico M. Lactitol
in chronic idiopathic constipation in children. Pediatria
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efficacy and safety of polyethylene glycol 3350 versus
liquid paraffin in the treatment of pediatric functional
constipation. DARU 2011;19(2):1548.
Ratanamongkol 2009 {published data only}
Ratanamongkola P, Lertmaharitb S, Jongpiputvanichc S.
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infants and young children: A randomized controlled trial.
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Thomson MA, Jenkins HR, Bisset WM, Heuschkel R,
Kalra DS, Green MR, et al.Polyethylene glycol 3350 plus
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Corazziari E, Badiali D, Habib FI, Reboa G, Pitto G,
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Dupont C, Leluyer B, Amar F, Kalach N, Benhamou
PH, Mouterde O, et al.A dose determination study of
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influencing the maintenance dose. Journal of Pediatric
Ferguson 1999 {published data only}
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Tolia V, Lin CH, Elitsur Y. A prospective randomized study
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Hejl 1990 {published data only}

Hejl M, Kamper J, Ebbesen F, Hansted C. Infantile
constipation and Allomin-lactulose. Treatment of infantile
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Kazak SS, Beketova HV, Voronina SS, Amanbaieva HT.
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Voskujl 2004 {published data only}

Voskuijl W, de Lorijn F, Verwijs W, Hogeman P, Heijmans
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Kinservik MA, Friedhoff MM. The efficacy and safety of
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Wang 2007 {published data only}

Wang BX, Wang MG, Jiang MZ, Xu CD, Shao CH, Jia
LY, et al.Forlax in the treatment of childhood constipation:
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Zhongguo Dang Dai Er Ke Za Zhi 2007;9(5):42932.

Loening-Baucke V. Polyethylene glycol without electrolytes
for children with constipation and encopresis. Journal of
Pediatric Gastroenterology and Nutrition 2002;34(4):3727.
References to studies excluded from this review

Loening-Baucke V, Krishna R, Pashankar DS. Polyethylene
glycol 3350 without electrolytes for the treatment of
functional constipation in infants and toddlers. Journal of
Pediatric Gastroenterology and Nutrition 2004;39(5):5369.
Berg 1983 {published data only}

Berg I, Forsythe I, Holt P, Watts J. A controlled trial of
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Journal of Child Psychology and Psychiatry and Allied
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Miller 2012 {published data only}

Miller MK, Dowd MD, Friesen CA, Walsh-Kelly CM.
A randomized trial of enema versus polyethylene glycol
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Clayden GS. Dioctyl sodium sulphosuccinate in
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Moulies 1961 {published data only}

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results obtained with a new medicinal agent prepared from
78

the pericarp of senna follicles. Gazette Medicale de France
1961;68:23944.
Quitadamo 2010 {published data only}
Quitadamo P, Coccorullo P, Del Giudice E, Mallardo S,
Ferra V, Poli E, et al.Prospective, randomized, controlled,
multicenter study on the effectiveness of polyethylene glycol
3350 with electrolytes versus a mixture of acacia fiber,
psyllium fiber and fructose in the treatment of chronic
functional constipation in childhood. Digestive and Liver
Disease 2010;42:S355.
Shevtsov 2005 {published data only}
Shevtsov SA. Clinical efficacy of duphalac in the treatment of
functional constipations.
ksperimentalnaia i Klinicheskaia
Gastro nterologiia 2005, (6):5860.

Sonheimer 1982 {published data only}
Sondheimer JM, Gervaise EP. Lubricant versus laxative in
the treatment of chronic functional constipation of children:
a comparative study. Journal of Pediatric Gastroenterology
and Nutrition 1982;1(2):2236.
Tolia 1988 {published data only}
Tolia V. Use of a balanced lavage solution in the treatment
of fecal impaction. Journal of Pediatric Gastroenterology and
Nutrition 1988;7(2):299301.
Youssef 2002 {published data only}
Youssef NN, Peters JM, Henderson W, Shultz-Peters S,
Lockhart DK, Di Lorenzo C. Dose response of PEG 3350
for the treatment of childhood fecal impaction. Journal of
Pediatrics 2002;141(3):4104.
Additional references
Anonymous 2006
Anonymous. Evaluation and treatment of constipation in
children: summary of updated recommendations of the
North American Society for Pediatric Gastroenterology,
Hepatology and Nutrition. Journal of Pediatric
Anonymous 2010
Anonymous. Constipation in children and young people:
diagnosis and management of idiopathic childhood
constipation in primary and secondary care. Available
from http://www.nice.org.uk/nicemedia/live/12993/48721/
48721.pdf [Accessed 13th July 2010]. Published by the
RCOG Press at the Royal College of Obstetricians and
Gynaecologists, London, UK, 2010.
Baker 1999
Baker SS, Liptak GS, Colletti RB, Croffie JM, Di Lorenzo
C, Ector W, et al.Constipation in infants and children:
evaluation and treatment. A medical position statement of
the North American Society for Pediatric Gastroenterology
and Nutrition. Journal of Pediatric Gastroenterology and
Nutrition 1999;29(5):61226.
Guyatt 2008
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y,
Alonso-Coello P, et al.GRADE: an emerging consensus on
rating quality of evidence and strength of recommendations.

