MiniCAT-RT6 WK1 PICO- PEG vs lactulose for chronic constipation

Clinical Question: As in the past, please briefly outline the scenario and state your clinical question as concisely and specifically as possible

98 year old male with bladder cancer is admitted for hematuria and now complains of constipation. Reports he has not moved bowels in 3 days and has severe pain whenever he tries to defecate. The patient was given Colace and lactulose with no improvement in bowel movements.

Is PEG more effective than lactulose for treatment of constipation in geriatric patients?

PICO Question:

Identify the PICO elements – this should be a revision of whichever PICO you have already begun in a previous week

P	I	C	O
Geriatric	Polyethylene glycol	Lactulose	Bowel movement
Male	PEG		Resolution of constipation
Constipation			Reduced constipation

Search Strategy:

Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on.  This will likewise be a revision and refinement of what you have already done.

PubMed:

• Constipation, PEG, lactulose – 383
• Geriatric, constipation, PEG, lactulose – 44

Cochrane Library

• constipation, PEG, lactulose – 3

Google Scholar

• geriatric, constipation, PEG, lactulose – 1160
  • since 2020 – 124

• Narrowed search by focusing on systematic reviews and RCTs as these would provide the highest levels of evidence to answer my question. Focused on articles that compared PEG and lactulose. There were many studies that compared various laxatives used for chronic constipation in elderly populations and these were considered as well if PEG and lactulose were included.

Articles Chosen (4 or more) for Inclusion (please copy and paste the abstract with link):

Article 1:

Lee‐Robichaud  H, Thomas  K, Morgan  J, Nelson  RL. Lactulose versus Polyethylene Glycol for Chronic Constipation. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD007570. DOI: 10.1002/14651858.CD007570.pub2. Accessed 01 July 2021.

Abstract:

Background

Constipation is a common clinical problem. Lactulose and Polyethylene Glycol (PEG) are both commonly used osmotic laxatives that have been shown to be effective and safe treatments for chronic constipation. However, there is no definitive data as to which provides the best treatment.

Objectives

To identify and review all relevant data in order to determine whether Lactulose or Polyethylene Glycol is more effective at treating chronic constipation and faecal impaction.

Search methods

We searched the MEDLINE, EMBASE and CINAHL databases, and the Cochrane Central Register of Controlled Trials for all randomised controlled trials (RCTs) comparing the use of lactulose and polyethylene glycol in the management of faecal impaction and chronic constipation.

Selection criteria

Studies were included if they were randomised controlled trials which compared lactulose with polyethylene glycol in the management of chronic constipation.

Data collection and analysis

Data on study methods, participants, interventions used and outcomes measured was extracted from each study. Data was entered into the Cochrane Review Manager software (RevMan 5.0) and analysed using Cochrane MetaView.

Main results

In the present meta‐analysis, we considered for the first time all ten randomised controlled trials so far performed. The ten trials enrolled a total of 868 participants and were conducted between 1997 and 2007. The trials were conducted in six different countries. Participant age ranged from 3 months to 70 years. Adults only were recruited for 4 studies. Five trials reported stool frequency per week. Singularly taken, all showed that PEG resulted in a higher stool frequency per week when compared with Lactulose. Two trials reported form of stool on the Bristol Stool Scale, both studies reported a higher Bristol Stool Score when using PEG compared with lactulose (softer stool). Three trials reported relief of abdominal pain. Two favoured PEG in this outcome; one found Lactulose and PEG to be comparable in this outcome. Three trials reported on use of additional products, all favoured PEG as requiring less use of additional products.

Authors’ conclusions

The findings of our work indicate that Polyethylene glycol is better than lactulose in outcomes of stool frequency per week, form of stool, relief of abdominal pain and the need for additional products. On subgroup analysis, this is seen in both adults and children, except for relief of abdominal pain. Polyethylene Glycol should be used in preference to Lactulose in the treatment of Chronic Constipation.

https://www-cochranelibrary-com.york.ezproxy.cuny.edu/cdsr/doi/10.1002/14651858.CD007570.pub2/full?highlightAbstract=constipation%7Cpeg%7Clactulose%7Cconstip%7Clactulos

Article 2:

Chassagne, P., Ducrotte, P., Garnier, P. et al. Tolerance and long-term efficacy of polyethylene glycol 4000 (Forlax®) compared to lactulose in elderly patients with chronic constipation. J Nutr Health Aging 21, 429–439 (2017). https://doi.org/10.1007/s12603-016-0762-6

Abstract:
Objectives

To assess the tolerance and potential nutritional consequences of long-term repeated doses of PEG 4000 (10 to 30 g/day) in elderly patients with chronic constipation as compared to lactulose (10-30 g/ day).

