MOVICOL® (PEG3350 plus electrolytes): 20 years of evidence-based use Back

David Candy, Heinz Hammer, Peter Layer, Jorge Serra, Alessandra Barraco, Ansuya Naidoo, Patricia Dixon

Abstract

Introduction Polyethylene glycol (PEG)-based laxatives are a mainstay of treatment for constipation. MOVICOL®, the first formulation of PEG3350 plus electrolytes (PEG3350+E) licensed in Europe has now been available for more than 20 years.

Objective The objective was to identify and review evidence for PEG-based laxatives in adults and children with constipation or faecal impaction.

Method A systematic review of published data relating to the use of PEG-based laxatives in constipation was carried out. Studies relating to PEG3350+E were identified and used as the basis of a narrative review. Lack of consistency in patient groups, treatment regimens, comparators and duration of follow-up precluded the use of meta-analysis.

Results Overall, 80 qualifying studies were identified, of which 29 used PEG3350+E; MOVICOL® (n=18) or generic PEG3350+E (n=12). PEG3350+E showed superior efficacy and tolerability versus lactulose and ispaghula husk, and was non-inferior to prucalopride in the treatment of constipation. Efficacy was maintained over the long-term with no additional tolerability concerns and maintenance of electrolyte balance. PEG3350+E was effective in disimpaction and significantly more effective than lactulose in maintaining disimpaction in children.

Conclusion MOVICOL® has now been used for over 20 years and has demonstrated efficacy across all types of constipation, with an excellent safety record and comprehensive evidence-base in children, adults and older people.

Key words: constipation, faecal impaction, osmotic laxative, lactulose, MOVICOL®, electrolyte, polyethylene glycol

Introduction

The osmotic laxative, MOVICOL®, was the first polyethylene glycol (PEG)-based laxative (macrogol) licensed in Europe to treat constipation and faecal impaction. MOVICOL® has now been available for more than 20 years and products in the MOVICOL® range are approved in more than 45 countries throughout Europe, Australia, New Zealand, South Africa, Asia and the Middle East. MOVICOL® is a branded formulation of PEG3350 plus electrolytes (PEG3350+E), and all other subsequent formulations of PEG3350+E have used MOVICOL® as the reference product. This article reviews 20 years of evidence-based use of MOVICOL® by bringing together background information about MOVICOL® and updating the evidence-base for PEG3350+E and other PEG-based laxatives in constipation and faecal impaction.

Worldwide, constipation is one of the most common gastrointestinal disorders affecting adults and children. The prevalence ranges from 0.7% to 79% (median 16%) in adults,1,2 and 0.7% to 29.6% (median 12%) in children,1 depending on the diagnostic criteria used.

Constipation is a symptom rather than a disease in itself and the treatment is symptomatic. There are numerous causes of constipation and many patients do not have a clearly identifiable cause. Constipation is generally defined as either functional (which can be divided into normal transit, slow transit and defaecation disorders, and includes constipation related to irritable bowel syndrome [IBS]), or secondary constipation with an underlying cause, such as colorectal cancer, opioid-induced constipation or pregnancy).

The Rome Criteria are used to define functional gastrointestinal disorders including constipation.3 Functional constipation is defined as at least two of the following in any 12-week period during the previous year: infrequent bowel movements (<3 per week), hard stool in ≥25% of bowel movements, sense of incomplete evacuation in ≥25% of bowel movements, sensation of anorectal obstruction in ≥25% of bowel movements and the need for manual evacuation in ≥25% of bowel movements. However, patients tend to have a wider view of symptoms, including abdominal discomfort, bloating and distention.4,5 Constipation is more common in women than men and prevalence increases with age; lower socioeconomic status and educational level also impact negatively on the prevalence of constipation.1,2

Inadequate dietary fibre and fluid, lack of exercise and ignoring the urge to defecate all contribute to constipation. However, there are specific patient groups who are at high risk of constipation, including women in the later stages of pregnancy, older people, patients with comorbidities (which may be structural, systemic or neurological) or those taking constipation-inducing drugs (for example, opiates, iron supplements).4 Older people are five times more likely than younger adults to develop constipation; this is not due to physiological ageing, but rather to poor diet (inadequate fluid or fibre), lack of exercise, use of constipating medication and poor bowel habits.4

Constipation has a significant impact on patients’ quality of life, comparable to other common chronic diseases such as musculo-skeletal conditions and inflammatory bowel disease.6 Patients with constipation are also at significantly increased risk of existing and new comorbidities, both gastrointestinal and non-gastrointestinal, compared to patients without constipation.7

Constipation is also common in children, affecting around one in eight children worldwide;1 symptoms become chronic in more than one-third of patients and constipation is a common reason for referral to secondary care.8 Constipation in children is generally functional and is mainly due to withholding behaviour, although inadequate fibre or liquid intake and lack of physical activity are also important. However, some children with physical disabilities, such as cerebral palsy, are more prone to secondary constipation as a result of impaired mobility and gastrointestinal dysmotility.9 Children and young people with Down’s syndrome or autism are also more prone to the condition.10 Guidelines highlight that early identification of constipation in children and effective treatment are important and have been shown to improve outcomes.10

Faecal impaction is defined as an immobile build-up of hardened faeces in the rectum and/or colon. Uncontrolled constipation is the most significant risk factor leading to faecal impaction. Poor management of constipation in older nursing home patients means that a significant proportion, in one study almost one-half, of nursing home residents have faecal impaction.11

In children, painful defaecation is a common trigger for withholding behaviour, which may lead to a cycle of chronic constipation and faecal impaction.8,12 Retention of faeces may lead to faecal incontinence/soiling as liquid or semi-solid faeces leak around the accumulated stool,13 which has a considerable impact on the child and their family.

Current management strategies for constipation include lifestyle measures (increasing dietary fibre and fluid intake, and exercise) and reviewing any constipation- causing medication as an initial starting point. If such measures do not alleviate constipation then laxatives are recommended. In adults, osmotic laxatives (PEG-based laxatives or lactulose) or bulk-forming laxatives (ispaghula husk or methylcellulose) are recommended. Stimulant laxatives are added into the treatment pathway if osmotic or bulk-forming laxatives are inadequate (Figure 1).4,5,14,15 In adult patients with functional defaecation disorders, biofeedback treatment can be helpful. In patients with opioid-induced constipation, bulk-forming laxatives should be avoided and first-line treatment should be PEG-based laxatives together with a stimulant laxative.16

In children, PEG-based laxatives are recommended as first-line treatment.10,15

The aim of treatment for faecal impaction is the achievement of complete disimpaction, with the minimum of discomfort. This may require several days’ treatment in which doses and combinations of laxatives are adjusted. PEG-based laxatives are recommended first-line to empty the bowel and regular use of a PEG-based laxative as maintenance treatment may also be needed to maintain comfortable defaecation. Enemas are also effective in faecal disimpac- tion, but the administration route is uncom- fortable and guidelines recommend they should only be used in children when all oral treatments have failed.10,14 Manual evacuation is an extremely unpleasant procedure and should only be practised when all other methods of disimpaction have failed.

