Adverse events related to herbal dietary supplements and over-the-counter medications containing laxatives: a 10-year update from the Italian Phytovigilance and Pharmacovigilance systems.

INTRODUCTION: Products containing anthraquinones (AQ) are associated with an increased risk of serious adverse events (AEs). We performed an update of the available evidence retrieved by the spontaneous reports of AE associated with herbal dietary supplement (DS) and over-the-counter medications (OTC-M) used as laxatives. METHODS: Analysis and evaluation of AE reports retrieved from the Italian Phytovigilance and Pharmacovigilance systems was performed from February 2011 to December 2020. RESULTS: Totally 110 AE reports, 24 related to herbal DS and 86 to OTC-M, were analyzed. Most subjects were females. Herbal products analyzed mostly contained AQ derivatives. Most AEs were gastrointestinal (41.6%), central nervous system (18.2%), and dermatological disorders (12.6%). CONCLUSIONS: The number of AE reports recorded in the last 10 years is still relatively low. However, given the seriousness of some AEs, that does not represent a guarantee of safety. This study may contribute to enhance public awareness on the risks associated with misuse or abuse of laxatives.

Biofeedback, biofeedback plus fiber laxative, and biofeedback plus osmotic laxative regimens to treat constipation in patients with pelvic floor dyssynergia: A randomized controlled trial.

BACKGROUND: Pelvic floor dyssynergia (PFD) is one of the causes of chronic constipation. Laxative-based therapies are not very effective in treating this type of constipation. The therapeutic effectiveness of three therapeutic strategies, including biofeedback (BOF) alone, BOF+ fiber laxative (psyllium), and BOF +osmotic laxative (polyethylene glycol; [PEG]), was assessed in patients with constipation secondary to PFD. METHODS: Eighty-eight patients with constipation were included during a period from 2017 to 2018. Thirty-two patients were treated with BOF alone, 25 patients received BOF+ fiber laxative (psyllium), and 31 patients received BOF+ osmotic laxative (PEG) for 2 to 3 months. A checklist was used to compare outcomes before and after the interventions. RESULTS: Satisfaction rates from the treatments were 60.83%, 46.88%, and 41.32% in the BOF, BOF + psyllium, and BOF + PEG groups, respectively. Women had a higher satisfaction rate compared to men. Defecation quality improved, and the frequency of enema usage decreased (p <0.05) in all the groups after intervention. Difficulty in evacuation, need for digitation, and return to the toilet after defecation significantly improved in the BOF alone group. Using laxatives reduced straining during evacuation and increased the duration of defecation. All the three regimens reduced rectal bleeding (p <0.05). CONCLUSIONS: Combinations of laxatives with BOF did not offer significant therapeutic benefit. As laxatives may cause dissatisfaction and incomplete/prolonged defecations in patients with PFD, adding laxatives to the BOF regimen is not recommended for these patients.

[Acute phosphate nephropathy secondary to the use of oral sodium phosphate laxatives. Report of one case]. / Nefropatía aguda por fosfatos secundaria al uso de laxantes con fosfato de sodio: caso clínico-patológico.

Acute phosphate nephropathy (APN) is an acute renal failure secondary to the use of oral sodium phosphate (OSP) laxatives, with a high risk of progression to chronicity. We report a 60-year-old woman with mixed connective tissue disease whose serum creatinine increased up to 2.0 mg/dL in her regular control tests, without an evident causative factor. Kidney biopsy showed numerous intratubular calcium phosphate deposits, consistent with APN. She had a history of OSP laxative intake, and a sodium phosphate enema was used before a colonoscopy performed six months earlier. The temporal association between the use of OSP laxatives and acute kidney injury, should lead to the suspicion of APN. The urine sediment is generally normal or with mild to moderate proteinuria. The diagnosis is confirmed with a kidney biopsy. Until now, there is no specific treatment for APN, thus prevention is essential. In high-risk patients for developing APN, the administration of these laxatives should be avoided.

