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Nonpharmacologic Treatment for Children with Functional Constipation: A Systematic Review and Meta-analysis.
Wegh, CAM, Baaleman, DF, Tabbers, MM, Smidt, H, Benninga, MA
The Journal of pediatrics. 2022;:136-149.e5
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OBJECTIVE To evaluate the effectiveness and safety of nonpharmacologic interventions for the treatment of childhood functional constipation. STUDY DESIGN Randomized controlled trials (RCTs) evaluating nonpharmacologic treatments in children with functional constipation which reported at least 1 outcome of the core outcome set for children with functional constipation. RESULTS We included 52 RCTs with 4668 children, aged between 2 weeks and 18 years, of whom 47% were females. Studied interventions included gut microbiome-directed interventions, other dietary interventions, oral supplements, pelvic floor-directed interventions, electrical stimulation, dry cupping, and massage therapy. An overall high risk of bias was found across the majority of studies. Meta-analyses for treatment success and/or defecation frequency, including 20 RCTs, showed abdominal electrical stimulation (n = 3), Cassia Fistula emulsion (n = 2), and a cow's milk exclusion diet (n = 2 in a subpopulation with constipation as a possible manifestation of cow's milk allergy) may be effective. Evidence from RCTs not included in the meta-analyses, indicated that some prebiotic and fiber mixtures, Chinese herbal medicine (Xiao'er Biantong granules), and abdominal massage are promising therapies. In contrast, studies showed no benefit for the use of probiotics, synbiotics, an increase in water intake, dry cupping, or additional biofeedback or behavioral therapy. We found no RCTs on physical movement or acupuncture. CONCLUSIONS More well-designed high quality RCTs concerning nonpharmacologic treatments for children with functional constipation are needed before changes in current guidelines are indicated.
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The efficacy and safety of probiotics for patients with constipation-predominant irritable bowel syndrome: A systematic review and meta-analysis based on seventeen randomized controlled trials.
Wen, Y, Li, J, Long, Q, Yue, CC, He, B, Tang, XG
International journal of surgery (London, England). 2020;:111-119
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BACKGROUND & Objectives: Constipation-predominant irritable bowel syndrome (IBS-C) is functional bowel disorders that may involve disturbance of the gastrointestinal microbiota. We performed a systematic review and meta-analysis of the efficacy and safety of probiotics in patients with IBS-C. METHODS We searched the Cochrane Library, PubMed, EMBASE and Web of Science databases up to 1 May 2019. Randomized controlled trials (RCTs) involving adults with IBS-C that compared probiotics to placebo or no therapy were eligible for the analysis. Dichotomous symptom data were pooled to calculate the relative risk (RR) with a 95% confidence interval (CI) of remaining symptoms after therapy. Continuous data were pooled using a standardized or weighted mean difference (MD) with the 95% CI. Two reviewers assessed trial quality and extracted data independently. The analysis was performed using Review Manager version 5.2. RESULTS Seventeen RCTs involving 1469 patients were included in the analysis. Overall, probiotics significantly increased stool frequency by 1.29 bowel movements (BM)/wk (95% CI: 0.69 to 1.89 BM/wk; P < 0.0001), and improved stool consistency (SMD: 0.55; 95% CI: 0.27 to 0.82; P = 0.0001). Compared with placebo, patients using probiotics experienced a shorter gut transit time by 12.36 h (95% CI: -20.74 to -3.98 h; P = 0.004). No serious adverse events were reported. CONCLUSIONS Generally, probiotics may be safe and may improve whole gut transit time, stool frequency, and stool consistency. However, adequately powered RCTs are required to better determine the species or strains, doses, and duration of use of probiotics that are most efficacious. Further research and evidence is required before probiotics is adopted as one of treatments of IBS-C.
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Impact of Clinical Outcome Measures on Placebo Response Rates in Clinical Trials for Chronic Constipation: A Systematic Review and Meta-analysis.