BMJ 2008;336(7650):9246.
Higgins 2003
Higgins JP, Thompson SG, Deeks JJ, Altman DG.
Measuring inconsistency in meta-analyses. BMJ 2003;327
(7414):557560.
Higgins 2011a
Hggins JPT, Altman DG, Sterne JAC (editors). Chapter
8: Assessing risk of bias in included studies. In: Higgins
JPT, Green S editor(s). Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 (updated March
2011). The Cochrane Collaboration, 2011. Available from
www.cochranehandbook.org.
Higgins 2011b
Higgins JPT, Deeks JJ (editors). Chapter 7: Selecting
studies and collecting data. In: Higgins JPT, Green
S editor(s). Cochrane Handbook for Systematic Reviews
of Interventions Version 5.1.0 (updated March 2011).
The Cochrane Collaboration, 2011. Available from
Hyman 2006
Hyman PE, Milla PJ, Marc A. Childhood functional
gastrointestinal disorders: neonate/toddler. Gastroenterology
2006;130(5):151926.
Lee-Robichaud 2010
Lee-Robichaud H, Thomas K, Morgan J, Nelson
RL. Lactulose versus polyethylene glycol for chronic
constipation. Cochrane Database of Systematic Reviews 2010,
Issue 7. [DOI: 10.1002/14651858.CD007570.pub2]
Partin 1992
Partin JC, Hamill SK, Fischel JE, Partin JS. Painful
defecation and fecal soiling in children. Pediatrics 1992;89
(6 Pt 1):10079.
Pijpers 2008
Pijpers MA, Tabbers MM, Benninga MA, Berger
MY. Currently recommended treatments of childhood
constipation are not evidence based: a systematic literature
review on the effect of laxative treatment and dietary
measures. Archives of Disease in Childhood 2009;94(2):
11731.
Pitkin 1999
Pitkin RM, Branagan MA, Burmeister LF. Accuracy of data
in abstracts of published research articles. JAMA 1999;281
(12):11101.
Price 2001
Price KJ, Elliot TM. Stimulant laxatives for constipation and
soiling in children. Cochrane Database of Systematic Reviews
2001, Issue 3. [DOI: 10.1002/14651858.CD002040]
Rasquin 2006
Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams
J, Staiano A, et al.Childhood functional gastrointestinal
disorders: child/adolescent. Gastroenterology 2006;130(5):
152737.
79

Rasquin-Weber 1999
Rasquin-Weber A, Hyman PE, Cucchiara S, Fleisher
DR, Hyams JS, Milla PJ, et al.Childhood functional
gastrointestinal disorders. Gut 1999;45 (Suppl 2):11608.
Schnemann 2011
Schnemann HJ, Oxman AD, Vist GE, Higgins JPT,
Deeks JJ, Glasziou P, et al.Chapter 12: Interpreting
results and drawing conclusions. In: Higgins JPT, Green
S editor(s). Cochrane Handbook for Systematic Reviews
of Interventions Version 5.1.0 (updated March 2011).
The Cochrane Collaboration, 2011. Available from
Van den Berg 2006

Van den Berg MM, Benninga MA, Di Lorenzo C.
Epidemiology of childhood constipation: a systematic
review. American Journal of Gastroenterology 2006;101(10):
24019.
Zanetti 2007
Zanetti G, Marchiori E, Gasparetto TD, Escuissato
DL, Soares Souza A Jr. Lipoid pneumonia in children
following aspiration of mineral oil used in the treatment of
constipation: high-resolution CT findings in 17 patients.
Pediatric Radiology 2007;37(11):11359.
Indicates the major publication for the study
80

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Bekkali 2009
Methods
Randomised controlled open label trial of polyethylene glycol (PEG) + electrolytes versus
enemas for faecal impaction
Participants
90 children between 4 and 16 years of age and demonstrated evidence of faecal impaction
on rectal examination. to fulfill > 1 of the other Rome III criteria for functional constipation present for 8 weeks, that is, (1) defecation frequency of 3 times per week, (2)
> 1 faecal incontinence episode per week, (3) history of retentive posturing or excessive
volitional stool retention, (4) history of painful or hard defecation, and (5) history of
large-diameter stools that may obstruct the toilet. Patients with a history of colorectal
surgery or an organic cause for constipation were excluded
Interventions
Peg 3350 + electrolytes (Movicolon, Norgine, Amsterdam),1.5 g/kg per day) for 6 consecutive days. Then maintenance (0.5 g/kg per day) for 2 weeks. Dioctylsulfosuccinate
sodium enemas (Klyx, Pharmachemie, Haarlem, The Netherlands).Once daily for 6
consecutive days (60 mL for children < 6 years of age and 120 mL for children > 6 years
of age)
Outcomes
The primary outcome was successful disimpaction. Secondary outcome measures of

defecation and faecal incontinence frequency, abdominal pain, watery stools, CTT values, and childs behavior scores were calculated for children who completed the study
protocol. Follow up for 2 weeks
Notes
Risk of bias
Bias
Authors judgement
Support for judgement
Random sequence generation (selection Unclear risk

bias)
Not described
Allocation concealment (selection bias)
Not described
Unclear risk
Blinding (performance bias and detection High risk

bias)
All outcomes
Open label
Incomplete outcome data (attrition bias)

All outcomes
Low risk
Full details reported
Selective reporting (reporting bias)
High risk
No adverse event data reported
Other bias
Low risk
None apparent
81

Candy 2006
Methods
Open label treatment of faecal impaction with PEG + electrolytes followed by a randomised double blind controlled trial of PEG + electrolytes versus lactulose. Only data
from second phase of the trial were analysed
Participants
Children aged 2 to 11 years could be enrolled in the study if they had intractable
constipation that had failed to respond to conventional treatment and would require
hospital admission for disimpaction. 58 children were enrolled. All patients included had
successfully been disimpacted in phase 1 of the trial. Children were excluded if they had
any condition contraindicating the use of PEG + E or lactulose or pre-existing organic
pathology
Interventions
PEG 3350 + electrolytes (Movicol, Norgine, UK) 1 sachet per day (mean) versus lactulose
(10 g lactulose powder dissolved in at least 125 mL water), 2.5 sachets per day (mean).
Concomitant use of senna allowed
Outcomes
The primary outcome was the mean number of defecations per week. Secondary outcomes included amount of stool, problems on defaecation (pain, straining, abdominal
pain, rectal bleeding or soiling). Follow up for 12 weeks
Notes
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Low risk

bias)
Study sponsor contacted and confirmed

they generated a computerised randomisation list
Not described
Unclear risk
Blinding (performance bias and detection Low risk

bias)
All outcomes
Similar appearance of products, identical

packaging

All outcomes
Low risk
Low risk
Data reported appropriately
Other bias
Unclear risk
Supported by Norgine. Extent of involvement unclear
82