Nefropatía aguda por fosfatos secundaria al uso de laxantes con fosfato de sodio: caso clínico-patológico / Acute phosphate nephropathy secondary to the use of oral sodium phosphate laxatives: report of one case

Acute phosphate nephropathy (APN) is an acute renal failure secondary to the use of oral sodium phosphate (OSP) laxatives, with a high risk of progression to chronicity. We report a 60-year-old woman with mixed connective tissue disease whose serum creatinine increased up to 2.0 mg/dL in her regular control tests, without an evident causative factor. Kidney biopsy showed numerous intratubular calcium phosphate deposits, consistent with APN. She had a history of OSP laxative intake, and a sodium phosphate enema was used before a colonoscopy performed six months earlier. The temporal association between the use of OSP laxatives and acute kidney injury, should lead to the suspicion of APN. The urine sediment is generally normal or with mild to moderate proteinuria. The diagnosis is confirmed with a kidney biopsy. Until now, there is no specific treatment for APN, thus prevention is essential. In high-risk patients for developing APN, the administration of these laxatives should be avoided.

A meta-analysis of randomized controlled trials of a traditional Chinese medicine prescription, modified RunChang-Tang, in treating functional constipation.

BACKGROUND: Modified Runchang-Tang (MRCT), a Chinese herbal medicine, is widely used to treat functional constipation (FC), which is a common digestive system disease. However, its efficacy has not been evaluated systematically and objectively. Thus, a meta-analysis was conducted to assess the efficacy and safety of MRCT for treating functional constipation. METHODS: We searched for relevant publications from Embase, Medline, The Cochrane Library, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journals Database, and Wanfang Data for relevant literature. The timeframe of retrieval was set from the founding date of each database to July 15, 2020. RESULT: A total of 26 randomized controlled trials with 2103 individuals were included in this meta-analysis. All trials were conducted in mainland China and were written in Chinese. The results showed that MRCT monotherapy provided better symptom relief in FC patients compared to prokinetic agent monotherapy (odds ratio, [OR] = 4.06), osmotic laxatives (OR = 4.39) and stimulant laxatives (OR = 2.99). Additionally, there were no obvious adverse effects in MRCT group compared with control group. CONCLUSION: MRCT treatment is an efficient and safe treatment for FC. However, considering the limitations of this study, further well-designed randomized controlled trials are required to validate this conclusion.

Portal hypertension in prolonged anorexia nervosa with laxative abuse: a case report with liver and kidney biopsy data.

PURPOSE: We previously reported three cases of portal hypertension in patients with prolonged anorexia nervosa (AN) with laxative abuse and self-induced vomiting; we now report a fourth, similar case. METHODS: A 34-year-old woman with anorexia nervosa, binge-eating/purging type (AN-BP), presented to the Kohnodai Hospital National Center for Global Health and Medicine Psychosomatic Medicine Department for treatment of low body weight. We conducted hepatic and renal biopsies and cardiac magnetic resonance imaging (CMR) to evaluate her complicated liver disease, renal failure, and cardiac insufficiency, respectively. RESULTS: Enhanced computed tomography revealed ascites, splenomegaly, and gastroesophageal varices, indicating portal hypertension. The liver and kidney biopsies demonstrated chronic hepatitis without evidence of hepatic cirrhosis and tubulointerstitial nephritis, respectively. CMR demonstrated decreased myocardial mass. CONCLUSION: We found tubulointerstitial nephritis and decreased myocardial mass in a patient with non-cirrhotic portal hypertension and prolonged AN with laxative abuse and habitual self-induced vomiting. We propose that reciprocal interactions between multiple factors related to AN, including laxative toxicity, dehydration, renal disorder, and cardiac insufficiency, result in portal hypertension. Level of Evidence Level V.

The hospital-based evaluation of laxative prophylaxis in ICU (HELP-ICU): A pilot cluster-crossover randomized clinical trial.

PURPOSE: Prophylactic laxative regimens may prevent constipation but may increase diarrhea and subsequent rectal tube insertion. Our aim was to compare three prophylactic laxative regimens on the rate of rectal tube insertion (primary outcome) and major constipation- or diarrhea-associated complications. MATERIAL AND METHODS: We conducted a cluster-crossover trial. Three pods in a single ICU were each randomized to one of three regimens for four months with rolling cross-over. All mechanically-ventilated and enterally-fed adult patients received either regimen: A) one coloxyl with senna BD from day one; B) two coloxyl with senna +20 ml lactulose BD commencing on day 3; or C) two coloxyl with senna tablets +20 ml lactulose BD commencing on day 6. RESULTS: We enrolled 570 patients (A = 170, B = 205, C = 195) with similar baseline features. Overall, 53 (9.3%) patients received a rectal tube, and insertion rate was not statistically different between the three regimens (A = 12.9%, B = 7.8%, C = 7.7%; p = 0.15). The proportions of patients with other major constipation- or diarrhea-associated complications were similar, as were major patient-centred outcomes. CONCLUSION: Earlier commencement of a prophylactic coloxyl-based laxative regimen (day 1 or 3) did not affect the rates of complications associated with constipation or diarrhea when compared to delayed introduction (day 6).

