Polyethylene glycol for chronic constipation in adults

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the efficacy and safety of PEG for the treatment of chronic constipation in adults.

Background

Constipation is a common disorder characterized by unsatisfactory defecation. It is not a single disease but a group of syndromes with symptoms including hard stools, infrequent defecation (typically fewer than three per week), excessive straining with defecation, feeling of incomplete evacuation, and excessive time spent on the toilet or in unsuccessful defecation, as well as abdominal discomfort or pain (Koch 1997; Mertz 1999a; Pare 2001). Since the pattern of symptoms varies between individuals, there is no single definition of constipation. The Rome criteria were developed to promote consistency in the diagnosis of constipation. Recently, the Rome criteria were modified and are now referred to as the Rome III criteria (Longstreth 2006). The Rome III criteria for the diagnosis of chronic constipation differ from the Rome II criteria in that the time frame requirement for diagnostic criteria are changed: a required frequency of ">=25%" is substituted for ">25%"and laxative‐induced loose stools are taken into account (Longstreth 2006; Thompson 1999). To be diagnosed with chronic constipation using the Rome III criteria for Functional Bowel Disorders, patients must experience 2 or more of the following symptoms for at least 3 months with symptom onset at least 6 months prior to diagnosis: a. Straining during at least 25% of defecations; b. Lumpy or hard stools in at least 25% of defecations; c. Sensation of incomplete evacuation for at least 25% of defecations; d. Sensation of anorectal obstruction/blockage for at least 25% of defecations; e. Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor); and f. Fewer than 3 defecations per week.

Furthermore, loose stools are rarely present without the use of laxatives and there are insufficient criteria for irritable bowel syndrome (IBS). Due to the somewhat restrictive nature of the Rome criteria, the American College of Gastroenterology (ACG) Chronic Constipation Task Force recommends using a more broad definition of chronic constipation in clinical practice, "unsatisfactory defecation characterized by infrequent stools, difficult stool passage or both" (Brandt 2005). From 1958 to 1986, constipation accounted for about 20,000 hospitalizations and 2.5 million physician visits every year in the United States (Sonnenberg 1989). Based on a systematic review of the prevalence of constipation in North America, prevalence estimates vary between 1.9% and 27.2%, with most estimates ranging from 12% to 19%. Approximately 63 million North Americans meet the Rome II criteria for constipation and an additional 50 million North Americans self‐report constipation (Higgins 2004). In China, there have been no large scale surveys of constipation prevalence. A study of adults in the Beijing area found an incidence of 6.07% based on Rome II criteria (Guo 2002). The prevalence of chronic constipation varies in different studies because of different definitions and populations. In Canada, the population prevalence of self‐reported, Rome I‐defined, and Rome II‐defined constipation is 27.2%, 16.7% and 14.9% respectively (Pare 2001). In all populations, constipation is more frequent in women, children and the elderly (Johanson 1989; Stewart 1999; Guo 2002). Although chronic constipation is usually not life‐threatening, it is associated with medical comorbidities and significant complications, such as intestinal impaction, anal fissures, hemorrhoids, volvulus, intestinal obstruction, stercoral or rectal ulcers, and IBS (Singh 2005). Constipation can cause a significant adverse impact on patients' health‐related quality of life as a result of altered mental and physical functioning (Irvine 2002; Koloski 2000). Moreover, symptom severity correlates negatively with the perceived quality of life (Glia 1997). Accordingly, chronic constipation imposes a substantial economic burden. Patients with chronic constipation are more likely to use health care services. In America, the average annual expenditure per patient for additional tertiary care evaluations was $2752, and the total annual labor and supply cost per long‐term care resident with constipation was approximately $2253 (Dennison 2005).

Constipation is frequently multifactorial and can result from systemic or neurologic disorders or medications. If there is no other secondary causes found, constipation may be primary or idiopathic. Because there is little knowledge yet about the pathophysiology underlying chronic constipation, the classification of chronic constipation is not very clear. Primary constipation may be classified as normal‐transit constipation (i.e. stool transit time is normal, however, evacuation is difficult or hard stools are present), slow‐transit constipation (i.e. colonic inertia; neuromuscular dysfunction), pelvic floor dysfunction (i.e. outlet obstruction, obstructed defecation, anismus, dyssynergia), or a combination of slow‐transit and pelvic floor dysfunction (Mertz 1999b; Lembo 2003; Bleser 2005; Wald 2006 ).