PEG-based laxatives are supported by a comprehensive evidence-base; two large systematic reviews carried out in 2009 and 2010 demonstrate that PEG-based laxatives result in consistently good outcomes in constipation and faecal impaction in children and adults. PEG-based treatment results in a significant increase in defaecations per week over both placebo and lactulose.17,18 Two Cochrane reviews carried out in adults in 201019 and in children in 201220 confirm the advantage of PEG-based laxatives over lactulose.

The purpose of this review is to update the systematic reviews for PEG-based laxatives and to specifically review the clinical evidence for PEG3350+E.

Osmotic laxatives

Mode of action

Water makes up 75–80% of the weight of a normal stool, but a difference of only 10% in hydration will result in marked changes in stool consistency.21 PEG, a water-soluble polymer with a large molecular weight, has the capacity to form hydrogen bonds with 100 molecules of water per molecule of PEG (average molecular weight: 3350). In doing so, PEG exerts more of an osmotic effect than would be predicted from its molecular weight due to interactions between PEG and water molecules that alter the physical chemistry of the solution and sequester water from the solution.22 When PEG is taken orally, the resulting hydration of the colonic content facilitates transit and painless defaecation in a linear dose-dependent fashion, as illustrated in Figure 2.23 Most side-effects with PEG-based laxatives result from the mode of action and are gastrointestinal in nature, and include abdominal pain, flatulence and diarrhoea.

Lactulose is an alternative osmotic laxative, which has a pure osmotic effect. Lactulose is a non-absorbable synthetic disaccharide, which is metabolised by colonic bacteria to form short-chain fatty acids and gases. The laxative effect results from osmotic binding of water by short-chain fatty acids, electrolytes and any remaining unmetabolised lactulose.24 Given that lactulose is metabolised in the colon, increasing the dose eventually results in a plateau as the metabolic capacity of the colon becomes saturated.13 The gases produced as a by-product of bacterial metabolism of lactulose can cause abdominal pain, bloating and flatulence.

The differing modes of action mean that when PEG is compared with lactulose there are significant differences in stool weight and stool transit time. PEG leads to a dose-dependent and linear increase in stool weight, which is greater than that seen with lactulose.23 In a study in healthy volunteers, all patients receiving PEG had stool weight above the upper limit of normal (200g/day), whereas 20% of patients receiving lactulose had stool weight <200g per day.24 Furthermore at a similar stool weight, colonic transit was significantly slower with lactulose than with PEG. In healthy volunteers, transit time in the distal colon was 2.5-times longer with lactulose compared with PEG; 403±55 minutes with lactulose (99g/day) versus 160±42 minutes with PEG (59g/day).24

A potential factor in the superiority  of PEG-based laxatives over lactulose may be that, unlike lactulose, whose metabolic by-products enhance colonic water absorption, PEG is not metabolised by intestinal bacteria and hence no osmotic activity is lost during transit through the colon.25 Because of this, PEG-based laxatives induce less bloating and flatulence.26

There are a number of PEG-based laxatives, which differ by the average molecular weights (3350 or 4000). It should be noted, however, that the quoted figure is a mean value and by virtue of the spread of the individual molecular weights within preparations, there is likely to be overlap at the molecular level between PEG3350 and PEG4000.

The presence or absence of electrolytes is a second difference between preparations. The addition of electrolytes (sodium bicarbonate, sodium chloride, potassium chloride) is designed to ensure a balance of electrolytes (sodium, potassium, bicarbonate), particularly when agents are used in high doses or for a prolonged period of time. The electrolytes are exchanged across the intestinal mucosa with serum electrolytes and excreted in faecal water without net gain or loss of sodium, potassium and water, avoiding harm to the patient.27 Clinical experience has demonstrated that electrolyte balance is maintained in patients treated with PEG3350+E across the full age range from children to older patient.13,26,28

The mode of action of PEG means that there is no impact on nutrient absorption from the gut. Studies have demonstrated that the use of PEG3350 and PEG4000 in adults and children does not impact on the absorption of total protein, serum albumin, iron, folates and vitamins A, B12 and D from the gut.29–31

 

 

Evolution of MOVICOL® over 20 years

MOVICOL® was developed by Norgine in the early 1990s and was first registered in December 1995 in the UK, which subsequently acted as Reference Member State during the European Mutual Recognition Procedure. Products in the MOVICOL® range are now approved for the treatment of constipation and faecal impaction across the world. Formulations of PEG3350+E other than MOVICOL® are also available; however, it should be noted that these products used MOVICOL® as the reference product in their registration process.

MOVICOL® is available in a broad range of doses, formulations and flavours to suit most patients’ requirements. Formulations include powder for reconstitution (two flavours and unflavoured) and a liquid concentrate formulation (flavoured). Both formulations need to be mixed with water prior to use; the liquid concentrate mixes more quickly than powder and may be more convenient than powder for some patients to use. MOVICOL® liquid concentrate (25ml) is equivalent to one sachet of MOVICOL® powder (13.125g) and the two formulations are equivalent in terms of efficacy and tolerability.32 MOVICOL® is also available in a lower dose in a half formulation and a paediatric formulation (6.563g PEG per sachet), providing flexible dosing to suit each patient’s individual needs.

MOVICOL® is indicated for the treatment of chronic constipation. MOVICOL® is also effective in resolving faecal impaction, defined as refractory constipation with faecal loading of the rectum and/or colon.27 The different preparations of MOVICOL® have slightly different licences; however, the broad indication of chronic constipation is common to all preparations.

MOVICOL® may be used for the treatment of constipation in patients aged two and upward, including pregnant and breastfeeding women. It is also suitable for patients with most concomitant diseases, including impaired renal function. MOVICOL® is contraindicated in patients, like all laxatives, with intestinal perforation or obstruction due to structural or functional disorder of the gut wall, ileus, severe inflammatory conditions of the intestinal tract, such as Crohn’s disease and ulcerative colitis and toxic megacolon. MOVICOL® may be used for the treatment of faecal impaction in patients aged five years and over.27

Due to their specific mechanism of action PEG-based laxatives, such as MOVICOL®, have no specific drug–drug interactions, although it should be noted that there may be a reduction in drug absorption due to an increased rate of gastrointestinal transit.27

 

Clinical evidence for PEG-based laxatives

The objective of this review was to identify evidence for PEG-based laxatives in adults and children with constipation or faecal impaction and to assess their efficacy versus both placebo and active comparators. The systematic review identified studies using all PEG-based laxatives regardless of molecular weight and inclusion of electrolytes, and summary results are given for all products (see Supplementary Information at the end of this KOM). Given the scope of this article, the results section focuses on the evidence for MOVICOL® and other PEG3350+E preparations.