A Case-control Study on the Risk Factors for Ischemic Colitis.

OBJECTIVE: Ischemic colitis (IC) is a relatively common acute inflammation disorder of the intestine. It was considered to be a disorder of elderly people with risk factors for arteriosclerosis; however, a considerable number of young people with IC have been reported recently. We performed a case-control study to determine the risk factors for IC and compare the risk factors between elderly and non-elderly people. METHODS: The study included 209 consecutive patients diagnosed with IC between December 2004 and March 2017 at Tokai University Hospital. The study also included 209 randomly selected controls in the same calendar year so as to match age and sex. Possible risk factors for IC were identified and compared between age groups. RESULTS: The mean age of IC group was 64.9 with 60 males and 115 elderly patients aged 65 or more in each group. On multivariable conditional logistic regression analysis, drinking, abdominal surgery, hypertension, and malignant diseases were risk factors for IC in all ages. In non-elderly patients, only hypertension and laxative/enema use were significant factors, while in elderly, abdominal surgery, hypertension, COPD, malignant disease and antiplatelet drugs were significant. CONCLUSION: The risk factors in elderly people might be quite different from younger ones, while hypertension seemed to be a common risk in all ages.

Efficacy and safety of laxatives for chronic constipation in long-term care settings: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Constipation is a common disorder among long-term care (LTC) patients due to several factors. However, there are no systematic reviews investigating the use of laxatives for chronic constipation in LTC settings. This study aims to explore the safety and efficacy of laxatives in LTC patients. METHODS: A systematic review of randomized controlled trials (RCTs) describing the efficacy and safety of laxatives for chronic constipation in LTC patients was conducted using the following databases and search engines: MEDLINE, Cochrane Database of Systematic Reviews, ScienceDirect, ProQuest and Google Scholar. Two of the investigators independently performed the searches, and the data were extracted using a standardized data abstraction tool. RESULTS AND DISCUSSION: Seven RCTs involving 444 patients were included in the review. These studies included senna (with or without fibre, ie Plantago ovata), lactulose, sodium picosulphate, docusate sodium, docusate calcium, isotonic and hypotonic polyethylene glycol and Chinese herbal medicine. Senna and lactulose were the most studied laxatives in LTC patients, and senna was found to be superior to or as effective as other laxatives. Generally, the frequency and severity of adverse drug reactions (ADRs) were similar between the arms of the studies, and no serious ADRs were reported. WHAT IS NEW AND CONCLUSION: Considering the short duration of the trials, the lack of trials including newer laxatives and the low quality of some of the included trials, the long-term efficacy and safety of these laxatives are not conclusive. There is a need to conduct more robust RCTs that include newer agents to evaluate long-term outcomes.

Refractory Constipation: What is the Clinician to Do?

Most clinicians will agree that chronic constipation is characterized by abnormal bowel movement consistency and/or frequency plus or minus evacuation symptoms, but patient perception of constipation varies widely and includes symptoms that may or may not meet official defining criteria. Although intermittent constipation is extremely common, only a small minority of patients seek care for their symptoms. Among these patients, dissatisfaction with the currently available laxative options is not uncommon, and many patients will require specialized care for severe or refractory symptoms-especially those with abdominal pain, irritable bowel syndrome overlap, bloating or distention, and psychological comorbidities. This review outlines a physiological assessment of the patient with refractory constipation, exploring treatment options among patients with slow transit, rectal evacuation disorders, and normal transit. In addition, we explore nonlaxative approaches to normal-transit patients bothered by ongoing symptoms, with an emphasis on the biopsychosocial model of functional gastrointestinal disease and treatment of visceral hypersensitivity using neuromodulators. Finally, we propose a comprehensive evaluation algorithm for the management of patients with refractory slow-transit constipation considering surgery and examine surgical options including colectomy and cecostomy using an antegrade continent enema.

When a cure becomes the pathology: mechanical bowel obstruction due to herbal pharmacobezoar. A case report with review of literature.