The clinical evaluation of patients is necessary to identify primary constipation. In most cases chronic constipation may be diagnosed based on the presenting symptoms, and a thorough history and physical examination to rule out constipation secondary to an underlying condition. Although evidence to support the use of blood tests, radiography, or endoscopy in the routine workup of patients with constipation without alarm features is lacking (Rao 2005), a consensus guideline from the American Gastroenterological Association (AGA) recommends that most patients have tests for a complete blood count and serum glucose, thyroid stimulating hormone, calcium, and creatinine levels (Locke 2000a; Locke 2000b). A sigmoidoscopy or colonoscopy to exclude colon cancer is indicated in patients older than 50 years who have not had a recent examination and in those with concomitant rectal bleeding, heme‐positive stool or weight loss (Qureshi 2005). When constipation does not respond to simple treatment, specific diagnostic testing may be performed to elucidate the underlying pathophysiologic process by assessing for colonic transit time and anorectal function. This may include measurement of colonic transit time, anorectal manometry, defecography, or a balloon expulsion test.

Management of chronic constipation generally includes both nonpharmacologic and pharmacologic measures. The goals of management include improving symptoms, restoring normal bowel function, increasing colonic transit if abnormal, and facilitating defecation (Bleser 2005). Empiric treatment should be tried initially for functional constipation when no secondary cause of constipation is identified. Although few data support diet, fluid, and exercise to positively influence fecal elimination (Annells 2003; Meshkinpour 1998), a healthy lifestyle is generally recommended for the initial management of chronic constipation and should proceed to the use of laxatives when changing diet and lifestyle fail. Laxatives are the most commonly used intervention for treatment of constipation and are generally classified by the mode of action into the categories of bulking agents, stimulant laxatives, faecal softeners and osmotic laxatives. Other agents may also be effective for constipation, such as Colchicine (Verne 1997; Verne 2003), Misoprostol (Roarty 1997; Soffer 1994) Tegaserod (Brandt 2005; Ramkumar 2005; Kamm 2005) and Lubiprostone (Johanson 2005a; Johanson 2005b). If constipation is refractory to medical treatment, further diagnostic evaluation may be warranted to identify the subgroup of constipation. Alternative treatment methods such as biofeedback and surgery may be considered for pelvic floor dysfunction and slow‐transit constipation respectively (Locke 2000b; Chiarioni 2005; Chiarioni 2006; Nyam 1997; Beck 2005).

Polyethylene glycol (PEG) is a large polymer with substantial osmotic activity (DiPalma 2004). It is chemically inert and cannot be metabolized by colonic bacteria, thus ingested PEG is delivered quantitatively to the colon. In the gastrointestinal tract, PEG obligates intraluminal water and exerts its substantial osmotic activity, leading to modification of stool consistency and increased faecal bulk (Schiller 1988). For some time, high dose PEG with electrolytes has been used widely in lavage solutions for gut cleansing before colonoscopy or bowel surgery. These solutions have been shown to be safe and effective. Electrolytes are added to the PEG solution to prevent their loss through the faeces due to the large volume of the lavage. However, this gives the lavage solution an unpleasant salty taste (Toledo 2001). Recently, polyethylene glycol based osmotic laxatives have been shown to provide short and long term benefit in patients with idiopathic constipation and faecal impaction (Puxty 1986; Culbert 1998; Andorsky 1990; Attar 1999;DiPalma 2000; Cleveland 2001; Zhang 2003; Chaussade 2003). Puxty 1986 first used a balanced electrolyte solution containing polyethylene glycol (Golytely) to treat fecal impaction caused by constipation in the elderly. From then on, more and more studies were carried out to assess the efficacy of polyethylene glycol‐based laxatives for the treatment of chronic constipation. Two systematic reviews of medical therapies for chronic constipation concluded that there was good evidence supporting the use of polyethylene glycol (Brandt 2005; Ramkumar 2005). However, both of these reviews were restricted to published English language studies indexed in 2 databases (MEDLINE and PUBMED) and focused on the North American population. At present, commercially available PEG products for use as laxatives have been developed using PEG 3350 and PEG 4000, with or without added electrolytes, such as MiraLax (i.e. PEG 3350 without electrolytes, Braintree Laboratories), Movicol (i.e. PEG 3350 with electrolytes, Norgine Ltd) and Forlax (i.e. PEG 4000 without electrolytes, Beaufour‐Ipsen). In China, the available PEG for the treatment of constipation is "fusong" (i.e. Forlax). Polyethylene glycol‐based laxatives appear to be a promising treatment for chronic constipation and are increasingly being used as first line treatment.

