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  • Effect of laxatives and pharmacological therapies inchronic idiopathic constipation: systematic reviewand meta-analysis

    Alexander C Ford,1,2 Nicole C Suares1

    ABSTRACTBackground There has been no definitive systematicreview and meta-analysis to date examining the effect oflaxatives and pharmacological therapies in chronicidiopathic constipation (CIC).Objective To assess efficacy of these therapiessystematically in CIC.Design Systematic review and meta-analysis ofrandomised controlled trials (RCTs).Data sources MEDLINE, EMBASE, and the Cochranecentral register of controlled trials were searched (up toSeptember 2010).Eligibility criteria for selecting studies Placebo-controlled trials of laxatives or pharmacological therapiesin adult CIC patients were eligible. Minimum duration oftherapy was 1 week. Trials had to report eithera dichotomous assessment of overall response totherapy at last point of follow-up in the trial, or meannumber of stools per week during therapy.Study appraisal and synthesis methods Symptomdata were pooled using a random effects model. Effectof laxatives or pharmacological therapies compared toplacebo was reported as RR of failure to respond totherapy, or a weighted mean difference (WMD) in meannumber of stools per week, with 95% CIs.Results Twenty-one eligible RCTs were identified.Laxatives (seven RCTs, 1411 patients, RR0.52; 95% CI0.46 to 0.60), prucalopride (seven trials, 2639 patients,RR0.82; 95% CI 0.76 to 0.88), lubiprostone (threeRCTs, 610 patients, RR0.67; 95% CI 0.56 to 0.80), andlinaclotide (three trials, 1582 patients, RR0.84; 95% CI0.80 to 0.87) were all superior to placebo in terms ofa reduction in risk of failure with therapy. Treatmenteffect remained similar when only RCTs at low risk ofbias were included in the analysis. Diarrhoea wassignificantly more common with all therapies.Limitations Only two RCTs were conducted in primarycare, and total adverse events data for laxatives andlinaclotide were sparse.Conclusions Laxatives, prucalopride, lubiprostone andlinaclotide are all more effective than placebo for thetreatment of CIC.

    INTRODUCTIONChronic idiopathic constipation (CIC) is a func-tional disorder of the gastrointestinal tract, charac-terised by persistently difcult, infrequent, orincomplete defaecation, in the absence of anyphysiological abnormality.1 The condition iscommon, with a prevalence of between 4% and 20%in cross-sectional community-based surveys.2e6

    Chronic idiopathic constipation is more common infemales, those of lower socioeconomic status and

    lower educational level, and older individuals.2 6 7

    Up to 20% of sufferers consult a physician withtheir symptoms,2 and the impact of CIC on qualityof life for patients is comparable with that fororganic conditions, such as chronic obstructivepulmonary disease, diabetes and depression.8

    Traditionally, individuals with CIC are told toincrease dietary bre intake in order to alleviatesymptoms, but there is little evidence from rando-mised controlled trials (RCTs) that this approachis of any benet, even in the short-term treatmentof the condition.9 10 In a recent multi-nationalsurvey of CIC patients, between 16% and 40%reported that they used laxatives, with almost two-thirds using them on at least a monthly basis.6

    However, levels of dissatisfaction with laxativesare high, primarily due to concerns about efcacyand safety.11 In addition, laxatives do not targetthe pathophysiological abnormalities that maycontribute to the symptoms of CIC.As a result, novel drug therapies for the disorder

    have been developed within the last 10 years.Prucalopride is a selective agonist at the 5-hydroxy-tryptamine-4 (5-HT4) receptor, leading to increasedcolonic motility and transit.12 Lubiprostone and

    1Leeds GastroenterologyInstitute, Leeds GeneralInfirmary, Great George Street,Leeds, UK2Leeds Institute of MolecularMedicine, University of Leeds,Leeds, UK

    Correspondence toDr Alex Ford, LeedsGastroenterology Institute,Room 230, D Floor, ClarendonWing, Leeds General Infirmary,Great George Street, Leeds,LS1 3EX, UK;alexf12399@yahoo.com

    Revised 1 October 2010Accepted 26 October 2010

    Significance of this study

    What is already known about this subject?< Chronic idiopathic constipation is a common

    functional disorder of the gastrointestinal tract.< The condition is difficult to treat.< Evidence for any benefit of laxatives is

    conflicting, and there has been no definitivesummary of the evidence for efficacy of newerpharmacological agents.