Dupont 2005
Methods
Randomised double blind controlled trial of PEG 4000 versus lactulose
Participants
96 children aged 6 months to 3 years with constipation despite the usual dietary treatment
for at least 1 month. Children were ineligible if they had a history of intractable fecaloma
or organic gastrointestinal disease such as Hirschsprung disease
Interventions
PEG 4000 1 sachet (4 g/sachet) versus Lactulose 1 sachet /(3.33grames/sachet). The

dose could be doubled if ineffective. If the maximum authorized dose was unsuccessful,
one micro-enema (glycerol) per day could be prescribed for a maximum of 3 consecutive
days. If the child produced no stools after treatment two enemas could be administered
at a 48-hour interval
Outcomes
The primary endpoint was biological tolerance,. Secondary endpoints included clinical
efficacy measured by stool frequency and consistency, disappearance of abdominal pain
and bloating, Follow up was up to 12 weeks
Notes
Risk of bias
Bias
Authors judgement

bias)
Not described
Not described
Unclear risk

bias)
All outcomes
Described and appropriate

All outcomes
Low risk
Low risk
Other bias
Low risk
None apparent
Farahmand 2007
Methods
Randomised controlled open label trial comparing liquid paraffin versus lactulose
Participants
247 children aged 1 month to 12 years with diagnosis of functional constipation. Children with organic causes for defecation disorders were excluded from the study
Interventions
Liquid paraffin or lactulose, 1-2 ml/kg twice daily for each drug, for 8 weeks, increase
or decrease of volume of each drug allowed by 25% every 3 days as required, to yield, 1
or 2, firm to loose stools. Patients received one or two enemas daily for two days to clear
any rectal impaction at study entry
83

Farahmand 2007
(Continued)
Outcomes
Primary outcome was the number of successful bowel movements per week, with treatment success defined as three or more episodes per week. Secondary outcomes were the
incidence and severity of adverse events.Follow up was for 8 weeks
Notes
Risk of bias
Bias
Authors judgement

bias)
Not described
Not described
Unclear risk

bias)
All outcomes
Open label

All outcomes
Low risk
Low risk
Other bias
Low risk
None apparent
Gomes 2011
Methods
Randomised controlled open label trial comparing PEG versus magnesium hydroxide
Participants
38 children aged 1 to 15 years old with functional constipation according to the Rome
III criteria. Children with excluded organic causes, neurological problems or previous
surgery to the digestive system were excluded
Interventions
1 mL/kg/day for magnesium hydroxide (maximum dose 3 mL/kg/day, up to 60 mL/

day) and 0.5 g/kg/day for PEG (maximum dose 1.5 g/kg/day, up to 48 g/day)
Outcomes
Outcomes included: Stool characteristics (Bristol),5 frequency of bowel movements

(number of movements per week), abdominal pain, straining, faecal incontinence, and
acceptance of medication. Therapeutic interventions were considered failures when there
was lack of acceptance, vomiting upon administration or absence of improvement in frequency of bowel movements and/or ongoing Bristol types 1, 2 or with use of maximum
doses of the medication from the moment of the first return appointment
Notes
Risk of bias
84

Gomes 2011
(Continued)
Bias
Authors judgement

bias)
Not described
Not described
Unclear risk

bias)
All outcomes
Open label

All outcomes
High risk
No details regarding dropouts reported
High risk
No details regarding adverse events reported
Other bias
Low risk
None apparent
Gremse 2002
Methods
Randomised controlled open label crossover trial of PEG versus lactulose
Participants
37 children aged 2 to 16 years of age who were referred for subspecialty evaluation of
constipation completed the study.Those with organic disease were excluded
Interventions
PEG 3350 (Miralax, Braintree Laboratories, Inc, Braintree,MA) 10 g/m2/day or lactulose

1.3 g/kg/day both for two weeks and then patients switched agents for a further two
weeks
Outcomes
Primary outcome was number of defecations per week. Secondary outcomes included
stool form, ease of passage and global assessments by parents. 4 week follow up
Notes
Risk of bias
Bias
Authors judgement

bias)
Not described
Not described
Unclear risk

bias)
All outcomes
Open label
85

Gremse 2002
(Continued)

All outcomes
Low risk
High risk
Details not reported - no response from author
Other bias
Low risk
None apparent
Kokke 2008
Methods
Randomised double blind controlled trial of a dietary fibre mix versus lactulose
Participants
135 children ages 1 to 13 years were included. Children with organic causes of defecation
disorders were excluded
Interventions
Patients received either a yogurt drink containing lactulose (10 g/125 mL, Duphalac
Lactulose, Solvay, the Netherlands).or a mixed dietary fibres (10 g/125 mL). The fibre
mixture yogurt contained 3.0 g transgalacto-oligosaccharides (Vivinal GOS Elixor Sirup,
Friesland Foods Domo, Zwolle, the Netherlands), 3.0 g inulin (Frutafit TEX, Cosun,
Roosendaal, the Netherlands), 1.6 g soy fibre (Fibrim 2000, J. Rettenmaier & Sohne,
Ellwangen, Germany), and 0.33 g resistant starch 3 (Novelose 330, National Starch&
Chemical GmbH, Neustadt, Germany) per 100 mL
Outcomes
The primary outcome parameter was defecation frequency per week. Secondary outcome
parameters included faecal incontinence each day stool consistency and flatulence. Follow
up was for 12 weeks
Notes
Risk of bias
Bias
Authors judgement

bias)
Computer generated list
Low risk
Sequence allocation coordinated by external research organisation

bias)
All outcomes
Bottles with yogurt were prepared and

packed by Numico Research (Wageningen,
the Netherlands). Storage and delivery were
supervised by the local hospital pharmacist.
The treatment products could not be distinguished from each other with respect to
colour, taste, or consistency
86

Kokke 2008
(Continued)