Design

Single blind, randomised, multicentre, parallel group comparative study.

Setting

Community-dwelling patients and nursing homes residents aged 70 years and older with a history of chronic constipation.

Treatment intervention

PEG 4000 (10-30 g/day) or lactulose (10-30 g/day) for six months.

Assessments

Clinical nutritional status (Mini Nutritional Assessment), blood and stool samples were taken at baseline and after three and six months for assay of nutritional and absorption parameters. A patient diary documented digestive symptoms and adverse events were recorded. Information on efficacy (stool frequency and consistency) was collected as a secondary outcome measure.

Results

Of the 316 patients screened, 245 eligible patients constituted the ITT population (PEG 4000: N = 118; lactulose group: N = 127). The proportion of patients receiving PEG 4000 with abnormal levels of electrolytes, nutritional markers or vitamins did not significantly change in the six months after initiating laxative treatment and do not differ between the two groups. After a D-xylose challenge test, the proportion of patients with abnormally low xylosaemia (suggesting malabsorption) varied from 24.6% at baseline to 35.8% after six months in the PEG 4000 group and from 29.1% to 42.4% in the lactulose group, with no significant between-group or within-group differences. The proportion of patients with poor nutritional status (MNA score <17) varied from 8.5% at baseline to 9.8% after 6 months in the PEG 4000 group and from 3.9% to 5.0% in the lactulose group. No changes in stool fat or total or soluble stool nitrogen were observed in the minority of patients for whom stool analysis was performed. A significantly higher stool frequency p <0.05) and improved stool consistency p <0.05) was observed in the PEG 4000 group compared to the lactulose group at each monthly evaluation period.

Conclusions

After six months of treatment with PEG 4000, no clinically relevant changes in biochemical and nutritional parameters and no unanticipated treatment-related adverse events were detected, demonstrating the good clinical tolerance of PEG 4000 in this population of elderly constipated patients. This tolerance was associated with a better clinical efficacy of PEG 4000 compared to lactulose.

https://link.springer.com/article/10.1007%2Fs12603-016-0762-6#citeas

Article 3:

Alsalimy, N, Madi, L, Awaisu, A. Efficacy and safety of laxatives for chronic constipation in long-term care settings: A systematic review. J Clin Pharm Ther. 2018; 43: 595– 605. https://doi.org/10.1111/jcpt.12721

Abstract:

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.

https://onlinelibrary.wiley.com/doi/full/10.1111/jcpt.12721

Article 4:

Piche, T. and Dapoigny, M. (2020), Comparative efficacy and safety of lactulose plus paraffin vs polyethylene glycol in functional constipation: a randomised clinical study. UEG Journal, 8: 923-932. https://doi.org/10.1177/2050640620937913

Abstract

Background

Few head-to-head comparisons of the different classes of laxatives have been conducted.

Objective

The objective of this work is to compare the efficacy of lactulose plus paraffin vs polyethylene glycol in the treatment of functional constipation (non-inferiority study).

Methods

This randomised, parallel-group, multicentre phase 4 study recruited patients with functional constipation diagnosed according to Rome III criteria. Patients received lactulose plus paraffin or polyethylene glycol for 28 days. The primary end point was the change from baseline in the Patient Assessment of Constipation–Symptoms (PAC-SYM) score.

Results

A total of 363 patients were randomised to lactulose plus paraffin (n  = 179) or polyethylene glycol (n  = 184). On day 28, the mean PAC-SYM score decreased significantly vs baseline with both treatments (p  < 0.001). The lower boundary of the 95% CI exceeded the pre-specified limit of −0.25, therefore establishing non-inferiority of lactulose plus paraffin vs polyethylene glycol. At least one adverse event occurred in 20 patients (11.2%) in the lactulose plus paraffin group and in 26 patients (14.2%) in the polyethylene glycol group, most of which were of mild or moderate severity and unrelated to study drugs.