Chen, J, Liu, X, Bai, T, Hou, X
Clinical and translational gastroenterology. 2020;(11):e00255
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OBJECTIVES Chronic constipation (CC) is a recurrent functional bowel disorder worldwide. The purpose of this study is to examine its pooled placebo response rate and compare placebo response level in randomized controlled trials (RCTs) with different endpoint assessments. METHODS PubMed, Cochrane Library, and Embase were electronically searched for therapeutic RCTs of CC with placebo control. Data extraction and assessment of risk of bias were performed independently by 2 reviewers. All the statistical calculation and analysis were performed using R 3.6.0. Our protocol has registered in PROSPERO with registration number: CRD42019121287. RESULTS There were 46 studies included with 5,992 constipated patients allocated to the placebo arm in total. The pooled placebo response rate was 28.75% (95% confidence interval: 23.83%-33.67%) with significant heterogeneity among trials ((Equation is included in full-text article.)= 93.6%). Treatment efficacy assessed using subjective improvement had a significantly higher placebo response rate than that assessed with improvement in complete (spontaneous) bowel movements or composite improvement (41.40% vs 18.31% or 20.35%, P < 0.001). According to the results of meta-regression, active treatment and endpoint assessment were most likely to lead to the huge heterogeneity among studies. DISCUSSION Patients with CC have significant response level to placebo. Based on findings in this study, we do not recommend subjective improvement as endpoint while designing therapeutic RCTs for chronic constipated patients.
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Treatment of childhood constipation: a synthesis of systematic reviews and meta-analyses.
Southwell, BR
Expert review of gastroenterology & hepatology. 2020;(3):163-174
Abstract
Introduction: Constipation occurs in many children and can become chronic. Many grow out of it but for one third, it continues into adulthood. For most patients, there is no identifiable organic disorder and it is classified as functional constipation.Areas covered: In 2016, treatment of childhood constipation was extensively reviewed by Rome IV. This review covers meta-analyses and evidence for treatment of paediatric constipation since 2016 and new emerging treatments.Expert opinion: Since 2016, meta-analyses conclude 1) fibre should be included in a normal diet, but further supplementation does not improve constipation; 2) probiotics may increase stool frequency in children, but evidence from larger RCTs is needed; 3) comparing laxatives, polyethylene glycol (PEG) is superior to placebo, lactulose and milk of magnesia, and 4) appendix stomas are effective and should be considered before surgery. Emerging areas of study include food intolerance, electrical stimulation and faecal microbiota transplant. For research, outcome measures need standardising to allow comparison between studies and allow meta-analyses. To assist this, validated GI instruments have been developed by Rome IV and PedsQl.
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Efficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis.
Nee, J, Zakari, M, Sugarman, MA, Whelan, J, Hirsch, W, Sultan, S, Ballou, S, Iturrino, J, Lembo, A
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;(10):1569-1584.e2
Abstract
BACKGROUND & AIMS Opioid-induced constipation (OIC) is a common problem in patients on chronic opioid therapy for cancer-related and non-cancer-related pain. Approved treatments for OIC are methylnaltrexone, naloxone, naloxegol, alvimopan, naldemedine, and lubiprostone. Since a meta-analysis performed in 2014, 2 new agents have been approved by the Food and Drug Administration for treatment of OIC (naloxegol and naldemedine). METHODS We conducted a search of the medical literature following the protocol outlined in the Cochrane Handbook for systematic review. We searched MEDLINE, EMBASE, EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials until March 2017 to identify randomized controlled trials of peripheral μ-opioid-receptor antagonists (methylnaltrexone, naloxone, naloxegol, alvimopan, axelopran, or naldemedine), lubiprostone, or prucalopride. Response to therapy was extracted in a dichotomous assessment as an overall response to therapy. The effect of pharmacologic therapies was pooled and reported as a relative risk (RR) of failure to respond to the treatment drug, with 95% CIs. RESULTS We included 27 placebo-controlled trials in our meta-analysis (23 trials evaluated μ-opioid-receptor antagonists, 3 trials evaluated lubiprostone, and 1 trial evaluated prucalopride). In these trials, 5390 patients received a drug and 3491 received a placebo. Overall, μ-opioid-receptor antagonists, lubiprostone, and prucalopride were superior to placebo for the treatment of OIC, with a RR of failure to respond to therapy of 0.70 (95% CI, 0.64-0.75) and an overall number needed to treat of 5 (95% CI, 4-7). When restricted to only Food and Drug Administration-approved medications for OIC, the RR of failure to respond to therapy was 0.69 (95% CI, 0.62-0.77), with a number needed to treat of 5 (95% CI, 4-7). Sensitivity analyses and meta-regression performed to account for heterogeneity showed that treatment was more likely to be effective in study populations taking higher doses of opiates at baseline or refractory to laxatives. Study duration and prespecified primary outcome did not affect the RR of failure. Participants who received μ-opioid-receptor antagonists were significantly more likely to have diarrhea, abdominal pain, nausea, or vomiting than patients who received placebo. CONCLUSIONS In a systematic review and meta-analysis, we found μ-opioid-receptor antagonists to be safe and effective for the treatment of OIC. Prescription-strength laxatives (prucalopride, lubiprostone) are slightly better than placebo in reducing OIC.
