Constipation in adults

Abstract

Introduction

Although there are defined criteria for the diagnosis of constipation, in practice, diagnostic criteria are less rigid and depend in part on the perception of normal bowel habit. Constipation is highly prevalent, with approximately 12 million general practitioner prescriptions for laxatives in England in 2001.

Methods and outcomes

We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of medications in people with idiopathic chronic constipation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).

Results

At this update, searching of electronic databases retrieved 356 studies published in this time period. After deduplication, 95 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 62 studies and the further review of 33 full publications. Of the 33 full articles evaluated, three systematic reviews and one RCT were added to the overview at this update. We performed a GRADE evaluation for four PICO combinations.

Conclusions

In this systematic overview, we categorised the efficacy for three interventions, based on information relating to the effectiveness and safety of linaclotide, lubiprostone, and prucalopride.

Key Points

People with idiopathic chronic constipation can be divided into two main categories: those with difficulty defecating (but with normal bowel motion frequency) and those with a transit abnormality (which can present as infrequent defecation).

• Although there are defined criteria for the diagnosis of constipation, in practice diagnostic criteria are less rigid and depend in part on the perception of normal bowel habit.

• Constipation is highly prevalent, with approximately 12 million general practitioner prescriptions for laxatives being written in England in 2001.

• Patients are often dissatisfied with laxatives, mainly due to concerns regarding their safety and efficacy.

• Emerging therapies have been tested, and meta-analyses pooling data from the relevant RCTs are reviewed in this overview.

Lubiprostone, linaclotide, and prucalopride seem to be more effective than placebo at improving frequency of bowel movements and spontaneous complete bowel movements in people with chronic constipation.

In terms of adverse events, lubiprostone is particularly associated with an increase in rates of nausea.

The studies we found were conducted in secondary and tertiary care, and the patients were predominantly women; therefore, the results may not be truly applicable to all people, particularly men and patients being treated in primary care.

Clinical context

General background

Idiopathic chronic constipation is common, affecting up to 20% of the general population.

Focus of the review

Patients are often dissatisfied with laxatives, mainly due to concerns regarding their safety and efficacy. In recent years, new therapies have been developed and tested and are now available in many countries. This updated overview examines the efficacy of these new therapies.

Comments on evidence

We identified three separate meta-analyses pooling data from three RCTs of lubiprostone, three RCTs of linaclotide, and 12 RCTs of prucalopride. These RCTs were conducted in secondary and tertiary care, and the patients were predominantly women; therefore, the results may not be truly applicable to all patients, particularly men and patients being treated in primary care. One RCT of lubiprostone, three RCTs of linaclotide, and six RCTs of prucalopride were judged as being at low risk of bias. It is important to point out that there have been no head-to-head trials of the individual drugs to summarise data from, and that individual trials used different endpoints to judge response to therapy, meaning that it is difficult to draw meaningful conclusions about the comparative efficacy of lubiprostone, linaclotide, or prucalopride.

Search and appraisal summary

The updated literature search from the previous version of this overview (October 2009) was carried out to search for studies up to July 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 356 studies published in this time period. After deduplication, 95 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 62 studies and the further review of 33 full publications. Of the 33 full articles evaluated, three systematic reviews and one RCT were added at this update.

Additional information

All three treatments were more effective than placebo for the treatment of idiopathic chronic constipation, in terms of increasing spontaneous bowel movements to three times or more per week, and prucalopride was also more effective than placebo at increasing the proportion of stools of normal consistency. In the UK, lubiprostone and prucalopride are recommended by the National Institute for Health and Care Excellence (NICE) for patients with idiopathic chronic constipation who fail to respond to two different types of laxatives at the highest possible recommended dose, for at least 6 months, and when invasive treatment options are being considered. Linaclotide is licensed for the treatment of idiopathic chronic constipation in the US, but not in the UK.

About this condition

Definition

Bowel habits and perception of bowel habits vary widely within and among populations, making constipation difficult to define. People with constipation can be divided into two main categories: those with difficulty defecating (but normal bowel motion frequency) and those with a transit abnormality (which can present as infrequent defecation). The Rome III criteria is a standardised tool that diagnoses chronic constipation on the basis of two or more of the following symptoms for at least 12 weeks in the preceding 6 months: straining at defecation on at least one quarter of occasions, stools that are lumpy/hard on at least one quarter of occasions, sensation of incomplete evacuation, sensation of anorectal obstruction, or manual manoeuvres to facilitate defecation on at least one quarter of occasions, and three or less bowel movements per week. In practice, however, diagnostic criteria are less rigid and are in part dependent on perception of normal bowel habit. Typically, constipation is diagnosed when a person has bowel actions twice a week or less for two consecutive weeks, especially in the presence of features such as straining at stool, abdominal discomfort, and sensation of incomplete evacuation. Population For the purposes of this overview, we included all RCTs stating that all participants had chronic constipation, whether or not this diagnosis was made according to strict Rome III criteria. Where the definitions of constipation in the RCTs differ markedly from those presented here, we have made this difference explicit. In this overview, we deal with chronic constipation not caused by a specific underlying disease (sometimes known as idiopathic constipation) in adults aged over 18 years, although we have included adults with pelvic floor dyssynergia. We excluded studies in pregnant women and in people with constipation associated with underlying specific organic diseases such as dehydration, autonomic neuropathy, spinal cord injury, bowel obstruction, irritable bowel syndrome, or paralytic ileus. We excluded people with Parkinson's disease and dementia, people who were postoperative, or people who were terminally ill. Opioid-induced constipation was also excluded (see overview on Constipation in people prescribed opioids). Diagnosis The diagnosis of constipation is initially based on history (see above). Specific tests available for further investigation include thyroid function tests, calcium concentration, colonoscopy, defecation proctogram, anorectal manometry, and colon transit time studies.