Methods

Initial literature search

Online searches were carried out on MEDLINE, EMBASE and Cochrane Library from 1980 to January 2015. Specific search strategies were developed using the appropriate nomenclature for each source. The general strategy was: [Polyethylene glycol] OR [macrogol] OR [PEG3350] OR [PEG4000] OR [MOVICOL® OR Miralax OR Transipeg OR GoLytely OR Endofalk OR Isopeg OR Forlax OR Idrolax OR Isocolan] AND [Constipation] OR [Fecal impaction] NOT [Bowel preparation].

Although the list of brand names used in the search is not exhaustive, it includes the major brands and, in combination with the generic terms, was considered sufficient to identify all relevant papers.

Identified abstracts were scanned for the possibility of compliance with inclusion/exclusion criteria (see below). Full texts of papers that passed the initial scan were obtained to ascertain the final inclusion decision. Secondary searches were carried out by scanning reference lists of all full text papers obtained, specifically sourcing all previous systematic reviews to scan reference lists and index searching of the top journals featuring in our search results.

Inclusion and  exclusion  criteria

Inclusion and exclusion criteria are shown in Table 1.

 

Results

The results of the literature searches are documented in Figures 3 and 4. After applying all inclusion and exclusion criteria, 80 studies were identified – 53 randomised controlled trials (RCTs) and 27 non-RCTs. Details of all the identified studies are shown in Tables S1 and S2 in the Supplementary Information at the end of this KOM.

Of the identified studies, 30 were carried out using PEG3350+E: 10 RCTs and eight observational studies with MOVICOL®, and nine RCTs and three observational studies with generic PEG3350+E. Details of the PEG3350+E studies are shown in Tables 2 and 3.

Efficacy: evidence for PEG3350+E

This section will focus on the evidence-base for PEG3350+E, as both the branded product (MOVICOL®) and the unbranded generic product.

Constipation: evidence in adults

Where possible, the results have been standardised by considering the impact on weekly bowel movements and tabulating the data (Table 4); however, this endpoint is not shared by all the studies and additional data are presented where necessary.

PEG3350+E versus placebo

There were six RCTs in patients with constipation versus placebo, two large studies (n=308 and n=139) using MOVICOL® in critically ill patients with multiple organ failure38 and constipation associated with IBS,34 two small studies (n=37 and n=34) using PEG3350+E in patients with functional constipation39,40 and two small studies using PEG3350+E (both n=57) in patients with secondary constipation due to Parkinson’s disease and opiate use.43,47

In all six studies the use of PEG3350+E was more efficacious than placebo. In four of the studies, weekly bowel movements were included as an endpoint and the results are shown in Table 4 and Figure 5 below.

Turning to the two studies without weekly bowel movement data, both studies showed benefit with PEG3350+E over placebo in the relief of constipation. In the study of critically ill patients, participants received MOVICOL®, lactulose or placebo for a maximum of four days or until a bowel movement. Defaecation occurred in 74% of MOVICOL® patients versus 32% of placebo patients (p=0.001) during the four-day study period.38 In the study of patients with constipation due to Parkinson’s disease, the response rate (composite of frequency, straining and consistency) was 78% with PEG3350+E versus 25% with placebo (p=0.0003) at four weeks and 80% versus 30% (p=0.0012) at eight weeks.47

PEG3350+E versus lactulose

There were three RCTs in patients with constipation versus lactulose: two large studies using MOVICOL® – one in functional constipation (n=115)26 and one in critically ill patients (n=308),38 and a third using PEG3350+E in patients with opiate-induced constipation.43

In two of the three studies, PEG3350+E was more efficacious than lactulose (see Table 2)26,43 and in the remaining study in critically ill patients, PEG3350+E was comparable to lactulose.38 Data were not available on weekly bowel movements in the study of critically ill patients. In this study, participants received MOVICOL®, lactulose or placebo for a maximum of four days or until a bowel movement (MOVICOL® versus placebo data have already been presented). Defaecation occurred in 74% of MOVICOL® patients versus 69% of lactulose patients, during the four-day study period.38

PEG3350+E versus other agents

One RCT considered MOVICOL® versus ispaghula husk28 in patients with functional constipation; MOVICOL® was significantly more efficacious than ispaghula husk in terms of weekly bowel movements, 8.48 versus 5.71 (p<0.001), see Table 4.

One RCT considered MOVICOL® versus prucalopride, which is a selective serotonin 5-HT4 receptor agonist with prokinetic properties.35 Prucalopride is licensed for the treatment of chronic constipation in women when other laxatives have failed to provide an adequate response. MOVICOL® was non-inferior to prucalopride in terms of the primary endpoint (proportion of patients having ≥3 spontaneous bowel movements in the last treatment week, 66.7% versus 56.5%) and superior in terms of weekly bowel movements (13.1 versus 9.03; p<0.001), see Table 4.

PEG3350+E versus PEG4000 without E

There were two RCTs in patients with functional constipation that compared PEG3350+E to PEG4000 without E with differing results.41,42 One study showed that the two formulations had similar efficacy; PEG3350+E had numerically higher weekly stool rate compared with PEG4000 without E although this was not statistically significant.41 The other study showed that the weekly stool rate was higher with PEG4000 without E and that PEG4000 without E was superior to PEG3350+E on a range of efficacy measures,42 see Table 4.

A number of open studies also provide evidence for the long-term efficacy of PEG3350+E and confirm the results seen in the RCTs and shown in Table 4.

Long-term data

The longest published exposure to PEG3350+E is for 24 months. Data were assessed retrospectively from an open study in institutionalised patients with severe learning disabilities (n=54) treated with MOVICOL®. Efficacy was maintained over the 24-month study period and there were no changes in body weight or blood biochemistry.53

Long-term data on the use of PEG3350+E for six months are available from an observational study of 231 patients with chronic functional constipation.54 Information on efficacy and safety was collected using patient diaries and investigator interviews. Initial treatment was two sachets/day and the dose was self-titrated to achieve one bowel movement per day.

PEG3350+E resulted in a rapid increase in the number of daily bowel movements from 0.32 at baseline to 0.9 at week one and 1.1 at week two. The increase in the number of bowel movements was sustained and was associated with improvements in the symptoms of constipation (stool consistency, pain, ease of bowel movement and flatulence).

Long-term data on the use of MOVICOL® for three months are available from a subset of patients in the Attar et al study.26 Twenty of the 105 patients enrolled in the study, which compared MOVICOL® and lactulose over a one-month period, were followed for a further two months.36 All patients received MOVICOL® for the final two months of treatment. Efficacy was maintained in all patients; however, patients who switched from lactulose to MOVICOL® for months two and three (n=10) showed a significant improvement in ease of defaecation and reduction in flatulence.