All outcomes
Low risk
Low risk
Other bias
Low risk
None apparent
Loening-Baucke 2006
Methods
Randomised controlled open label trial comparing PEG 3350 without electrolytes with
milk of magnesia
Participants
79 children aged > 4 years and presence of functional constipation with faecal incontinence. Exclusion criteria included organic causes for symptoms, toileting refusal or
medication refusal
Interventions
PEG 0.7 g/kg body weight daily or Milk of magnesia 2 mL/kg body weight daily.
Instructions were given to parents on how to vary doses to achieve acceptable stools.
Children were disimpacted with 1 or 2 phosphate enemas in the clinic on the day of the
visit, if necessary, and started laxative therapy that evening. Senna was allowed
Outcomes
Primary outcome was Improvement defined as 3 bowel movements per week, 2 episodes
of faecal incontinence per month, and no abdominal pain, with or without laxative
therapy. Secondary outcomes included (1) improvement in stool frequency per week,
improvement in episodes of faecal incontinence per week, and resolution of abdominal
pain; (2) safety profile; and (3) patients acceptance and compliance. Follow up was for
12 months
Notes
Risk of bias
Bias
Authors judgement

bias)
Drawing lots
Assignments in sealed envelopes
Low risk

bias)
All outcomes
Open label

All outcomes
Low risk
Low risk
87

Loening-Baucke 2006
(Continued)
Other bias
Low risk
None apparent
Nurko 2008
Methods
Randomised, multicenter, double-blind trial comparing PEG 3350 with placebo
Participants
103 children 4 to 16 years of age. Patients who were taking other laxatives were included
only if they had > 3 bowel movements per week while taking the laxative, and all laxatives
were stopped at least 2 days before the run-in period started. Exclusion criteria included
children with organic causes of constipation
Interventions
PEG3350, (MiraLax, Braintree Laboratories, Inc; Braintree, MA) at doses of 0.2, 0.4,
0.6 or 0.8 grams per kilogram per day or placebo. (CrystalLight, Proctor and Gamble;
Cincinnati, OH). All received behavioural modification
Outcomes
The primary outcome was the proportion of patients who responded to treatment. Response to treatment was defined as >3 BM during the second week of treatment. Secondary efficacy variables included the weekly number of BM and faecal incontinence
episodes and changes in the scores of stool consistency, straining, and abdominal cramping. 2 weeks follow up
Notes
Additional Mean and Standard deviation data regarding the frequency of defecations
were obtained from Braintree Labs Inc
Risk of bias
Bias
Authors judgement

bias)
Not described
Not described
Unclear risk

bias)
All outcomes
Identically labelled bottles that were reconstituted with water to 4,000 mL by study
personnel in the pharmacy. There was no
difference in the colour, appearance, or
taste among the different doses

All outcomes
Low risk
Low risk
Other bias
Low risk
Supported by Braintree Labs Inc. They

confirmed they had no involvement in the
running of the study or the writing of the
published manuscript
88
Perkin 1977
Methods
Randomises controlled crossover trial of lactulose versus senna
Participants
21 children under 15 years of age with a history of greater than 3 weeks constipation.
Children with other organic causes of constipation were excluded
Interventions
Lactulose 10-15 mL per day or Senna 10-20 mL per day for 1 week, then1 week with
no treatment and then patients switched to received the other treatment
Outcomes
Stool consistency, number of stools per day and adverse events. Follow up for 3 weeks
Notes
Risk of bias
Bias
Authors judgement

bias)
Random number list, but method of creation not described
Assignments in sealed envelopes
Low risk
Blinding (performance bias and detection Unclear risk

bias)
All outcomes
Although author describes that identical

bottles with no identification were used,
further detail to confirm blinding are not
given

All outcomes
Low risk
Low risk
Other bias
Low risk
None apparent
Pitzalis 1995
Methods
Randomised controlled trial comparing lactitol with lactulose
Participants
42 children aged 8 months - 16 years old with less than 3.5 stools per week. Patients
with other organic pathology were excluded
Interventions
Lacitol (Portolac zyma) 250 mg/kg/day single dose, Can be increased to 400mg/kg/day.
Lactulose (Epalfen zambon) 500 mg/kg/day single dose, Can be increased to 750 mg/
kg/day
Outcomes
Primary outcome measure was the frequency of defecation and secondary measures
included palatability and colonic transit time. Follow up was for 1 month
89

Pitzalis 1995
(Continued)
Notes
Italian publication
Risk of bias
Bias
Authors judgement

bias)
Not described
Unclear risk
Not described

bias)
All outcomes
Not described

All outcomes
Low risk
High risk
No adverse events mentioned
Other bias
Low risk
None apparent
Rafati 2011
Methods
Randomised controlled trial comparing PEG with liquid paraffin
Participants
158 children aged 2 to 12 years with a history of functional constipation
Interventions
1.0-1.5 g/kg/day PEG 3350 or 1.0-1.5 ml/kg/day liquid paraffin orally for 4 months.
PEG 3350 powder was prepared as a 40% solution to trust reliable to apply the paediatric dosing and to increase compliance and liquid paraffin was provided from a pharmaceutical factory. For rectal disimpaction, bisacodyl suppositories were applied at the
beginning of the study
Outcomes
Primary outcomes were stool and encopresis frequency per week
Notes
Risk of bias
Bias
Authors judgement

bias)
Not described
Not described
Unclear risk
90

Rafati 2011
(Continued)

bias)
All outcomes
Not described

All outcomes
High risk
Dropouts are not explained
High risk
No adverse event data reported
Other bias
Low risk
None apparent
Ratanamongkol 2009
Methods
Randomised controlled trial comparing PEG 4000 without electrolytes to milk of magnesia
Participants
94 infants and children aged one-four years. Patients were organic causes for their constipation or renal insufficiency were excluded
Interventions
PEG400 without electrolytes, 0.5 g/kg/day, maximal does 1 g/kg/day or milk of magnesia
suspension, 400 mg/5mL, 0.5 mL/kg/day, maximal does 3 mL/kg/day
Outcomes
The primary outcome measure was the improvement rate, defined as the proportion of
patients who had > three bowel movements per week, < two episodes of faecal incontinence per month, and no painful defecation, with or without laxative therapy. Other
outcome studies were: 1) improvement in stool frequency per week; 2) the proportion
of the patients who had any adverse effects; and 3) the compliance rate, defined as the
proportion of patients who received more than 80% of the medication. Follow up was
for 4 weeks
Notes
Risk of bias
Bias
Authors judgement