Bezoars are intra-luminal concretions of ingested material which accumulate within the bowel. They are termed pharmacobezoars when the constituent material is drugs. We report a 64-year-old female with abdominal pain and obstipation for 3 days. Patient had completed anti-tuberculous combination therapy for suspected abdominal tuberculosis 25 years ago. She exhibited features of shock with a right iliac fossa lump. Abdominal X-ray displayed multiple air-fluid levels with densely cluttered radio-opacities in the right lower quadrant. Laparotomy revealed a palpable mid-ileal intra-luminal lump, adherent to the ascending colon and proximal ileum necessitating resection. Ex vivo examination of resected specimen revealed numerous tablets aggregating proximal to an ileal stricture. The patient post-operatively confirmed the tablets resembled the herbal laxatives she had been consuming. Pharmacobezoars can lead to subacute intestinal obstruction. Numerous drugs have been implicated. Patients with partial gastrectomy and vagotomy are at risk. CT is the pre-eminent diagnostic modality. The treatment options for pharmacobezoars include lavage, endoscopic retrieval, in addition to surgery. Pharmacobezoars need a high index of suspicion for pre-operative diagnosis. A detailed history and correlation with radioimaging can offer important cues. One can prevent pharmacobezoars by abstaining from unwarranted medications and identifying those at risk.

Are Senna based laxatives safe when used as long term treatment for constipation in children?

BACKGROUND AND AIM: Senna is a stimulant laxative commonly used by pediatricians, pediatric gastroenterologists, and pediatric surgeons. Many clinicians avoid Senna for reasons such as tolerance or side effects but this has little scientific justification. We recently found several patients we were caring for developed perineal blistering during the course of Senna treatment. Because of this we chose to review the literature to identify side effects in children taking this medication as well as to analyze our Center's experience with Senna's secondary effects. METHODS: We performed a literature review (MEDLINE, PUBMED) using the keywords of Senna, sen, sennosides and children, and pediatric and functional (idiopathic) constipation. We looked for articles with information regarding perineal blisters related to Senna as well as other secondary effects of Senna laxatives in children when used on a long-term basis. We also reviewed the charts of our patients who had previously taken Senna or are currently taking Senna, looking for adverse reactions. RESULTS: Eight articles in the literature reported perineal blisters after administration of Senna laxatives in 28 patients. Of those occurrences, 18 patients (64%) had accidental administration of Senna and 10 (36%) had Senna prescribed as a long term treatment. All of the blistering episodes were related to high dose, night-time accidents, or intense diarrhea with a long period of stool to skin contact. At our institution, from 2014 to 2017, we prescribed Senna and have recorded data to 640 patients. During the study period, 17 patients (2.2%) developed blisters during their treatment. Patients who developed blisters had higher doses 60mg/day; 60 [12-100] vs. 17.5 [1.7-150] (p<0.001). All of the blistering episodes were related to night-time accidents, with a long period of stool to skin contact. 83 (13%) patients presented minor side effects such as abdominal cramping, vomiting or diarrhea which resolved once the type of laxatives were changed or enemas were started. The doses of Senna was not significantly different in these patients 15mg/day [4.4-150] vs. 17.5mg/day [1.5-150]. There were no other long-term side effects from Senna found in the pediatric literature for long-term treatment besides abdominal cramping or diarrhea during the first weeks of administration. We found no evidence of tolerance to Senna in our review. CONCLUSION: There is a paucity of information in the literature regarding side effects of sennosides as a long-term therapy, and to our knowledge, this is the first review of Senna side effects in children. Senna induced dermatitis is rare, but may occur when patients need a higher dose. All of the cases described had a long period of exposure of the skin to stool. Besides the perineal rash with blisters, we could find no other described major side effect with Senna administration in the pediatric population or evidence of the frequently mentioned concern of the development of tolerance to Senna. Pediatric caregivers should advise families of the rare side effect of skin blistering and educate them to change the diaper frequently in children who are not toilet- trained to reduce stool to skin exposure. We can conclude from this review that Senna is a safe treatment option for constipation in children. LEVEL OF EVIDENCE: IV.

Occupational allergy to Spagulax®(Plantago ovata seed).

SUMMARY: We report the case of a 36-year-old male pharmaceutical laboratory worker. On handling Spagulax® sachets whose content is a laxative called Plantago ovata, he immediately presented rhinoconjunctivitis. Methods. Specific allergy study included SDS-PAGE with Western Blot and specific nasal challenge to Plantago ovata extract. Results. Prick by prick for Spagulax® was negative. Total IgE: 126.5 U/mL. Western Blot recognized two proteins of 15 and 20 kDa in the extract of Plantago ovata and three proteins of 15, 18 and 50 kDa in the extract of Plantago lanceolata. Conclusions. We present a case of occupational allergy due to inhalation of and/or contact with Plantago ovata seeds.