Objectives

To evaluate the efficacy and safety of PEG for the treatment of chronic constipation in adults.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) comparing polyethylene glycol based osmotic laxatives with placebo, lactulose, psyllium or tegaserod for the treatment of chronic constipation in adults. Quasi‐randomised studies will also be considered for inclusion. In randomised cross‐over trials only data from the first period will be included.

Types of participants

Participants will be patients aged 18 years and over, diagnosed with chronic constipation. Studies which include healthy volunteers, patients with constipation resulting from pregnancy, medications, or other disease (such as diabetes mellitus, hypothyroidism, tumour, anal fissure, bowel obstruction, inflammatory bowel disease) will be excluded.

Physicians and patients differ dramatically in their definition of constipation. Physicians tend to use infrequent defecation (typically fewer than three per week) to define constipation. Whereas, many patients focus on symptoms such as straining, hard stools, incomplete evacuation and abdominal discomfort rather than stool frequency (Stark 1999; Sandler 1987). Since the definition of chronic constipation is symptom‐based, study inclusion criteria may be patient self‐report, physician diagnosis, or consensus criteria (e.g. Rome). The definition of constipation is variable or inadequately described in many studies and no single symptom or diagnostic test was used to define this condition. Thus, studies that enrolled patients with chronic constipation symptoms will be considered for inclusion. In order to define constipation as a chronic disorder, some combination of these symptoms should be present for at least 12 weeks out of the last 12 months.

Types of interventions

Any type of polyethylene glycol based osmotic laxative compared to placebo, lactulose, psyllium or tegaserod. Other controlled interventions will not be included. Polyethylene glycol based osmotic laxatives can be polyethylene glycol 3350, polyethylene glycol 4000, or polyethylene glycol‐electrolyte solution. Studies that use polyethylene glycol combined with other agents will be excluded.

Types of outcome measures

The primary outcome measure will be global improvement of symptoms (patient and/or physician evaluated).

The secondary outcome measures will include: 1 Bowel movement frequency; 2 Improvement of ease of defecation including but not limited to straining , sensation of incomplete evacuation, sensation of anorectal obstruction/blockage, manual maneuvers to facilitate defecation (e.g., digital evacuation, support of the pelvic floor); 3 Stool consistency; 4 Gastrointestinal transit time (GITT); 5 Quality of life; and 6 Number and types of adverse events.

Search methods for identification of studies

1. Electronic searches The following electronic databases will be searched irrespective of language and publication status: IBD/FBD Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (latest issue), MEDLINE (1966‐ present), EMBASE (1980‐ present), Chinese Biomedical Database (CBM, 1980‐ present). The details of the search strategy are as follows: A. Condition MeSH subject headings #1 exp constipation/ all subheadings #2 exp defecation/ all subheadings #3 exp fecal impaction / all subheadings Text word terms/synonyms #4 bowel function$.tw. #5 bowel habit$.tw. #6 bowel movement$.tw. #7 bowel symptom$.tw. #8 bowel motility.tw. #9 colon adj3 transit.tw. #10 evacuation.tw. #11 intestinal adj motility.tw. #12 stool$.tw. #13 constipat$.tw. #14 Obstipation.tw. #15 intestinal dysmotility.tw. #16 colonic inertia .tw. #17 dyschezia .tw., #18 colonic motility.tw. #19 or/1‐18 B. Interventions MeSH headings #1 exp Polyethylene glycols / all subheadings Text word terms/synonyms #2 polyethylene glycol$.tw. #3 macrogol$.tw. #4 PEG$.tw. #5 polyethylene glycol 3350.tw. #6 polyethylene glycol 4000.tw. #7 polyethylene glycol adj5 solution.tw. # 8 (Miralax or Transipeg or Movicol or Forlax or Idrolax or GoLytely or PMF‐100 or Golitely or Nulitely).tw. #9 or/1‐8 [/=MeSH term, exp=explode, tw=textword, $=truncation] C. The above search terms will be combined with the Cochrane RCT filter given in the appendix 5c of Cochrane Handbook (Higgins 2005). The search filter and MeSH headings will be adapted for each database used. 2. Reference searching The references of all identified studies will be inspected for more trials. 3. Personal contact The first author of each included study will be contacted for information regarding unpublished trials. 4. Drug company The manufacturers of PEG will be contacted for additional data.