bias)
Computer generated random number list
Sealed opaque assignment envelopes sequentially opened
Low risk

bias)
All outcomes
Not clear whether this was a blinded study

All outcomes
Low risk
91

Ratanamongkol 2009
(Continued)
Low risk
Other bias
Low risk
None apparent
Thomson 2007
Methods
Randomised controlled double blind crossover trial comparing PEG 3350 with electrolytes versus placebo
Participants
51 children aged 24 months to 11 years were eligible for enrolment. Constipation was
defined according to the Rome criteria. Children were excluded from the study if they had
current or previous faecal impaction or organic pathology causing their constipation Also,
if they were currently receiving doses of stimulant laxatives considered by local observers
to be at the higher end of their own dose spectrum (senna or sodium picosulphate) with
no effect, having assessed to their clinical satisfaction adequate compliance
Interventions
Placebo or PEG 3350 with electrolytes (Movicol, Norgine Pharnaceuticals, UK). The
dosing regimen was based on age and clinical response. Participants received 2 weeks
of therapy, followed by a 2 week washout period and then a further 2 weeks with the
alternate therapy
Outcomes
The primary efficacy variable was the mean number of complete defaecations per week.
Secondary efficacy variables included the total number of complete and incomplete
defaecations per week, pain on defaecation, straining on defaecation, faecal incontinence,
stool consistency, and a global assessment of treatment by the investigator and by the
child or his or her parent or guardian, as well as recording of adverse events. Follow up
for 6 weeks
Notes
Risk of bias
Bias
Authors judgement

bias)
Sealed opaque envelopes used
Low risk

bias)
All outcomes
Described and appropriate

All outcomes
Low risk
Low risk
92

Thomson 2007
(Continued)
Other bias
Low risk
Sponsored by Norgine Pharmaceuticals.

The author confirmed that they had no
involvement in the writing of the final
manuscript
Tolia 1993
Methods
Randomised controlled open trial comparing PEG 3350 with mineral oil (liquid paraffin)
for the treatment of faecal impaction
Participants
36 children older than 2 years in age with constipation were potentially acceptable for
the study. Patients were excluded if they had any other organic cause for their impaction.
physical examination by the presence of firm to hard faecal impaction in the anal canal
and rectal ampulla on an otherwise normal complete initial physical examination
Interventions
PEG 3350 (Colyte, 20 mL/kg/hour for 4 hours) on two days or 30 mL/10kg of mineral
oil twice a day for two days. Those receiving PEG had a single dose of metoclopramide
Outcomes
Outcomes included time to first stool, frequency of stool movements, consistency, distention, cramps, nausea and vomiting, as well as side effects.Follow up were after two
days
Notes
Risk of bias
Bias
Authors judgement

bias)
Not described
Unclear risk

bias)
All outcomes
Open label

All outcomes
Low risk
Low risk
Other bias
Low risk
None apparent
93

Urganci 2005
Methods
Randomised open label trial of Liquid paraffin versus lactulose
Participants
40 children 2 to 12 years old with constipation with evidence of faecal impaction were
enrolled in the study.Those with organic pathology were excluded
Interventions
Liquid paraffin or lactulose 1 ml/kg, twice daily for each drug. For determination of
the best dose for each child, parents were asked to increase or decrease the volume of
each drug by 25% every 3 days as required, to yield two firm-loose stools per day. The
maximum dose used throughout the study was 3 mL/kg per day for each drug. All
participants received behavioural advice and saw a nutritionist
Outcomes
Primary outcome was effective treatment, defined as clearance of the impaction (more
than three bowel movements per week and improvement in stool consistency). Secondary
outcomes included stool frequency and stool consistency in first 4 weeks and last 4 weeks,
as well as adverse events. Follow up was for 8 weeks
Notes
Risk of bias
Bias
Authors judgement

bias)
Not described
Not described
Unclear risk

bias)
All outcomes
Open label

All outcomes
Low risk
Low risk
Other bias
Low risk
None apparent
Voskujl 2004
Methods
Randomised double blind trial comparing PEG 3350 with Lactulose
Participants
100 children aged six month to 15 years were included in this study. Children with an
organic cause for their constipation were excluded
Interventions
Patients had a 1 week run in and then received daily rectal enemas for 3 days (<6 years of
age received 60 ml Klyx (sodium dioctylsulfosuccinate and sorbitol) while those >6 years
of age received 120 ml Klyx). Lactulose (6 g (sachet)) versus PEG 3350 (2.95 g (sachet)
94

Voskujl 2004
(Continued)
) 1 sachet per day under 6 starting, 2 over 6. Reassed at 1 week and either increase by 1
sachet or decreased by 50%
Outcomes
The primary outcomes were frequency of stools, frequency of encopresis, and overall
treatment success at eight weeks. An increase in defecation frequency was considered to
have improved if it rose to three or more times a week while encopresis had to decrease
to an incidence of one episode or less every two weeks. The incidence of adverse events
was also documented. Follow up was for 8 weeks
Notes
Risk of bias
Bias
Authors judgement

bias)
Not described
Not described
Unclear risk

bias)
All outcomes
Identical sachets, released by central pharmacy

All outcomes
Low risk
Low risk
Other bias
Low risk
None apparent
Wang 2007
Methods
Randomised controlled multi-centre trial comparing PEG 4000 with lactulose
Participants
216 children from 8-18 years old. Those with other organic disease were excluded
Interventions
Patients received either PEG 4000 (Forlax, 2 sachets x 20g/day) versus lactulose (15 mL/
day, then drop to 10 mL after 3 days)
Outcomes
Primary outcome was frequency of bowel movements. Secondary outcomes included

stool consistency, abdominal symptoms and safety. Follow up was for 2 weeks
Notes
Chinese publication
Risk of bias
Bias
Authors judgement