    What are the new findings?< Polyethylene glycol, sodium picosulfate, bisa-

    codyl, prucalopride, lubiprostone and linaclotidewere all more effective than placebo for treatingchronic idiopathic constipation, but data tosupport efficacy of lactulose were limited.

    < Diarrhoea was significantly more common inpatients assigned to both laxatives and phar-macological therapies.

    How might it impact on clinical practice in theforeseeable future?< Guidelines for the management of chronic

    idiopathic constipation should be updated toinclude this useful information.

    Gut 2011;60:209e218. doi:10.1136/gut.2010.227132 209

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  • linaclotide are drugs that act on chloride channels and guanylatecyclase receptors in the intestinal enterocyte, respectively.Both of these agents increase the chloride concentration ofintestinal uid, thereby stimulating intestinal uid secretion andaccelerating transit.13 14

    At present, management guidelines for CIC do not make anyrm recommendations to support the use of laxatives or phar-macological therapies in the condition.15e17 Part of the expla-nation for this may be that there has been no recent denitivequantitative summary of all available evidence for their efcacyin CIC. We have therefore conducted a systematic review andmeta-analysis of RCTs to examine this issue.

    METHODSSearch strategy and study selectionA search of the medical literature was conducted usingMEDLINE (1950 to September 2010), EMBASE and EMBASEClassic (1947 to September 2010), and the Cochrane centralregister of controlled trials (Issue 3, July 2010). Randomisedplacebo-controlled trials examining the effect of laxatives(osmotic or stimulant) or pharmacological therapies (pruca-lopride, lubiprostone or linaclotide) in adult patients (>90% ofparticipants over the age of 16 years) with CIC were eligible forinclusion (box 1). The rst period of cross-over RCTs were alsoeligible for inclusion. A diagnosis of CIC could be based onclinical symptoms, a physicians opinion, or the Rome I, II or IIIdiagnostic criteria,1 18 19 supplemented by negative investiga-tions where trials deemed this necessary. Studies that recruitedpatients with organic constipation, drug-induced constipation,or highly selected groups of patients (such as elderly patientswho were also institutionalised) were ineligible. Duration oftreatment had to be at least 1 week. Trials using any dose oflaxative or pharmacological therapy were considered eligible.Studies had to report either a dichotomous assessment of overallresponse to therapy at the last point of follow-up in the trial, orcontinuous data in the form of mean number of stools per weekduring therapy. First and senior authors of studies werecontacted to provide additional information on trials whererequired.Studies on CIC were identied with the terms: constipation or

    gastrointestinal transit (both as medical subject headings (MeSH)and free text terms), or functional constipation, idiopathic consti-pation, chronic constipation, or slow transit (as free text terms).These were combined using the set operator AND with studiesidentied with the terms: laxatives, cathartics, anthraquinones,phenolphthaleins, indoles, phenols, lactulose, polyethylene glycol,

    senna plant, senna extract, bisacodyl, phosphates, dioctyl sulfosuccinicacid, magnesium, magnesium hydroxide, sorbitol, poloxamer, serotoninagonists, receptors, serotonin, 5-HT4, or receptors, prostaglandin E(both as MeSH terms and free text terms), or the following freetext terms: sodium picosulphate, docusate, milk of magnesia,danthron, senna$, poloxalkol, prucalopride, lubiprostone, or linaclotide.There were no language restrictions. Abstracts of the papers

    identied by the initial search were evaluated independently byboth investigators for appropriateness. All potentially relevantpapers were obtained and evaluated in detail. Foreign languagepapers were translated. Abstract books of conference proceed-ings between 2002 and 2010 were hand-searched to identifypotentially eligible studies published only in abstract form.Bibliographies of all identied relevant studies were used toperform a recursive search. Articles were assessed independentlyby two investigators using pre-designed eligibility forms,according to the pre-dened eligibility criteria. Disagreementbetween investigators was resolved by discussion.