Identification of the Causes for Chronic Hypokalemia: Importance of Urinary Sodium and Chloride Excretion.

BACKGROUND: Uncovering the correct diagnosis of chronic hypokalemia with potassium (K+) wasting from the kidneys or gut can be fraught with challenges. We identified clinical and laboratory parameters helpful for differentiating the causes of chronic hypokalemia. METHODS: Normotensive patients referred to our tertiary academic medical center for the evaluation of chronic hypokalemia were prospectively enrolled over 5 years. Clinical features, laboratory examinations-including blood and spot urine electrolytes, acid-base status, biochemistries, and hormones-as well as genetic analysis, were determined. RESULTS: Ninety-nine patients with chronic normotensive hypokalemia (serum K+ 2.8 ± 0.4 mmol/L, duration 4.1 ± 0.9 years) were enrolled. Neuromuscular symptoms were the most common complaints. Although Gitelman syndrome (n = 33), Bartter syndrome (n = 10), and distal renal tubular acidosis (n = 12) were the predominant renal tubular disorders, 44 patients (44%) were diagnosed with anorexia/bulimia nervosa (n = 21), surreptitious use of laxatives (n = 11), or diuretics (n = 12). Patients with gastrointestinal causes and surreptitious diuretics use exhibited a female predominance, lower body mass index, and less K+ supplementation. High urine K+ excretion (transtubular potassium gradient >3, urine K+/Cr >2 mmol/mmol) was universally present in patients with renal tubular disorders, but also found in >50% patients with gastrointestinal causes. Of interest, while urine sodium (Na+) and chloride (Cl-) excretions were high and coupled (urine Na+/Cl- ratio ∼1) in renal tubular disorders and "on" diuretics use, skewed or uncoupled urine Na+ and Cl- excretions were found in anorexia/bulimia nervosa and laxatives abuse (urine Na+/Cl- ratio: 5.0 ± 2.2, 0.4 ± 0.2, respectively) and low urine Na+ and Cl- excretions with fixed Na+/Cl- ratios (0.9 ± 0.2) when "off" diuretics. CONCLUSION: Besides body mass index, sex, and blood acid-base status, integrated interpretation of the urine Na+:Cl- excretion and their ratio is important to make an accurate diagnosis and treatment plan for patients with chronic normotensive hypokalemia.

Contact Burn with Blister Formation in Children Treated with Sennosides.

Eight children treated for severe constipation with sennosides unexpectedly developed contact burns with blisters secondary to the use of these laxatives. All patients wore diapers, and the injuries occurred overnight. To avoid this side effect, we recommend that patients treated with sennosides, especially those in diapers, receive the medication at a time that allows for bowel movements to occur during the day and not overnight.

Severe hyperphosphatemia after oral laxative administration in a 7-year-old patient.

Sodium phosphate based laxatives are commonly used for constipation and pre-procedural bowel cleansing. Phosphate intoxication related with these preparations is well recognized. Herein, we present a case of severe hyperphosphatemia and seizure in a 7-year-old male patient after administration of an oral sodium phosphate based laxative. At the time of admission, serum phosphorus level was 25.6 mg/dl. Aggressive fluid therapy was started. Although serum phosphorus level decreased to 20.9 mg/dl eight hours after admission, hemodialysis was performed because of the preexisting renal disease and declined glomerular filtration rate. Serum phosphorus level and blood gas analysis returned to normal after hemodialysis and the patient was discharged on hospital day two. In conclusion, sodium phosphate based laxatives should be used carefully in patients with preexisting renal diseases. Intravenous hydration and correction of hypocalcemia are important components of treatment. Hemodialysis is indicated in patients with renal failure.

Osmotic and stimulant laxatives for the management of childhood constipation.