Data in patients with comorbid conditions

A small open study in patients with Parkinson’s disease or multiple system atrophy (n=10) with severe chronic constipation refractory to treatment with other laxatives (all but one patient had a mean of one stool per week or less for at least one year before study entry despite receiving treatment with lactulose ± other agents) revealed that treatment with MOVICOL® resulted in marked improvements in bowel function within 2–10 days in all patients.50 After two weeks, patients were able to reduce the dose of MOVICOL® and stop using concomitant laxatives. Patients were followed up for between 9 and 21 weeks (mean: 13 weeks) and efficacy was maintained during the follow-up period.

Another open study, already mentioned, which was conducted in institutionalised mentally handicapped patients with severe learning disabilities (n=54) and assessed retrospectively, revealed that treatment with MOVICOL® doubled the number of monthly bowel movements from 12.4 at baseline to 24.9 at the end of the 24-month study (p<0.001).53 Efficacy was maintained over the 24-month study period. Use of rectal laxatives was reduced from 2325 units at baseline to 978 by the end of the study and most patients stopped using concomitant oral laxatives, with resultant cost savings (€2021 per hospital ward per year, 1985–1998 costs).

Two open studies with PEG3350+E considered the treatment of palliative care patients with opiate-induced constipation. The studies revealed that PEG3350+E was effective as part of a stepped regimen for the prophylaxis and management of constipation,55 and that patients receiving PEG3350+E (n=95) had more weekly bowel movements than those receiving lactulose (n=32) or sodium picosulphate (n=36): 4.06 versus 1.26 versus 2.52.56

Constipation: evidence in children

PEG3350+E versus placebo

One RCT in children aged 2–11 years with chronic functional constipation considered MOVICOL® versus placebo (n=51).37 The study was crossover in design with two 2-week treatment periods, separated by a 2-week placebo washout. MOVICOL® was significantly more efficacious than placebo in terms of weekly bowel movements (3.12 versus 1.45; p<0.001) and other measures of constipation (pain, straining, faecal incontinence, stool consistency and global assessment of treatment).

PEG3350+E versus lactulose

Two RCTs compared PEG3350+E with lactulose, one using MOVICOL® as maintenance treatment after disimpaction for three months (n=58)13 and one using PEG3350+E (n=100) in children aged six months to 15 years with chronic functional constipation.46 Both studies demonstrated significant benefit with PEG3350+E over lactulose.

MOVICOL® was more efficacious than lactulose as maintenance after disimpaction, with significantly more weekly bowel movements (9.4 versus 5.9; p=0.007). Furthermore none of the children receiving MOVICOL® reimpacted during the three-month maintenance period versus 23% of those receiving lactulose (p=0.011). Senna was allowed as rescue therapy; this was not required in any of the children randomised to MOVICOL®, but was required in 31% of those who received lactulose (p<0.002).13

PEG3350+E was more efficacious than lactulose in terms of successful treatment (56% versus 29%; p=0.02), although there was no significant difference in the number of weekly bowel movements (7.10 versus 6.43) with each agent. PEG3350+E was associated with less straining, abdominal pain, flatulence and pain at defaecation than lactulose.46

PEG3350+E versus other agents

One RCT compared PEG3350+E with fibre and fructose (n=100) over an eight-week study period.44 Both agents resulted in relief of constipation, with similar efficacy in terms of weekly bowel movements (5.8 versus 5.6) and proportion of patients showing improvement (83% versus 78%).

PEG3350+E versus PEG4000 without E

One RCT compared MOVICOL® with PEG4000 without E for four weeks (n=96).8 Both agents resulted in relief of constipation, although patients receiving PEG4000 without E had more weekly bowel movements than those treated with MOVICOL® (9.2 versus 7.8; p=0.025).

Long-term data in children

Two open long-term studies of 12 weeks51 and six months52 provide evidence that MOVICOL® is effective over the long-term. In the 12-week study, the mean number of bowel movements per week increased from 1.4 at baseline to 6.8 after 14 days, and was maintained at 7.1 bowel movements per week at 12 weeks (p<0.001).51 In the six-month study, the number of bowel movements per week increased from 2.4 at baseline to 6.2 at six months (p<0.001).52

Faecal impaction: evidence in adults

Two open studies show that MOVICOL® is effective in disimpaction in adults.48,49 In both studies high-dose MOVICOL® (eight sachets/24 hours, corresponding to 105g of PEG3350) given over three days was highly effective. In one study, 89% of patients (50/56) had a successful response to treatment with 39 complete responses and 11 partial responses.48 All measures (volume of bowel movement, number and ease of evacuations, form of bowel movement) showed improvements within two days. In the other study, all 30 patients had a successful response to treatment with 26 complete responses and four partial responses.49 Complete resolution was seen after one day in 13 patients, after two days in 11 patients and after three days in one patient.

Faecal impaction: evidence in children

One RCT compared six consecutive days’ treatment with MOVICOL® with enemas in 90 children;33 both approaches were successful although successful disimpaction rates were numerically higher with enemas (68% versus 80%; p=0.28). A large (n=224) retrospective chart review of case notes for children aged 2–11 years assessed the clinical outcomes of patients who had received MOVICOL® (n=112) or enemas/ suppositories (n=101) or manual evacuation (n=11) for the treatment of faecal impaction.12 Successful disimpaction was significantly more frequent with MOVICOL®, with almost all of the children achieving disimpaction within five days (97%) versus 73% of those receiving enemas/suppositories and 89% undergoing manual disimpaction (p<0.001).

One open study assessed MOVICOL® in faecal impaction for up to seven days followed by a three-month double-blind comparison of MOVICOL® and lactulose for maintenance.13 Disimpaction was achieved in 92% of patients (58/62) and median time to disimpaction was six days (range three to seven days). None of the children receiving MOVICOL® reimpacted during the three-month maintenance period, whereas 23% of children receiving lactulose reimpacted (p=0.011).

One RCT compared PEG3350+E with mineral oil (n=36) for two days,45 and found that PEG3350+E was significantly more effective than mineral oil in disimpaction – 90% of patients receiving PEG3350+E achieved at least one bowel movement versus 71% of those receiving mineral oil (p<0.005).

Tolerability: evidence for PEG3350+E

PEG3350+E is well tolerated with rates of adverse events (AE) comparable to placebo in adults and children.34,37 Most AEs are gastrointestinal in nature, including abdominal pain, flatulence and diarrhoea, and are mild to moderate in severity.

A review of clinical data carried out  by Norgine57 assessed outcomes in 3259 patients (including children, adults and older people, patients with comorbid conditions) treated during the clinical trial programme, revealed that there were 11 deaths and six serious AEs, none of which were considered related to treatment with MOVICOL®. Allergic reactions were reported in two patients, one of whom was known to be allergic to citrus fruit (citrus flavouring is used in MOVICOL®) and one was considered to be possibly allergic to PEG itself.