Data collection and analysis

Study selection Titles and abstracts identified by the search strategy will be screened independently by two authors (Wang and He), and relevant studies will be selected according to the defined inclusion criteria. Any disagreement between authors will be resolved by discussion. If agreement cannot be reached, the third author (Dong) will be consulted. Assessment of methodological quality The methodological quality of eligible trials will be assessed independently by two authors (Wang and He) using the following quality components: i. generation of the random sequence: adequate (e.g. computer generated random numbers, table of random numbers or similar) or inadequate (e.g. other methods or not described); ii. allocation concealment: adequate (e.g. central independent unit, sealed envelopes, or similar) or inadequate (e.g. not described or open table of random numbers or similar); iii. blinding: adequate (e.g. identical or similar therapies) or inadequate (e.g. placebo not performed or no comparator described). Blinding of participants, study investigations and assessors to be recorded; and iv. follow‐up: adequate (e.g. number and reasons for drop‐out and withdrawal are described) or inadequate (e.g. number or reasons for drop‐outs or withdrawals not described). Based on these criteria, studies will be classified into the following three categories: A. all quality criteria met: low risk of bias; B. one or more of the quality criteria only partly met: moderate risk of bias; C. one or more criteria not met: high risk of bias.

Data extraction Two authors (Wang and He) will independently extract data using a designed data extraction form. Any disagreement among authors will be resolved by consensus. Where possible, the data extraction form will include: a. Study methods (trial design, duration, allocation method, blinding, setting, definition and diagnostic criteria, inclusion and exclusion criteria, follow‐up duration) b. Participants (number, age, gender, withdrawals, reasons for withdrawal) c. Interventions (type, dose, duration of therapy, control used) d. Outcomes (global improvement of symptoms, change in frequency of defecation; improvement in ease of defecation; relief of symptoms related to constipation; patient satisfaction/preference; improved quality of life), tolerance (ease of use) and adverse events (nausea / vomiting; rectal pain; abdominal pain; flatus; diarrhoea; faecal incontinence) If needed, the authors of primary studies will be contacted for additional information.

Data analysis Data will be analyzed using Review Manager (RevMan 4.2.8). Analyses will be performed using the intention to treat principle. Data from individual trials will be combined for meta‐analysis when the interventions and controls are sufficiently similar (i.e., individual trials compare the same PEG versus the same control intervention). The presence of significant heterogeneity among studies will be assessed using the chi‐square test. A p‐value of 0.10 will be regarded as statistically significant. A fixed effects model will be used for pooling of data when statistical heterogeneity is not present. When statistical heterogeneity is present a random effects model will be used. Dichotomous data will be presented as relative risk (RR) and continuous outcomes as weighted mean difference (WMD), both with corresponding 95% confidence intervals (95% CI).

Sensitivity analysis A sensitivity analysis will be performed to determine if the results from the primary analysis change when different trials are considered in the analysis. Sensitivity analyses will include: (1) excluding unpublished studies and studies reported in abstracts and languages other than English and (2) excluding studies with poor quality.

Subgroup Analyses: If a sufficient number of randomised trials are identified, subgroup analyses based on types of interventions, treatment duration, and drug dosage will be explored.

Publication bias If a sufficient number of studies are available, publication bias will be assessed using the funnel plot (Egger 1997).

What's new

Date	Event	Description
20 June 2019	Amended	This protocol is being withdrawn

Contributions of authors

Wang Binyou and Wu Taixiang are responsible for developing the protocol and will develop the review. Dong Birong is responsible for speciality consultation. He Ping and Yan Yuping are responsible for searching for articles.

Sources of support

Internal sources

• Chinese Cochrane Center, Chinese Center of Evidence‐Based Medicine, West China Hospital of Sichuan University, China.

External sources

• No sources of support supplied

Declarations of interest

None known.

Notes

This protocol is out of date and is being withdrawn.

Withdrawn from publication for reasons stated in the review