Conclusion

Lactulose plus paraffin may be used interchangeably with polyethylene glycol for the pharmacological treatment of functional constipation.

https://onlinelibrary.wiley.com/doi/full/10.1177/2050640620937913

Article 5:

Mínguez M, López Higueras A, Júdez J. Use of polyethylene glycol in functional constipation and fecal impaction. Rev Esp Enferm Dig. 2016 Dec;108(12):790-806. doi: 10.17235/reed.2016.4571/2016. PMID: 27871178.

Abstract

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).

https://pubmed.ncbi.nlm.nih.gov/27871178/

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Lee-Robichaud, Thomas, Morgan, Nelson (2010)	Systematic review	MEDLINE, EMBASE, CINAHL databases were used to identify 10 RCTs with a total of 868 participants between 1997-2008. Ages 3 months-70 years, 4 studies only recruited adults	The primary outcome as change in defecation frequency. Secondary outcomes include use of additional products, global improvement of symptoms, relief of abdominal pain	PEG had higher stool frequency per week compared to lactulose. Stool frequency per week also significantly better with PEG at 1, 3, and 6 month follow up. PEG also significantly better than lactulose for secondary outcomes with less need for additional products, relief of abdominal pain, and improved form of stool on Bristol stool scale. Sufficient quality of evidence to favor PEG over lactulose for chronic constipation	Significant heterogeneity was seen for stool frequency per week between some studies, this was greatly reduced after removing study where patients were disimpacted before treatment. Some studies used were sponsored by drug companies who supplied the PEG and lactulose used
Chassagne, Ducrotta, Garnier (2017)	RCT	Single blind, randomized, multicenter, parallel group comparative study evaluated community dwelling and nursing home patients age >70 with history of chronic constipation to compare long term (6 month) use of PEG and lactulose. 245 patients were evaluated, 118 in PEG group, 127 lactulose.	Clinical nutritional status, blood and stool samples for assay of nutritional and absorption parameters, digestive symptoms, adverse events, stool frequency and consistency	Stool frequency significantly higher in PEG group. Number of patients with soft or liquid stool higher in PEG group, hard stools in higher in lactulose group. PEG was significantly less likely to require and enema. PEG was not associated with malabsorption, metabolic or nutrition disorders, and was well tolerated. Higher incidence of diarrhea and abdominal pain with PEG group however was not considered significant. Conclude that PEG 4000 has excellent long term tolerance in this population and is associated with sustained clinical efficacy superior to lactulose	Principal weakness of this study was lack of placebo group however it would have been ethically difficult to administer placebo for long term study.
Alsalimy, Madi, Awaisu (2018)	Systematic Review	MEDLINE, Cochrane database of systematic reviews, ScienceDirect, ProQuest, and Google scholar were used to identify 7 RCTs with a total of 444 patients age 68-85 in LTC setting with chronic constipation	Frequency of defecation, number of spontaneous and complete bowel evacuations, need for rescue medications, adverse reactions	Evaluated various laxatives including senna, lactulose, sodium picosulphate (SPS), docusate sodium, docusate calcium, isotonic and hypotonic polyethylene glycol (PEG) and Chinese herbal medicine CCH1. Lactulose and senna were more studied laxatives. 3 RCTs evaluated lactulose, 2 were considered high quality. Lacutlose was compared to senna and CCH1 which were both found to be significantly more effective. Lactulose had more serious adverse reactions compared to other laxatives. 4 RCTs evaluated PEG, all were relatively high quality. PEG was compared to senna and lactulose, 2 studies concluded PEG was as effective as comparators, 2 concluded PEG was superior. Concluded that PEG was more efficacious and was well tolerated compared to lactulose in community dwelling patients. PEG was also more effective than lactulose in increasing stool frequency	Duration of treatment was short, only 2-8 weeks. Authors were unable to find sufficient evidence to provide recommendation for safest and most effective laxative due to high risk of bias in some studies, short duration of trials, and lack of placebo control.
Piche, Dapoigny. (2020)	RCT	Randomized, multicenter, parallel group phase 4 study evaluated 363 patients with functional constipation treated for 28 days with either PEG or lactulose plus paraffin. 184 in PEG group, 179 in lactulose plus paraffin group.	PAC-SYM (12 item questionnaire that was used to measure the presence and severity of constipation related symptoms, each item scored on 0-4 scale with 0 being absence of symptoms and 4 being very severe), PAC-QOL (patient assessment of constipation-quality of life questionnaire)	Mean PAC-SYM scores decreased in both groups. Between group difference was -0.017 which establishes the non-inferiority of lactulose plus paraffin compared to PEG. Number of stools per week significantly increased in both groups and number of hard stools decreased by >50%. Lactulose plus paraffin has reduced side effects including less bloating, gas, and abdominal pain compared to previously used lactulose solutions. Significant reduction in pain and discomfort with defecation seen in lactulose plus paraffin compared to PEG. Concluded that lactulose plus paraffin was non-inferior compared to PEG for treatment of functional constipation, both treatments increased frequency of bowel movements and improved quality of life.	Limited by absence of double-blinding procedure however masking procedure used was in line with recommendations for limiting bias. Short duration of washout period, 2 weeks.
Minguez, Lopez Higueras, Judez (2016)	Systematic review	MEDLINE, EMBASE, and Cochrane databases were used to identify 58 publications including 41 RCTs, 8 observational studies, 9 systematic reviews to compare effectiveness of PEG versus placebo and various treatments including lactulose for constipation or fecal impaction	Short term and long term efficacy, weekly bowel movements, tolerability, adverse effects	26 articles evaluated PEG use in adults, 17 RCTs, 4 observational, 2 reviews, 3 meta analyses. 2 of thse RCTs compared PEG and lactulose. In these studies PEG group had higher number of stools per week, significant decrease in straining, higher patient satisfaction compared to lactulose. Tolerance was similar between groups however less flatus was seen with PEG.	Variability was seen in the design of the studies used making comparative study difficult. Heterogeneity was seen between studies and high risk of bias indicate the quality of the data as low or very low