Patients treated over the long-term, up to 24 months, did not report any unexpected AEs.52,54 In a study using PEG3350+E for six months, discontinuation rates due to AEs were low at 6% (14/231) and AEs were considered to be related to PEG3350+E in only eight patients, all of which were gastrointestinal in nature. Two additional patients had AEs that were possibly related to PEG3350+E, both of which were gastrointestinal in nature.54

PEG3350+E appears to have improved tolerability compared with other agents, with less flatulence compared with lactulose and ispaghula husk.26,28,43 A study in 100 children indicated a trend towards more abdominal pain, straining and pain with lactulose than with PEG3350+E.46

Headache and gastrointestinal symptoms (including abdominal pain, nausea and diarrhoea) are the most frequent side-effects of prucalopride. Data from one study revealed that PEG3350+E was generally better tolerated than prucalopride.35

However, data are conflicting when PEG3350+E is compared with PEG4000 without E. Two studies show that tolerability is improved with PEG4000 without E, in particular acceptability of the taste of the treatment,8,42 and one shows that tolerability is similar.41

Conclusions

This systematic review brings the evidence for PEG-based laxatives in constipation and faecal impaction in adults and children up to date. It demonstrates that PEG-based laxatives are effective and well tolerated for the management of constipation and faecal impaction. PEG3350+E has a comprehensive evidence-base in children, adults and older people. Evidence extends to patients with functional constipation, constipation related to IBS and secondary constipation (patients with critical illness, Parkinson’s disease, multiple system atrophy, severe disability and opiate-induced constipation).

Looking specifically at MOVICOL®, the majority of the evidence in constipation suggests that MOVICOL® shows superior efficacy and tolerability versus lactulose.13,26 Evidence compared with other agents shows that MOVICOL® is more efficacious than ispaghula husk28 and is non-inferior to prucalopride.35

Long-term data, for patients treated for up to 24 months, provides evidence that the efficacy of MOVICOL® is maintained over the long term with no additional tolerability concerns and maintenance of electrolyte balance over the 24-month treatment period.53 Data are available for up to six months’ use of PEG3350+E in 231 patients with chronic functional constipation; efficacy and tolerability were maintained and discontinuation rates due to AEs were low at 6%.54

There is less evidence for PEG-based laxatives in faecal impaction than for constipation; however, the available data show that PEG-based laxatives are effective and well tolerated in the treatment of faecal impaction and maintenance of disimpaction in children and adults. Most evidence for disimpaction is with MOVICOL®. Successful disimpaction occurs in the majority of patients treated with MOVICOL®, with most patients achieving disimpaction within two days.48,49 MOVICOL® is significantly more effective than lactulose in maintaining disimpaction in children over the long term.13 MOVICOL® is as effective or more effective than enemas/suppositories or manual evacuation in disimpaction,12,33 without an unpleasant invasive procedure.

Efficacy in the relief of constipation and faecal impaction demonstrated with MOVICOL® is supported by studies using other formulations of PEG3350+E.

The safety of PEG-based laxatives has been demonstrated over the long-term. The inert nature of the product and the mode of action of PEG-based laxatives are such that there is no impact on nutrient absorption from the gut and no drug–drug interactions. Furthermore, PEG-based laxatives may be used in pregnancy and during breastfeeding, and in older people. Indeed, few patient groups are unsuitable for treatment with PEG-based laxatives.27

The addition of electrolytes (sodium bicarbonate, sodium chloride, potassium chloride) to MOVICOL® and other PEG3350+E preparations ensures that electrolyte balance (sodium, potassium, bicarbonate) is maintained. This is particularly pertinent in situations when agents are used at a high dose, for example during disimpaction, or for a prolonged period of time, for example in patients with secondary constipation. Clinical experience has demonstrated that electrolyte balance is maintained in patients treated with MOVICOL® across the full age range from children to older patients, during disimpaction, routine use for constipation and long-term use in secondary constipation for 24 months.13,26,28,53

Guidelines recommend osmotic laxatives (PEG-based laxatives or lactulose) early in the treatment.4,5,10,14,15 If PEG- based laxatives or bulk-forming laxatives are inadequate, then a stimulant laxative should be added into treatment. Unlike bulk-forming laxatives, PEG-based laxatives are recommended in frail, immobile or palliative care patients. PEG-based laxatives are recommended over lactulose due to the improved efficacy and tolerability of PEG-based products compared with lactulose.

Recent guidelines from the National Institute for Health and Care Excellence (NICE) in the UK recommend PEG3350+E as first-line treatment for children and young people for disimpaction and ongoing treatment of constipation.10 Enemas and manual disimpaction should only be considered in patients in whom oral measures have been unsuccessful. NICE recommends that children who have had disimpaction continue on a lower dose of PEG3350+E as maintenance therapy. Some children may need maintenance therapy for several years and treatment should be gradually reduced in response to bowel habit.

To conclude, MOVICOL® has a long heritage and has been trusted for the treatment of constipation for 20 years. MOVICOL® is an effective laxative that restores and maintains healthy bowel function. It is supported by an extensive evidence-base and is considered the laxative of choice in childhood disimpaction and constipation. Its use is recommended early in the treatment pathway for adults with constipation, and particularly those with opioid-induced constipation. The addition of E ensures that the electrolyte balance is maintained, and MOVICOL® can be used at high doses for faecal disimpaction and over the long-term in patients with secondary constipation.