95

Wang 2007
(Continued)

bias)
Not described
Unclear risk
Not described

bias)
All outcomes
Not described

All outcomes
Low risk
Low risk
Other bias
Low risk
None apparent
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Berg 1983
Study does not include patients with functional constipation, but those diagnosed with functional soiling
Clayden 1978
Not a RCT, Letter
Corazziari 1996
Not a Paediatric study
Dupont 2006
Not a RCT, no comparison group
Ferguson 1999
Not a Paediatric study
Hardikar 2007
Hejl 1990
Kazak 1999
Meets exclusion criteria, children have underlying pathology
Kinservik 2004
Review article
Loening-Baucke 2002
Not a RCT
Loening-Baucke 2004
Not a RCT, retrospective chart review
Miller 2012
The trial focused on the treatment of faecal impaction rather than treatment of constipation
Moulies 1961
Not a RCT
96

(Continued)
Quitadamo 2010
Abstract publication
Shevtsov 2005
Not a RCT
Sonheimer 1982
Not a RCT
Tolia 1988
Not a RCT
Youssef 2002
97

DATA AND ANALYSES
Comparison 1. PEG versus Placebo
Outcome or subgroup title

1 Frequency of defecation
2 Serious adverse events
No. of
studies
No. of
participants
2
2
101
101
Statistical method
Mean Difference (IV, Random, 95% CI)
Odds Ratio (M-H, Fixed, 95% CI)
Effect size
2.61 [1.15, 4.08]
0.17 [0.02, 1.48]
Comparison 2. PEG versus Lactulose

2 Need for additional therapies
3 Need for additional therapies
(sensitivity analysis)
4 Adverse events
No. of
studies
No. of
participants
4
3
3
328
254
254

Odds Ratio (M-H, Random, 95% CI)
1.09 [0.02, 2.17]

0.49 [0.27, 0.89]
0.51 [0.19, 1.38]
154
0.37 [0.14, 1.03]
Statistical method
Effect size
Comparison 3. PEG versus Milk of Magnesia

(sensitivity analysis)
No. of
studies
No. of
participants
3
3
211
211
Statistical method
Mean Difference (IV, Fixed, 95% CI)
Effect size
0.69 [0.48, 0.89]
0.69 [0.48, 0.89]
Comparison 4. Paraffin versus Lactulose

No. of
studies
No. of
participants
287
Statistical method
Effect size
4.94 [4.28, 5.61]
98

Comparison 5. PEG versus Enema
No. of
studies
No. of
participants
1
1
80
90
2 Successful disimpaction
Statistical method
Effect size

1.00 [-1.58, 3.58]

0.52 [0.20, 1.37]
Comparison 6. Lactulose versus Lactitol
No. of
studies
No. of
participants
42
Statistical method
Effect size
-0.80 [-2.63, 1.03]
Comparison 7. PEG versus Paraffin
No. of
studies
No. of
participants
158
Statistical method
Effect size
0.70 [-0.38, 1.78]
Analysis 1.1. Comparison 1 PEG versus Placebo, Outcome 1 Frequency of defecation.

Review:
Osmotic and stimulant laxatives for the management of childhood constipation
Comparison: 1 PEG versus Placebo

Outcome: 1 Frequency of defecation
Study or subgroup
PEG
Mean
Difference
Placebo
Weight
IV,Random,95% CI
Mean
Difference
Mean(SD)
Mean(SD)
IV,Random,95% CI
Nurko 2008
26
5.96 (3.81)
24
2.42 (2.104)
39.3 %
3.54 [ 1.85, 5.23 ]
Thomson 2007
27
3.59 (2.26)
24
1.58 (1.131)
60.7 %
2.01 [ 1.04, 2.98 ]
Total (95% CI)
53
100.0 %
2.61 [ 1.15, 4.08 ]
48
Heterogeneity: Tau2 = 0.68; Chi2 = 2.38, df = 1 (P = 0.12); I2 =58%

Test for overall effect: Z = 3.49 (P = 0.00048)
Test for subgroup differences: Not applicable
-20
-10
Favours Placebo
10
20
Favours PEG
99
Analysis 1.2. Comparison 1 PEG versus Placebo, Outcome 2 Serious adverse events.
Review:
Comparison: 1 PEG versus Placebo

Outcome: 2 Serious adverse events
Study or subgroup
PEG
Placebo
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
Nurko 2008
0/26
3/24
69.6 %
0.12 [ 0.01, 2.37 ]
Thomson 2007
0/27
1/24
30.4 %
0.28 [ 0.01, 7.33 ]
Total (95% CI)
53
48
100.0 %
0.17 [ 0.02, 1.48 ]
M-H,Fixed,95% CI
Total events: 0 (PEG), 4 (Placebo)

Heterogeneity: Chi2 = 0.16, df = 1 (P = 0.69); I2 =0.0%
0.001 0.01 0.1

Favours PEG
10 100 1000
Favours Placebo
100

Analysis 2.1. Comparison 2 PEG versus Lactulose, Outcome 1 Frequency of defecation.
Review:
Comparison: 2 PEG versus Lactulose

Study or subgroup
PEG
Mean
Difference
Lactulose
Weight
Mean(SD)
Mean(SD)
Candy 2006
28
9.4 (4.56)
30
5.9 (4.29)
14.2 %
3.50 [ 1.22, 5.78 ]
Dupont 2005
51
7.24 (1.48)
45
7.21 (2.67)
31.2 %
0.03 [ -0.85, 0.91 ]
Gremse 2002
37
14.8 (1.4)
37
13.5 (1.5)
34.3 %
1.30 [ 0.64, 1.96 ]
Voskujl 2004
50
7.12 (5.14)
50
6.43 (3.08)
20.3 %
0.69 [ -0.97, 2.35 ]
100.0 %
1.09 [ 0.02, 2.17 ]
Total (95% CI)
166
IV,Random,95% CI
Mean
Difference
IV,Random,95% CI
162