Summary of the Evidence:

Conclusion(s):
– Briefly summarize the conclusions of each article

– Then provide an overarching conclusion.

Lee-Robichaud et al. – Concluded that PEG was significantly better than lactulose in increasing stool frequency per week, form of stool on Bristol stool scale, relief of abdominal pain, and need for additional products. Stool frequency per week was significantly better with PEG at 1, 3, and 6 month follow up. The authors found sufficient quality of evidence to favor PEG over lactulose for chronic constipation.

Chassagne et al. – Concluded that PEG 4000 had excellent long term tolerance in elderly community dwelling and nursing home residents and had sustained clinical efficacy compared to lactulose. Stool frequency was significantly higher in PEG group. Greater number of patients had soft or liquid stool higher in PEG group, more hard stools were seen in lactulose group. PEG was significantly less likely to require and enema and was not associated with malabsorption, metabolic or nutrition disorders, and was well tolerated.

Alsalimy et al. – Concluded that PEG was more efficacious and better tolerated than lactulose in community dwelling patients. PEG was more effective than lactulose in increasing stool frequency. While this study evaluated various laxatives (including senna, lactulose, sodium picosulphate (SPS), docusate sodium, docusate calcium, isotonic and hypotonic polyethylene glycol (PEG) and Chinese herbal medicine CCH1) I focused on the portions that evaluated PEG and lactulose. 3 RCTs evaluated lactulose, 2 were considered high quality. Lactulose was significantly less effective than the laxatives it was compared to, it also had more serious adverse reactions. 4 RCTs evaluated PEG, all were relatively high quality. PEG was compared to senna and lactulose, 2 studies concluded PEG was as effective as comparators, 2 concluded PEG was superior.

Piche et al. – Concluded that lactulose with paraffin was non-inferior compared to PEG for treatment of functional constipation. Both treatments had increased frequency of bowel movements and improved quality of life. Mean PAC-SYM scores decreased in both groups. Between group difference was -0.017 which establishes the non-inferiority of lactulose plus paraffin compared to PEG. Number of stools per week significantly increased in both groups and number of hard stools decreased by >50%. Lactulose plus paraffin had reduced side effects including less bloating, gas, and abdominal pain compared to previously used lactulose solutions. Significant reduction in pain and discomfort with defecation seen in lactulose plus paraffin compared to PEG.