    Outcome assessmentThe primary outcomes assessed were the efcacy of laxatives orpharmacological therapies compared with placebo in CIC, interms of failure to respond to therapy, or effect on mean numberof stools per week during treatment. Secondary outcomesincluded effect on individual symptoms of CIC, and adverseevents occurring as a result of therapy (overall numbers, as wellas individual adverse events such as nausea, vomiting, diarrhoea,abdominal pain, abdominal bloating, or headache).

    Data extractionAll data were extracted independently by two investigators onto a Microsoft Excel spreadsheet (XP professional edition;Microsoft, Redmond, Washington, USA) as dichotomousoutcomes (response or no response to therapy), or mean numberof stools per week with a SD. In addition, the following clinicaldata were extracted for each trial, where available: setting(primary, secondary or tertiary care), number of centres, countryof origin, dose and duration of therapy, concomitant medica-tions allowed, criteria used to dene CIC, primary outcomemeasure used to dene response to therapy, method used togenerate the randomisation schedule and conceal allocation,level of blinding, and proportion of female patients. Data wereextracted as intention-to-treat analyses, with drop-outs assumedto be treatment failures (ie, no response to therapy), wherevertrial reporting allowed. If this was not clear from the originalarticle we performed an analysis on all patients with reportedevaluable data.

    Assessment of risk of biasThis was performed independently by two investigators, withdisagreements resolved by discussion. Risk of bias was assessedas described in the Cochrane handbook,20 by recording methodused to generate the randomisation schedule and conceal allo-cation, whether blinding was implemented, what proportion ofpatients completed follow-up, whether an intention-to-treatanalysis was extractable, and whether there was evidence ofselective reporting of outcomes.

    Data synthesis and statistical analysisData were pooled using a random effects model, to give a moreconservative estimate of the effect of laxatives and pharmaco-logical therapies in CIC, allowing for any heterogeneity betweenstudies.21 Impact on overall response to therapy in CIC wasexpressed as a RR of failure to respond to therapy compared

    Box 1 Eligibility criteria

    < Randomised controlled trials< Adults (>90% of participants aged >16 years)< Diagnosis of CIC based on either clinical symptoms,

    a physicians opinion, or meeting specific diagnostic criteria*,supplemented by negative investigations where trials deemedthis necessary.

    < Compared osmotic laxatives, stimulant laxatives, pruca-lopride, lubiprostone or linaclotide with placebo.

    < Minimum duration of therapy 7 days.< Dichotomous assessment of overall response to therapy or

    mean number of stools per week during therapy.

    *Rome I, II, or III criteria.

    210 Gut 2011;60:209e218. doi:10.1136/gut.2010.227132

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  • with placebo at last time point of assessment in the trial, ora weighted mean difference (WMD) in mean number of stoolsper week during therapy, with 95% CIs. Individual CICsymptom data and adverse events data were also summarisedwith relative risks. The number needed to treat (NNT) and thenumber needed to harm (NNH) with 95% CIs were calculatedfrom the reciprocal of the risk difference of the meta-analysis.Heterogeneity between studies was assessed using both the

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    Gut 2011;60:209e218. doi:10.1136/gut.2010.227132 211

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  • RESULTSThe search strategy generated 11 077 citations, 49 of whichappeared to be relevant to the systematic review and wereretrieved for further assessment (gure 1). Of these, 29 wereexcluded for various reasons, leaving a total of 20 eligible articlesreporting 21 separate trials. Eight RCTs studied the effect oflaxatives,24e31 seven prucalopride,32e38 three lubiprostone,39e41

    and three linaclotide.42 43 We contacted authors of seven of thetrials successfully to obtain supplementary information aboutthe methodology used.26e31 43 Agreement between investigatorsfor trial eligibility was substantial (k statistic0.83).

    Efficacy and safety of laxatives in CICThe eight RCTs comparing laxatives with placebo, involveda total of 1442 CIC patients (table 1).24e31 Five trials were at lowrisk of bias.27e31 Rescue laxatives were allowed if there was nobowel movement for 3 days in one trial,24 4 days in threetrials,29e31 and 5 days in two trials,26 27 and in the remaining twotrials this issue was unclear.25 28

    Response to therapy with laxativesDichotomous data were reported by seven RCTs,24 26e31

    containing 1411 patients. There were 351 (40.1%) of 876 patientsassigned...

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