-10
-5
Favours Lactulose
10
Favours PEG
101

Analysis 2.2. Comparison 2 PEG versus Lactulose, Outcome 2 Need for additional therapies.
Review:

Outcome: 2 Need for additional therapies
Study or subgroup
PEG
Lactulose
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Candy 2006
0/28
8/30
26.1 %
0.05 [ 0.00, 0.85 ]
Dupont 2005
14/51
19/45
47.4 %
0.52 [ 0.22, 1.22 ]
Voskujl 2004
9/50
10/50
26.5 %
0.88 [ 0.32, 2.39 ]
129
125
100.0 %
0.49 [ 0.27, 0.89 ]
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 23 (PEG), 37 (Lactulose)

Heterogeneity: Chi2 = 3.85, df = 2 (P = 0.15); I2 =48%
0.01
0.1
Favours PEG
10
100
Favours Lactulose
Analysis 2.3. Comparison 2 PEG versus Lactulose, Outcome 3 Need for additional therapies (sensitivity
analysis).
Review:

Outcome: 3 Need for additional therapies (sensitivity analysis)
Study or subgroup
PEG
Lactulose
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI
n/N
n/N
Candy 2006
0/28
8/30
10.3 %
0.05 [ 0.00, 0.85 ]
Dupont 2005
14/51
19/45
47.6 %
0.52 [ 0.22, 1.22 ]
Voskujl 2004
9/50
10/50
42.2 %
0.88 [ 0.32, 2.39 ]
129
125
100.0 %
0.51 [ 0.19, 1.38 ]
Total (95% CI)

0.01
0.1
Favours PEG
10
100
Favours Lactulose
102
Analysis 2.4. Comparison 2 PEG versus Lactulose, Outcome 4 Adverse events.

Review:

Outcome: 4 Adverse events
Study or subgroup
PEG
Lactulose
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
Candy 2006
17/28
25/30
75.6 %
0.31 [ 0.09, 1.05 ]
Dupont 2005
2/51
3/45
24.4 %
0.57 [ 0.09, 3.58 ]
Total (95% CI)
79
75
100.0 %
0.37 [ 0.14, 1.03 ]
M-H,Fixed,95% CI

0.01
0.1
Favours PEG
10
100
Favours Lactulose
103

Analysis 3.1. Comparison 3 PEG versus Milk of Magnesia, Outcome 1 Frequency of defecation.
Review:
Comparison: 3 PEG versus Milk of Magnesia

Study or subgroup
PEG
Mean
Difference
MOM
Weight
Mean(SD)
Mean(SD)
Gomes 2011
17
5 (1.56)
21
4.31 (1.89)
3.4 %
0.69 [ -0.41, 1.79 ]
Loening-Baucke 2006
39
9.7 (5.6)
40
9.7 (6)
0.6 %
0.0 [ -2.56, 2.56 ]
Ratanamongkol 2009
47
5.94 (0.652)
47
5.25 (0.32)
95.9 %
0.69 [ 0.48, 0.90 ]
100.0 %
0.69 [ 0.48, 0.89 ]
Total (95% CI)
103
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
108

Test for overall effect: Z = 6.61 (P < 0.00001)
-2
-1
Favours MOM
Favours PEG
104

Analysis 3.2. Comparison 3 PEG versus Milk of Magnesia, Outcome 2 Frequency of defecation (sensitivity
analysis).
Review:
Comparison: 3 PEG versus Milk of Magnesia

Outcome: 2 Frequency of defecation (sensitivity analysis)
Study or subgroup
PEG
Mean
Difference
MOM
Mean
Difference
Weight
Mean(SD)
Mean(SD)
Gomes 2011
17
5 (1.56)
21
4.31 (1.89)
3.4 %
0.69 [ -0.41, 1.79 ]
Loening-Baucke 2006
39
9.7 (5.6)
40
9.7 (6)
0.6 %
0.0 [ -2.56, 2.56 ]
Ratanamongkol 2009
47
5.94 (0.652)
47
5.25 (0.32)
95.9 %
0.69 [ 0.48, 0.90 ]
100.0 %
0.69 [ 0.48, 0.89 ]
Total (95% CI)
103
IV,Random,95% CI
IV,Random,95% CI
108
Heterogeneity: Tau2 = 0.0; Chi2 = 0.28, df = 2 (P = 0.87); I2 =0.0%

-2
-1
Favours MOM
Favours PEG
Analysis 4.1. Comparison 4 Paraffin versus Lactulose, Outcome 1 Frequency of defecation.

Review:
Comparison: 4 Paraffin versus Lactulose

Study or subgroup
Farahmand 2007
Urganci 2005
Total (95% CI)
Paraffin
Mean
Difference
Lactulose
Weight
Mean(SD)
Mean(SD)
127
13.1 (2.3)
120
8.1 (3.1)
95.2 %
5.00 [ 4.32, 5.68 ]
20
16.1 (2.2)
20
12.3 (6.6)
4.8 %
3.80 [ 0.75, 6.85 ]
100.0 %
4.94 [ 4.28, 5.61 ]
147
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
140

-4
-2
Favours Lactulose
Favours Paraffin
105
Analysis 5.1. Comparison 5 PEG versus Enema, Outcome 1 Frequency of defecation.