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Prevalence of Functional Defecation Disorders in Children: A Systematic Review and Meta-Analysis.
Koppen, IJN, Vriesman, MH, Saps, M, Rajindrajith, S, Shi, X, van Etten-Jamaludin, FS, Di Lorenzo, C, Benninga, MA, Tabbers, MM
The Journal of pediatrics. 2018;:121-130.e6
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OBJECTIVE To systematically review the literature regarding the epidemiology of functional constipation and functional nonretentive fecal incontinence (FNRFI) in children. Secondary objectives were to assess the geographical, age, and sex distribution of functional constipation and FNRFI and to evaluate associated factors. STUDY DESIGN The Cochrane Library, PubMed, and Embase databases were searched from 2006 until September 2017. The following inclusion criteria were applied: (1) prospective studies of population-based samples; (2) reporting on the prevalence of functional constipation or FNRFI according to the Rome III/IV criteria; (3) in children aged 0-18 years; and (4) published in full manuscript form. A quality assessment of included studies was conducted. Random effect meta-analyses with meta-regression analyses of study characteristics were performed. RESULTS Thirty-seven studies were included, of which 35 reported on the prevalence of functional constipation and 15 of FNRFI. The reported prevalence of functional constipation ranged from 0.5% to 32.2%, with a pooled prevalence of 9.5% (95% CI 7.5-12.1). The prevalence of FRNFI ranged from 0.0% to 1.8%, with a pooled prevalence of 0.4% (95% CI 0.2-0.7). The prevalence of functional constipation was 8.6% in boys compared with 8.9% in girls (OR 0.99, 95% CI 0.9-1.4). Geographical location, dietary habits, and exposure to stressful life events were reported to be associated with the prevalence of functional constipation. Data on FNRFI were scarce and no associated factors were identified. CONCLUSION Functional constipation is common in childhood and is associated with geographical location, lifestyle factors, and stressful life events. FNRFI is rare, and no associated factors were identified.
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Systematic review and meta-analysis of the effect of probiotic supplementation on functional constipation in children.
Jin, L, Deng, L, Wu, W, Wang, Z, Shao, W, Liu, J
Medicine. 2018;(39):e12174
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BACKGROUND To evaluate the effect of probiotic supplementation on functional constipation in children. METHODS We performed electronic searches in PubMed, Embase, and Cochrane Library without language restriction to identify relevant studies from the time of inception of these databases to March 2018. The relative risk or weighted mean difference was calculated to evaluate the treatment effect of probiotics using random-effects model. RESULTS We included 4 trials reporting data on 382 children with functional constipation. Overall, there were no significant differences in treatment success (P = .697), spontaneous bowel movements per week (P = .571), fecal soiling episodes per week (P = .642), straining at defecation (P = .408), use of lactulose (P = .238), use of laxatives (P = .190), fecal incontinence (P = .139), pain during defecation (P = .410), flatulence (P = .109), and adverse events (P = .979) between probiotics and placebo. Further, the use of probiotics was associated with lower frequency of glycerin enema use (weighted mean difference -2.40, P = .004) and abdominal pain (weighted mean difference -4.80, P < .001). CONCLUSION The findings of this study suggested that the use of probiotics was associated with significant improvement in glycerin enema use and abdominal pain but did not affect the treatment success and other function indices.
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Systematic review with meta-analysis: effect of fibre supplementation on chronic idiopathic constipation in adults.
Christodoulides, S, Dimidi, E, Fragkos, KC, Farmer, AD, Whelan, K, Scott, SM
Alimentary pharmacology & therapeutics. 2016;(2):103-16
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BACKGROUND Chronic idiopathic constipation is a common symptom-based gastrointestinal disorder responsible for a substantial economic health service burden. Current guidelines recommend the use of fibre as a first-line treatment. AIM: To investigate the effect of fibre (including prebiotic) supplementation on global symptom response, stool output, gut microbiota composition and adverse events in adults with chronic idiopathic constipation. METHODS Medline, EmBase, Web of Science, Scopus and the Cochrane central register of controlled trials were searched through to February 2016. Conference proceedings from 2003 to 2015 were hand-searched. There were no language restrictions. Forest plots with 95% CIs were generated using a random-effects model. RESULTS The search strategy generated 1072 citations, of which seven individual randomised controlled trials were eligible. Overall, 113 of 147 (77%) patients assigned to fibre responded to therapy, compared with 61 of 140 (44%) allocated to placebo (RR of success to respond 1.71, 95% CI 1.20-2.42, P = 0.003). Fibre significantly increased stool frequency (SMD, standardised mean difference = 0.39; 95% CI 0.03-0.76; P = 0.03) and softened stool consistency (SMD = 0.35; 95% CI 0.04-0.65; P = 0.02) compared with placebo. Flatulence was significantly higher with fibre compared to placebo (SMD 0.56, 0.12-1.00, P = 0.01). Overall quality of evidence was low. CONCLUSIONS This meta-analysis demonstrates that fibre is moderately effective, but also causes moderate gastrointestinal side effects. However, these findings need to be treated with caution due to a high risk of bias. Accordingly, further large, methodologically rigorous trials are required, before any definitive recommendation regarding its risk-benefit profile can be made. PROSPERO registration number CRD42014007005.