Incidence/ Prevalence

Twelve million general practitioner prescriptions were written for laxatives in England in 2001. Prevalence data are limited by small samples and problems with definition. One UK survey of 731 women found that 8.2% had constipation meeting Rome II criteria, and 8.5% defined themselves as being constipated. A larger survey (1892 adults) found that 39% of men and 52% of women reported straining at stool on more than one quarter of occasions. Prevalence rises in older people. Several surveys from around the world suggest that, in a community setting, prevalence among older people is about 20%. Levels of dissatisfaction with laxatives among patients with idiopathic chronic constipation are high.

Aetiology/ Risk factors

One systematic review suggested that factors associated with an increased risk of constipation included low-fibre diet and low fluid intake. One meta-analysis showed that the prevalence of constipation was higher in women (OR: 2.22; 95% CI 1.87 to 2.62) and increased with age.

Prognosis

Untreated constipation can lead to faecal impaction (with resulting faecal incontinence), particularly in older and confused people. Constipation has been suggested as a risk factor for haemorrhoids and diverticular disease; however, evidence of causality is lacking.

Aims of intervention

To relieve symptoms of constipation, to restore normal bowel habit, and to improve quality of life, with minimal adverse effects.

Outcomes

Frequency of bowel movements; stool consistency (hard/lumpy stools); use of laxatives; adverse effects. We have commented on additional outcomes, such as quality of life, in the Comment sections for specific interventions.

Methods

Search strategy BMJ Clinical Evidence search and appraisal July 2014. Databases used to identify studies for this overview include: Medline 1966 to July 2014, Embase 1980 to July 2014, The Cochrane Database of Systematic Reviews 2014, issue 7, the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this review were systematic reviews and RCTs published in English, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported questions: What are the effects of non-drug interventions in adults with idiopathic chronic constipation? What are the effects of fibre supplements in adults with idiopathic chronic constipation? What are the effects of paraffin (or similar compounds) in adults with idiopathic chronic constipation? What are the effects of osmotic laxatives in adults with idiopathic chronic constipation? What are the effects of stimulant laxatives in adults with idiopathic chronic constipation? We have added the following questions: What are the effects of medications in people with idiopathic chronic constipation? Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Constipation in adults.

Important outcomes	Frequency of bowel movement, Stool consistency (hard/lumpy stools)
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of medications in people with idiopathic chronic constipation?
4 (673)	Frequency of bowel movement	Lubiprostone versus placebo	4	–2	0	–1	0	Very low	Quality point deducted for weak methods and incomplete reporting of results; directness point deducted for unclear generalisability (mainly women, set in secondary and tertiary care)
3 (at least 1582)	Frequency of bowel movement	Linaclotide versus placebo	4	0	0	–1	0	Moderate	Directness point deducted for unclear generalisability (mainly women, set in secondary and tertiary care)
7 / at least 9 (2369 / at least 3325)	Frequency of bowel movement	Prucalopride versus placebo	4	0	–1	–1	0	Low	Consistency point deducted for significant heterogeneity; directness point deducted for unclear generalisability (mainly women, set in secondary and tertiary care)
6 (2661)	Stool consistency (hard/lumpy stools)	Prucalopride versus placebo	4	0	–1	–1	0	Low	Consistency point deducted for significant heterogeneity; directness point deducted for unclear generalisability (mainly women, set in secondary and tertiary care)

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

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.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Rome II criteria

(updated 1999) Rome criteria for constipation require two or more of the following symptoms to be present for at least 12 weeks out of the preceding 12 months: straining at defecation on at least a quarter of occasions; stools are lumpy/hard on at least a quarter of occasions; sensation of incomplete evacuation on at least a quarter of occasions; and three or fewer bowel movements a week.

Rome III criteria

Rome III criteria for constipation require two or more of the following symptoms for at least 12 weeks in the preceding 6 months: straining at defecation on at least one quarter of occasions, stools that are lumpy/hard on at least one quarter of occasions, sensation of incomplete evacuation, sensation of anorectal obstruction, or manual manoeuvres to facilitate defecation on at least one quarter of occasions, and three or less bowel movements per week.

Very low-quality evidence

Any estimate of effect is very uncertain.

Constipation in children and Constipation in people prescribed opioids

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.