References

      1. Mugie SM, Benninga MA, Di LC. Epidemiology of constipation in children and adults: a systematic review. Best Pract Res Clin Gastroenterol 2011;25:3–18.
      2. Schmidt FM, Santos VL. Prevalence of constipation in the general adult population: an integrative review. J WoundOstomy Continence Nurs 2014;41:70–6.
      3. Rome Foundation. Rome III Diagnostic Criteria for functional gastrointestinal disorders Raleigh NC, USA 2006 (www.romecriteria. org/assets/pdf/19_RomeIII_apA_885-898.pdf; accessed 26 May 2016).
      4. World Gastroenterology Organisation. World Gastroenterology Organisation Practice Guidelines: Constipation. 2007.
      5. Bharucha AE, Dorn SD, Lembo A, Pressman A. American Gastroenterological Association medical position statement on constipation. Gastroenterol 2013;144:211–7.
      6. Belsey J, Greenfield S, Candy D, Geraint M. Systematic review: impact of constipation on quality of life in adults and children. Aliment Pharmacol Ther 2010;31:938–49.
      7. Mody R, Guerin A, Fok B, et al. Prevalence and risk of developing comorbid conditions in patients with chronic constipation. Curr Med Res Opin 2014;30:2505–13.
      8. Savino F, Viola S, Erasmo M, et al. Efficacy and tolerability of peg-only laxative on faecal impaction and chronic constipation in children. A controlled double blind randomized study vs a standard peg-electrolyte laxative. BMC Pediatr 2012;12:178.
      9. Park ES, Park CI, Cho SR, et al. Colonic transit time and constipation in children with spastic cerebral palsy. Arch Phys Med Rehabil 2004;85:453–6.
      10. National Institute for Health and Care Excellence. Constipation in children and young people: diagnosis and management of idiopathic childhood constipation in primary and secondary care. Clinical guideline 99. 2010 (www.nice.org.uk/guidance/cg99; accessed 26 May 2016).
      11. Rey E, Barcelo M, Jimenez Cebrian MJ, et al. A nation-wide study of prevalence and risk factors for fecal impaction in nursing homes. PLoS One 2014;9:e105281.
      12. Guest JF, Candy DCA, Clegg JP, et al. Clinical and economic impact of using macrogol 3350 plus electrolytes (MOVICOL®/MOVICOL® paediatric pain) in an outpatient setting compared to enemas and suppositories and manual evacuation to treat paediatric faecal impaction based on actual clinical practice in England and Wales. Curr Med Res Opin 2007;23:2213–25.
      13. Candy DC, Edwards D, Geraint M. Treatment of faecal impaction with polyethelene glycol plus electrolytes (PEG+E) followed by a double-blind comparison of PEG+E versus lactulose as maintenance therapy. J Pediatr Gastroenterol Nutr 2006;43:65–70.
      14. NICE. Clinical knowledge summary: constipation. 2014.
      15. Andresen V, Enck P, Frieling T, et al. [S2k guideline for chronic constipation: definition, pathophysiology, diagnosis and therapy]. Z Gastroenterol 2013;51:651–72.
      16. Goodheart CRLSB. Managing opioid-induced constipation in ambulatory-care patients. Pain Treatment Topics. 2006.
      17. Belsey JD, Geraint M, Dixon TA. Systematic review and meta analysis: polyethylene glycol in adults with non-organic constipation. Int J Clin Pract 2010;64:944–55.
      18. Candy D, Belsey J. Macrogol (polyethylene glycol) laxatives in children with functional constipation and faecal impaction: a systematic review. Arch Dis Child 2009;94:156–60.
      19. Lee-Robichaud H, Thomas K, Morgan J, Nelson RL. Lactulose versus polyethylene glycol for chronic constipation. Cochrane Database Syst Rev 2010;CD007570.
      20. Gordon M, Naidoo K, Akobeng AK, Thomas AG. Osmotic and stimulant laxatives for the management of childhood constipation. Cochrane Database Syst Rev 2012;7:CD009118.
      21. Bernier JJ, Donazzolo Y. [Effect of low-dose polyethylene glycol 4000 on fecal consistency and dilution water in healthy subjects]. Gastroenterol Clin Biol 1997;21:7–11.
      22. Schiller LR, Emmett M, Santa Ana CA, Fordtran JS. Osmotic effects of polyethylene glycol. Gastroenterology 1988;94:933–41.
      23. Hammer HF, Santa Ana CA, Schiller LR, Fordtran JS. Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose. J Clin Invest 1989;84:1056–62.
      24. Fritz E, Hammer HF, Lipp RW, et al. Effects of lactulose and polyethylene glycol on colonic transit. Aliment Pharmacol Ther 2005;21:259–68.
      25. Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev 2001;81:1031–64.
      26. Attar A, Lemann M, Ferguson A, et al. Comparison of a low dose polythylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut 1999;44:226–30.
      27. Norgine Ltd. Summary of Product Characteristics for MOVICOL® 13.8g sachet, powder for oral solution (www. medicines.org.uk/emc/medicine/1244/SPC/movicol+13.8g+sachet,+powder+ for+oral+solution/; accessed 14 June 2016).
      28. Wang H-J, Liang X-M, Yu Z-L, et al. A randomised, controlled comparison of low-dose polyethylene glycol 3350 plus electrolytes with ispaghula husk in the treatment of adults with chronic functional constipation. Clinical Drug Investigation 2004;24:569–76.
      29. Dupont C, Leluyer B, Maamri N, et al. Double-blind randomized evaluation of clinical and biological tolerance of polyethelene glycol 4000 versus lactulose in constipated children. J Paed Gastroenterol Nutr 2005;41:625–33.
      30. Corazziari E, Badiali D, Bazzocchi G, et al. Long-term efficacy, safety, and tolerability of low daily doses of isosmotic polythylene glycol electrolyte balanced solution (PMF-100) in the treatment of functional chronic constipation. Gut 2000;46:522–6.
      31. Hudziak H, Bronowicki JP, Franck P, et al. [Low-dose polyethylene glycol 4000: digestive effects. Randomized double-blind study in healthy subjects]. Gastroenterol Clin Biol 1996;20:418–23.
      32. Norgine Ltd. Summary of product characteristics for MOVICOL® liquid (http://www.medicines.org.uk/emc/medicine/2465524655; accessed 14 June 2016).
      33. Bekkali NL, Berg MM, Dijkgraaf MG, et al. Rectal fecal impaction treatment in childhood constipation: enemas versus high doses oral PEG. Pediatrics 2009;124:e1108–15.
      34. Chapman RW, Stanghellini V, Geraint M, Halphen M. Randomized clinical trial: macrogol/PEG3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am J Gastroenterol 2013;108:1508–15.
      35. Cinca R, Chera D, Gruss HJ, Halphen M. Randomised clinical trial: macrogol/ PEG3350+electrolytes versus prucalopride in the treatment of chronic constipation — a comparison in a controlled environment. Aliment Pharmacol Ther 2013;37:876–86.
      36. Ferguson A, Culbert P, Gillett H, et al. New polythylene glycol electrolyte solution for the treatment of constipation and faecal impaction. Ital J Gastroenterol Hepatol 1999;31:S249–52.