Review:
Comparison: 5 PEG versus Enema

Study or subgroup
Bekkali 2009
Total (95% CI)
PEG
Mean
Difference
Enema
Mean(SD)
Mean(SD)
39
8.7 (6.4)
41
7.7 (5.3)
39
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
41
100.0 %
1.00 [ -1.58, 3.58 ]
100.0 %
1.00 [ -1.58, 3.58 ]
Heterogeneity: not applicable

-10
-5
Favours Enema
10
Favours PEG
106

Analysis 5.2. Comparison 5 PEG versus Enema, Outcome 2 Successful disimpaction.
Review:
Comparison: 5 PEG versus Enema

Outcome: 2 Successful disimpaction
Study or subgroup
Bekkali 2009
PEG
Enema
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
30/44
37/46
100.0 %
0.52 [ 0.20, 1.37 ]
44
46
100.0 %
0.52 [ 0.20, 1.37 ]
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 30 (PEG), 37 (Enema)

0.1 0.2
0.5
Favours Enema
10
Favours PEG
Analysis 6.1. Comparison 6 Lactulose versus Lactitol, Outcome 1 Frequency of defecation.

Review:
Comparison: 6 Lactulose versus Lactitol

Study or subgroup
Lactulose
Pitzalis 1995
Total (95% CI)
Mean
Difference
Lactitol
Mean(SD)
Mean(SD)
23
4.8 (2.1)
19
5.6 (3.6)
23
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
19
100.0 %
-0.80 [ -2.63, 1.03 ]
100.0 %
-0.80 [ -2.63, 1.03 ]

-10
-5
Favours Lactitol
10
Favours Lactulose
107

Analysis 7.1. Comparison 7 PEG versus Paraffin, Outcome 1 Frequency of defecation.
Review:
Comparison: 7 PEG versus Paraffin

Study or subgroup
Rafati 2011
Total (95% CI)
PEG
Mean
Difference
Paraffin
Mean(SD)
Mean(SD)
80
7 (3.8)
78
6.3 (3.1)
80
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
78
100.0 %
0.70 [ -0.38, 1.78 ]
100.0 %
0.70 [ -0.38, 1.78 ]

-4
-2
Favours Paraffin
Favours PEG
HISTORY
Protocol first published: Issue 5, 2011
Review first published: Issue 7, 2012
CONTRIBUTIONS OF AUTHORS
Morris Gordon conceived the review, carried out the search, data extraction and analysis and led the writing of the manuscript. Khimara
Naidoo also conducted the search, data extraction and assisted with the analysis, as well as commenting on drafts of the manuscript.
Anthony Akobeng and Adrian Thomas assisted with the analysis and contributed towards the writing and commented on drafts of the
review.
DECLARATIONS OF INTEREST
Morris Gordon received a travel grant from Norgine Pharmaceuticals to present the results of this review at Digestive Disease Week in
Chicago, May 2011. Norgine had no input in the design, execution or write up of the study. Additionally, Morris Gordon has received
travel grants since completing this review from Cassen Fleet Pharmaceuticals and Ferring Pharmaceuticals to attend Digestive Disease
Week 2012, but again they have had no involvement in this or any other research works completed.
108

INDEX TERMS
Medical Subject Headings (MeSH)
Constipation [ drug therapy]; Defecation [drug effects; physiology]; Dietary Fiber [adverse effects; therapeutic use]; Lactulose [adverse
effects; therapeutic use]; Laxatives [adverse effects; therapeutic use]; Magnesium Hydroxide [adverse effects; therapeutic use]; Mineral
Oil [adverse effects; therapeutic use]; Osmosis; Polyethylene Glycols [adverse effects; therapeutic use]; Randomized Controlled Trials
as Topic; Sugar Alcohols [adverse effects; therapeutic use]
MeSH check words

Adolescent; Child; Child, Preschool; Humans; Infant
109

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EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL

Evid.-Based Child Health 8:1: 57109 (2013)

Osmotic and stimulant laxatives for the management of

Evid.-Based Child Health 8:1: 57109 (2013)

Evid.-Based Child Health 8:1: 57109 (2013)

Osmotic and stimulant laxatives for the management of

and St Thomas NHS Foundation Trust, London, UK

Evid.-Based Child Health 8:1: 57109 (2013)

PLAIN LANGUAGE SUMMARY

PEG versus placebo

Quality of the evidence

Sparse data (101 patients)

GRADE Working Group grades of evidence

The mean number of

Illustrative comparative risks* (95% CI)

Frequency of defecation The mean number of

Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation

PEG versus placebo for the management of childhood constipation

Evid.-Based Child Health 8:1: 57109 (2013)

Evid.-Based Child Health 8:1: 57109 (2013)

Description of the condition

How the intervention might work

Why it is important to do this review

The primary objectives are to evaluate the efficacy and safety of

Evid.-Based Child Health 8:1: 57109 (2013)

4. Cochrane Inflammatory Bowel Disease and Functional Bowel

The search strategy was not limited by language.

Randomised controlled trials were considered for inclusion.

The primary outcome measure was the frequency of defecation

Secondary outcomes included:

Search methods for identification of studies

Evid.-Based Child Health 8:1: 57109 (2013)

Data collection and analysis

b. study methods, total number of patients originally assigned to

Assessment of risk of bias in included studies

Measures of treatment effect

Evid.-Based Child Health 8:1: 57109 (2013)

Evid.-Based Child Health 8:1: 57109 (2013)

Evid.-Based Child Health 8:1: 57109 (2013)

The total number of participants in the included trials was 1,643.

Risk of bias in included studies

Evid.-Based Child Health 8:1: 57109 (2013)

Evid.-Based Child Health 8:1: 57109 (2013)

Incomplete outcome data

Other potential sources of bias

PEG versus Placebo

Evid.-Based Child Health 8:1: 57109 (2013)

Episodes of faecal incontinence

Need for additional therapies

2.2. When a sensitivity analysis using a random-effects model was

Evid.-Based Child Health 8:1: 57109 (2013)

study and lack of blinding, incomplete outcome data and selective

PEG versus Milk of Magnesia

Liquid Paraffin versus Lactulose

Evid.-Based Child Health 8:1: 57109 (2013)

Dietary fibre mix versus Lactulose

Senna versus Lactulose

Lactitol versus Lactulose

PEG versus lactulose

Quality of the evidence