BACKGROUND: Constipation within childhood is an extremely common problem. Despite the widespread use of osmotic and stimulant laxatives by health professionals to manage constipation in children, there has been a long standing paucity of high quality evidence to support this practice. OBJECTIVES: We set out to evaluate the efficacy and safety of osmotic and stimulant laxatives used to treat functional childhood constipation. SEARCH METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane IBD Group Specialized Trials Register from inception to 10 March 2016. There were no language restrictions. We also searched the references of all included studies, personal contacts and drug companies to identify studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) which compared osmotic or stimulant laxatives to placebo or another intervention, with participants aged 0 to 18 years old were considered for inclusion. The primary outcome was frequency of defecation. Secondary endpoints included faecal incontinence, disimpaction, need for additional therapies and adverse events. DATA COLLECTION AND ANALYSIS: Relevant papers were identified and two authors independently assessed the eligibility of trials, extracted data and assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was frequency of defecation. Secondary endpoints included faecal incontinence, disimpaction, need for additional therapies and adverse events. For continuous outcomes we calculated the mean difference (MD) and 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes we calculated the risk ratio (RR) and 95% CI using a fixed-effect model. The Chi(2) and I(2) statistics were used to assess statistical heterogeneity. A random-effects model was used in situations of unexplained heterogeneity. We assessed the overall quality of the evidence supporting the primary and secondary outcomes using the GRADE criteria. MAIN RESULTS: Twenty-five RCTs (2310 participants) were included in the review. Fourteen studies were judged to be at high risk of bias due to lack of blinding, incomplete outcome data and selective reporting. Meta-analysis of two studies (101 patients) comparing polyethylene glycol (PEG) with placebo showed a significantly increased number of stools per week with PEG (MD 2.61 stools per week, 95% CI 1.15 to 4.08). Common adverse events in the placebo-controlled studies included flatulence, abdominal pain, nausea, diarrhoea and headache. Participants receiving high dose PEG (0.7 g/kg) had significantly more stools per week than low dose PEG (0.3 g/kg) participants (1 study, 90 participants, MD 1.30, 95% 0.76 to 1.84). Meta-analysis of 6 studies with 465 participants comparing PEG with lactulose showed a significantly greater number of stools per week with PEG (MD 0.70 , 95% CI 0.10 to 1.31), although follow-up was short. Patients who received PEG were significantly less likely to require additional laxative therapies. Eighteen per cent (27/154) of PEG patients required additional therapies compared to 31% (47/150) of lactulose patients (RR 0.55, 95% CI 0.36 to 0.83). No serious adverse events were reported with either agent. Common adverse events in these studies included diarrhoea, abdominal pain, nausea, vomiting and pruritis ani. Meta-analysis of 3 studies with 211 participants comparing PEG with milk of magnesia showed that the stools per week were significantly greater with PEG (MD 0.69, 95% CI 0.48 to 0.89). However, the magnitude of this difference was quite small and may not be clinically significant. One child was noted to be allergic to PEG, but there were no other serious adverse events reported. One study found a significant difference in stools per week favouring milk of magnesia over lactulose (MD -1.51, 95% CI -2.63 to -0.39, 50 patients), Meta-analysis of 2 studies with 287 patients comparing liquid paraffin (mineral oil) with lactulose revealed a relatively large statistically significant difference in the number of stools per week favouring liquid paraffin (MD 4.94 , 95% CI 4.28 to 5.61). No serious adverse events were reported. Adverse events included abdominal pain, distention and watery stools. No statistically significant differences in the number of stools per week were found between PEG and enemas (1 study, 90 patients, MD 1.00, 95% CI -1.58 to 3.58), dietary fibre mix and lactulose (1 study, 125 patients, P = 0.481), senna and lactulose (1 study, 21 patients, P > 0.05), lactitol and lactulose (1 study, 51 patients, MD -0.80, 95% CI -2.63 to 1.03), hydrolyzed guar gum and lactulose (1 study, 61 patients, MD 1.00, 95% CI -1.80 to 3.80), PEG and flixweed (1 study, 109 patients, MD 0.00, 95% CI -0.33 to 0.33), PEG and dietary fibre (1 study, 83 patients, MD 0.20, 95% CI -0.64 to 1.04), and PEG and liquid paraffin (2 studies, 261 patients, MD 0.35, 95% CI -0.24 to 0.95). AUTHORS' CONCLUSIONS: The pooled analyses suggest that PEG preparations may be superior to placebo, lactulose and milk of magnesia for childhood constipation. GRADE analyses indicated that the overall quality of the evidence for the primary outcome (number of stools per week) was low or very low due to sparse data, inconsistency (heterogeneity), and high risk of bias in the studies in the pooled analyses. Thus, the results of the pooled analyses should be interpreted with caution because of quality and methodological concerns, as well as clinical heterogeneity, and short follow-up. There is also evidence suggesting the efficacy of liquid paraffin (mineral oil). There is no evidence to demonstrate the superiority of lactulose when compared to the other agents studied, although there is a lack of placebo controlled studies. Further research is needed to investigate the long term use of PEG for childhood constipation, as well as the role of liquid paraffin. The optimal dose of PEG also warrants further investigation.