      37. Thomson MA, Jenkins HR, Bisset WM, et al. Polyethylene glycol 3350 plus electrolytes for chronic constipation in children: A double blind, placebo controlled, crossover study. Arch Dis Childhood 2007;92:996–1000.
      38. van der Spoel JI, Oudemans-van Straaten HM, Kuiper MA, et al. Laxation of critically ill patients with lactulose or polyethylene glycol: a two-center randomized, double-blind, placebo-controlled trial. Crit Care Med 2007;35:2726–31.
      39. Andorsky RI, Goldner F. Colonic lavage solution (polyethylene glycol electrolyte lavage solution) as a treatment for chronic constipation: a double-blind, placebo-controlled study. Am J Gastroenterol 1990; 85:261–5.
      40. Baldonedo YC, Lugo E, Uzcategui AA, et al. Polythylene glycol as a treatment for chronic constipation. GEN 1991;45:294–7.
      41. Chaussade S, Minic M. Comparison of efficacy and safety of two doses of two differences polythylene glycol-based laxatives in the treatment of constipation. Aliment Pharmacol Ther 2003;17:165–72.
      42. Couturier D. [Comparative study of Forlax and Transipeg in the treatment of functional constipation in the adult]. Ann Gastroenterol Hepatol (Paris) 1996;32:135–40.
      43. Freedman MD, Schwartz HJ, Roby R, et al. Tolerance and efficacy of polythylene glycol 3350/electrolyte solution versus lactulose in relieving opiate induced constipation: A double-blinded placebo-controlled trial. J Clin Pharmacol 1997; 37:904–7.
      44. Quitadamo P, Coccorullo P, Giannetti E, et al. A randomized, prospective, comparison study of a mixture of acacia fiber, psyllium fiber, and fructose vs polyethylene glycol 3350 with electrolytes for the treatment of chronic functional constipation in childhood. J Pediatr 2012;161:710–5.
      45. Tolia V, Lin CH, Elitsur Y. A prospective randomized study with mineral oil and oral lavage solution for treatment of faecal impaction in children. Aliment Pharmacol Ther 1993;7:523–9.
      46. Voskuijl W, de Lorijn F, Verwijs W, et al. PEG 3350 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial. Gut 2004; 53:1590–4.
      47. Zangaglia R, Martignoni E, Glorioso M, et al. Macrogol for the treatment of constipation in Parkinson’s disease. A randomized placebo-controlled study. Movement Dis 2007;22:1239–44.
      48. Chen CC, Su MY, Tung SY, et al. Evaluation of polyethylene glycol plus electrolytes in the treatment of severe constipation and faecal impaction in adults. Curr Med Res Opin 2005;21:1595–602.
      49. Culbert P, Gillett H, Ferguson A. Highly effective oral therapy (polyethylene glycol/electrolyte solution) for faecal impaction and severe constipation. Clin Drug Invest 1998;16:355–60.
      50. Eichhorn TE, Oertel WH. Macrogol 3350/ electrolyte improves constipation in Parkinson’s disease and multiple system atrophy. Movement Dis 2001;16:1176–7.
      51. Hardikar W, Heine R, Davidson N, et al. Macrogol 3350 plus electrolytes (MOVICOL®) for chronic constipation in children, a single-centre, open-label study. J Paediatr Child Health 2007;43:527–31.
      52. Infante PD, Segarra CO, Vilalta CR, et al. [Efficacy, tolerance and safety of polyethylene glycol 3350 plus electrolytes for the treatment of functional constipation in children]. An Pediatr (Barc) 2014;80:278–84.
      53. Migeon-Duballet I, Chabin M, Gautier A, et al. Long-term efficacy and cost-effectiveness of polyethylene glycol 3350 plus electrolytes in chronic constipation: a retrospective study in a disabled population. Curr Med Res Opin 2006;22:1227–35.
      54. Paille F, Colombey N, Alleaume B, et al. An open six-month study of the safety of Transipeg for treating constipation in community medicine. Journal of Drug Assessment 1999;2:97–108.
      55. Wirz S, Klaschik E. Management of constipation in palliative care patients undergoing opioid therapy: is polyethylene glycol an option? Am J Hosp Palliat Care 2005;22:375–81.
      56. Wirz S, Nadstawek J, Elsen C, et al. Laxative management in ambulatory cancer patients on opioid therapy: a prospective, open-label investigation of polyethylene glycol, sodium picosulphate and lactulose. Eur J Cancer Care 2012;21:131–40.
      57. Norgine Ltd. MOVICOL®: clinical overview. 2011. Data on file.
      58. Cleveland MvB, Flavin DP, Ruben RA, et al. New polythylene glycol laxative for treatment of constipation in adults. South Med J 2001;94:478–81.
      59. Di Palma JA. Braintree polyethylene glycol (PEG) laxative for ambulatory and long-term care facility constipation patients: report of randomized, cross-over trials. Online J Dig Health 1999;2:1–10.
      60. Di Palma JA, DeRidder PH, Orlando RC, et al. A randomized, placebo-controlled, multicenter study of the safety and efficacy of a new polyethylene glycol laxative. Am J Gastroenterol 2000;95:446–50.
      61. Di Palma JA, Smith JR, Cleveland M. Overnight efficacy of polyethylene glycol laxative. Am J Gastroenterol 2002;97:1776–9.
      62. Di Palma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter comparison of polyethylene glycol laxative and tegaserod in treatment of patients with chronic constipation. Am J Gastroenterol 2007;102:1964–71.
      63. Di Palma JA, Cleveland MvB, McGowan J, et al. A randomised multicenter placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol 2007;102:1–6.
      64. Di Palma JA, Cleveland MB, McGowan J, Herrera JL. A comparison of polyethylene glycol laxative and placebo for relief of constipation from constipating medications. South Med J 2007;100:1085–90.
      65. Gremse DA, Hixon J, Crutchfield A. Comparison of polythylene glycol 3350 and lactulose for treatment of chronic constipation in children. Clin Pediatr 2002;41:225–9.
      66. Karami H, Khademloo M, Niari P. Polyethylene glycol versus paraffin for the treatment of childhood functional constipation. Iran J Pediatr 2009;19:255–61.
      67. Loening-Baucke V. Polyethylene glycol without electrolytes for children with constipation and encopresis. J Pediatr Gastroenterol Nutr 2002;34:372–7.
      68. Loening-Baucke V, Pashankar DS. A randomized, prospective, comparison study of polyethylene glycol 3350 without electrolytes and milk of magnesia for children with constipation and fecal incontinence. Pediatr 2006;118:528–35.
      69. Miller MK, Dowd MD, Friesen CA, Walsh-Kelly CM. A randomized trial of enema versus polyethylene glycol 3350 for fecal disimpaction in children presenting to an emergency department. Pediatric Emerg Care 2012;28:115–9.
      70. Nardulli G, Limongi F, Sue G, et al. [Use of polyethylene glycol in the treatment of puerperal constipation]. GEN 1995;49:224–6.