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Comparison of the effectiveness of polyethylene glycol with and without electrolytes in constipation: a systematic review and network meta-analysis.
Katelaris, P, Naganathan, V, Liu, K, Krassas, G, Gullotta, J
BMC gastroenterology. 2016;:42
Abstract
BACKGROUND Polyethylene glycol is commonly used to manage constipation and is available with or without electrolytes. The addition of electrolytes dates back to its initial development as lavage solutions in preparation for gastrointestinal interventions. The clinical utility of the addition of electrolytes to polyethylene glycol for the management of constipation is not established. The objective of this systematic review and network meta-analysis (NMA) was to assess the relative effectiveness of polyethylene glycol with (PEG + E) or without electrolytes (PEG) in the management of functional constipation in adults. METHODS A systematic review was conducted to identify randomised controlled clinical trials that assessed the use of polyethylene glycol in functional constipation. The primary outcome was the mean number of bowel movements per week. RESULTS Nineteen studies were included in the NMA (PEG N = 9, PEG + E N = 8, PEG versus PEG + E N = 2; involving 2247 patients). PEG and PEG + E are both effective, increasing the number of bowel movements per week by 1.8 (95 % Crl 1.0, 2.8) and 1.9 (95 % Crl 0.9, 3.0) respectively versus placebo and by 1.8 (95 % Crl 0.0, 3.5) and 1.9 (95 % Crl 0.2, 3.6) respectively versus lactulose. There was no efficacy difference between PEG + E and PEG (0.1, 95 % Crl -1.1, 1.2) and there were no differences in safety or tolerability. CONCLUSIONS Polyethylene glycol with and without electrolytes are effective and safe treatments for constipation in adults. The addition of electrolytes to polyethylene glycol does not appear to offer any clinical benefits over polyethylene glycol alone in the management of constipation.
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Use of polyethylene glycol in functional constipation and fecal impaction.
Mínguez, M, López Higueras, A, Júdez, J
Revista espanola de enfermedades digestivas. 2016;(12):790-806
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OBJECTIVE The objective of this study was to evaluate in an analytical and descriptive manner the evidence published so far on the use of polyethylene glycol (PEG), with or without electrolytes, in the management of functional constipation and the treatment of fecal impaction. METHODOLOGY Search on MEDLINE, EMBASE and Cochrane databases until May 2016 of all publications adjusted to the following terms: constipation AND/OR fecal impaction AND (PEG OR polyethylene glycol OR macrogol OR movicol OR idralax OR miralax OR transipeg OR forlax OR golytely OR isocolan OR mulytely) NOT colonoscopy. Critical reading of selected articles (English or Spanish), sorting their description according to group age (adult/pediatric age) and within those, in accordance with study features (efficacy evaluation versus placebo, doses query, safety, comparison with other laxatives, observational studies and monographic review articles of polyethylene glycol or meta-analysis). RESULTS Fifty-eight publications have been chosen for descriptive analysis; of them, 41 are clinical trials, eight are observational studies and nine are systematic reviews or meta-analysis. Twelve clinical trials evaluate PEG efficacy versus placebo, eight versus lactulose, six are dose studies, five compare polyethylene glycol with and without electrolytes, two compare its efficacy with respect to milk of magnesia, and the rest of the trials evaluate polyethylene glycol with enemas (two), psyllium (one), tegaserod (one), prucalopride (one), paraffin oil (one), fiber combinations (one) and Descurainia sophia (one). CONCLUSIONS Polyethylene glycol with or without electrolytes is more efficacious than placebo for the treatment of functional constipation, either in adults or in pediatric patients, with great safety and tolerability. These preparations constitute the most efficacious osmotic laxatives (more than lactulose) and are the first-line treatment for functional constipation in the short and long-term. They are as efficacious as enemas in fecal impaction, avoid the need for hospital admission and are well tolerated by patients (mainly when administered without electrolytes).