      71. Nurko S, Youssef NN, Sabri M, et al. PEG3350 in the treatment of childhood constipation: a multicenter, double-blinded, placebo-controlled trial. J Pediatr 2008;153:254–61.
      72. Rafati MR, Karami H, Salehifar E, Karimzadeh A. Clinical efficacy and safety of polyethylene glycol 3350 versus liquid paraffin in the treatment of pediatric functional constipation. DARU: J Pharmaceut Sci 2011;19:154–8.
      73. Saneian H, Mostofizadeh N. Comparing the efficacy of polyethylene glycol (PEG), magnesium hydroxide and lactulose in treatment of functional constipation in children. J Res Med Sci 2012;17:S145–9.
      74. Youssef NN, Peters JM, Henderson W, et al. Dose response of PEG 3350 for the treatment of childhood fecal impaction. J Pediatr 2002;141:410–4.
      75. Corazziari E, Badiali D, Habib F, et al. Small volume isosmotic polythylene glycol electrolyte balanced solution (PMF-100) in treatment of chronic nonorganic constipation. Digest Dis 1996;41:1636–42.
      76. Rendeli C, Ausili E, Tabacco F, et al. Polyethylene glycol 4000 vs. lactulose for the treatment of neurogenic constipation in myelomeningocele children: a randomized-controlled clinical trial. Aliment Pharmacol Ther 2006;23:1259–65.
      77. Seinela L, Sairanen U, Laine T, et al. Comparison of polyethylene glycol with and without electrolytes in the treatment of constipation in elderly institutionalized patients: a randomized, double-blind, parallel-group study. Drugs Aging 2009;26:703–13.
      78. Bassotti G, Fiorella S, Roselli P, et al. Use of polythylene glycol solution in slow transit constipation. Ital J Gastroenterol Hepatol 1999;31:S255–6.
      79. Couturier D. [Comparative study of Forlax and lactulose in the treatment of functional constipation in the adult]. Abstr Gastroenterologie 1996;1–24.
      80. Dai X-S, Sun Q. Clinical effects of polyethylene glycol 4000 in the treatment of the elder patients with chronic functional constipation. W Chin J Pharmaceut Sci 2004;19:477–9.
      81. Fang X-C, Ke M-Y, Hu P-J, et al. Clinical evaluation for the efficacy and safety of polyethylene glycol 4000 in the treatment of functional constipation. Chin J New Drugs 2002;11:479–83.
      82. Gomes PB, Duarte MA, Melo MC. Comparison of the effectiveness of polyethylene glycol 4000 without electrolytes and magnesium hydroxide in the treatment of chronic functional constipation in children. J Pediatr 2011; 87:24–8.
      83. Klauser AG, Mühldorfer BE, Voderholzer WA, et al. Polythylene glycol 4000 for slow transit constipation. Z Gastroenterol 1995;33:5–8.
      84. Ratanamongkol P, Lertmaharit S, Jongpiputvanich S. Polyethylene glycol 4000 without electrolytes versus milk of magnesia for the treatment of functional constipation in infants and young children: a randomized controlled trial. Asian Biomedicine 2009;3:391–9.
      85. Treepongkaruna S, Simakachorn N, Pienvichit P, et al. A randomised, double-blind study of polyethylene glycol 4000 and lactulose in the treatment of constipa- tion in children. BMC Pediatr 2014;14.
      86. Wang Y, Wang B, Jiang X, et al. Polyethylene glycol 4000 treatment for children with constipation: a randomized comparative multicenter study. Exp Ther Med 2012;3:853–6.
      87. Yu Y, Yu X-F, Zheng S-B, et al. Macrogol 4000 in treatment of chronic functional constipation of aged patients. Chin J New Drugs Clin Remedies 2004;23:101–3.
      88. Zhang C-Q, Zhang G-W, Zhang K-L, et al. Clinical evaluation of polyethylene glycol 4000 in treatment of functional constipation in elderly patients. World Chin J Digestology 2003;11:1399–401.
      89. Zhou LY, Xia ZW, Lin SR, et al. A randomised controlled multicenter clinical trial on the treatment of chronic functional constipation with PEG4000. Chin J Clin Pharmacol 2001;17:7–10.
      90.  Di Palma JA, Cleveland MV, McGowan J, Herrera JL. An open-label study of chronic polyethylene glycol laxative use in chronic constipation. Aliment Pharmacol Ther 2007;25:703–8.
      91.  Erickson BA, Austin JC, Cooper CS, et al. Polythylene glycol 3350 for constipation in children with dysfunctional elimination. J Urol 2003;170:1518–20.
      92.  Loening-Baucke V, Krishna R, Pashankar DS. Polyethylene glycol 3350 without electrolytes for the treatment of functional constipation in infants and toddlers. J Pediatr Gastroenterol Nutr 2004;39:536–9.
      93.  Michail S, Gendy E, Preud’Homme D, Mezoff A. Polyethylene glycol for constipation in children younger than eighteen months old. J Pediatr Gastroenterol Nutr 2004;39:197–9.
      94.  Mimidis K, Mourvati E, Kaliontzidou M, et al. Efficacy of polyethylene glycol in constipated CAPD patients. Periton Dialysis Int 2005;25:601–3.
      95.  Pashankar DS, Bishop WP. Efficacy and optimal dose of daily polyethyleneglycol 3350 for treatment of constipation and encopresis in children. J Pediatr 2001;139:428–32.
      96.  Pashankar DS, Loening-Baucke V, Bishop WP. Safety of polyethylene glycol 3350 for the treatment of chronic constipation in children. Arch Pediatr Adolesc Med 2003;157:661–4.
      97.  Tran LC, Di Palma JA. Lack of lasting effectiveness of PEG 3350 laxative treatment of constipation. J Clinical Gastroenterol 2005;39:600–2.
      98.  Neri I, Blasi I, Castro P, et al. Polythylene glycol electrolyte solution (Isocolan) for constipation during pregnancy: an observational open-label study. J Midwifery Wom Health 2004;49:355–8.
      99.  Bae SH, Son JS, Lee R. Effect of fluid intake on the outcome of constipation in children: PEG 4000 versus lactulose. Pediatr Int 2010;52:594–7.
      100.  Bazzocchi G. Polythylene glycol solution in subgroups of chronic constipation patients: experience in obstructed defaecation. Ital J Gastroenterol Hepatol 1999;31:S257–9.
      101.  Denis P, Lerebours E. Study of the long-term tolerability of Forlax, in the case of 16 patients treated for an average of more than 17 months for chronic constipation. Medicines Chirurg Digest 1996;25.
      102.  Dupont C, Leluyer B, Amar F, et al. A dose determination study of polyethylene glycol 4000 in constipated children: factors influencing the maintenance dose. J Pediatr Gastroenterol Nutr 2006;42:178–85.
      103.  Guest JF, Clegg JP, Helter MT. Cost- effectiveness of macrogol 4000 compared to lactulose in the treatment of chronic functional constipation in the UK. Curr Med Res Opin 2008;24:1841–52.
      104.  Maiullari E, Bianco ER, Cortese MG, et al. Conservative treatment of children constipation with Macrogol 4,000. Minerva pediatrica 2008;60:407–10.
      105.  Zhang Ly, Yao Yz, Wang T, et al. Efficacy of polyethylene glycol 4000 on constipation of posttraumatic bedridden patients. Chin J Traumatol 2010;13:182–7.