Minguez et al. – Concluded that PEG with or without electrolytes was more effective, better tolerated, and had greater patient satisfaction than lactulose. This study compared PEG to placebo and various other laxatives in both children and adults, I focused on PEG compared to lactulose in adults. 26 articles evaluated PEG use in adults, 2 of these RCTs compared PEG and lactulose. In these studies PEG group had higher number of stools per week, significant decrease in straining, higher patient satisfaction compared to lactulose. Tolerance was similar between groups however less flatus was seen with PEG.

Overall conclusion is that PEG is more efficacious and better tolerated with less adverse effects compared to commonly used lactulose formulations for chronic constipation in elderly population. PEG was consistently associated with increased frequency in number of stools per week which is the most commonly studied outcome for effectiveness of treatment. A formulation of lactulose that includes paraffin was also compared to PEG and was associated with less adverse effects than lactulose alone. Lactulose plus paraffin was found to be non-inferior to PEG.

Clinical Bottom Line:

Please include an assessment of the following:

– Weight of the evidence

• Lee-Robichaud – I weighed this article the strongest as it was a systematic review from Cochrane with a large sample size (868) that used 10 RCTs to compare PEG and lactulose for chronic constipation. Followed patients for longer intervals of 1, 3, and 6 months and found increased stool frequency when PEG was used at all intervals. Found similar results for both children and adults showing PEG was significantly better than lactulose in increasing stool frequency per week and reduced need for additional products. Key difference in adult and pediatric population was that relief of abdominal pain was seen in adults but not seen in children.

• Alsalimy – I weighed this article next as it was also a systematic review published recently in 2018 however it had smaller sample size (444) and compared PEG to various laxatives, not just lactulose. Lactulose was one of the most studied laxatives and was significantly less effective than other comparators including PEG. This article had short duration of treatment compared to the previous study, and the authors were unable to provide sufficient evidence to provide a recommendation for safest and most effective laxative due to risk of bias in some trials and lack of placebo control.

• Minguez – I weighed this article evenly with Alsalimy article as it was also a systematic review published recently in 2016. This paper used greater number of publications compared to the previously mentioned systematic review. Like the Alsalimy review, PEG was compared to placebo and various other laxatives including lactulose. 58 publications were included in the study, only 2 compared PEG and lactulose. Results were consistent with other articles showing PEG increased number of stools per week and was well tolerated. Comparison was difficult as there was variability seen in the study design. The authors found heterogeneity and admit high risk of bias which made the quality of the data low.

• Chassagne – I weighed this article next as it was an RCT published in 2017 that compared long term use of PEG and lactulose in elderly nursing home and community dwelling patients. The focus of this article was more on how well tolerated the laxatives were including adverse effects and nutritional status, resolution of constipation and stool frequency were secondary outcomes measured. PEG was superior to lactulose in almost every outcome measured and had excellent long term tolerance with sustained clinical efficacy compared to lactulose.

• Piche – I weighed this article less than the others as it was the only one to use a different formulation of lactulose that included paraffin. The sample size was relatively large with 363 patients, however the lack of double blinding opens the results to potential bias. The authors were able to clearly demonstrate that lactulose plus paraffin was non-inferior than PEG

– Magnitude of any effects

• 4 articles came to the same conclusions showing that PEG was significantly more effective than lactulose in improvement frequency of stool per week and was well tolerated compared to lactulose. 1 article used lactulose with paraffin that was found to be non-inferior compared to PEG. Lactulose plus paraffin had reduced side effects compared to other formulations of lactulose, which is attributed to beneficial effects of paraffin.

– Clinical significance (not just statistical significance)

• 4 articles provided sufficient evidence to show that PEG was significantly more effective than lactulose in elderly community dwelling and nursing home patients and is associated with increased frequency of stools per week, improved stool consistency on Bristol stool scale, reduced adverse effects, and less need for additional products including enemas. This benefit was seen in both short term and long term. Some studies were able to recommend PEG as first line treatment; others did not find high enough quality evidence to make a definitive recommendation. 1 article used a different formulation of lactulose that included paraffin and was clearly shown to be non-inferior to PEG when used for 28 days. Lactulose plus paraffin can be considered for use in short term, no evidence demonstrates its long term effectiveness.
•  

– Any other considerations important in weighing this evidence to guide practice  –

• The results clearly show that PEG is more efficacious and better tolerated compared to commonly used formulations of lactulose. PEG was also associated with less adverse effects and less need for additional products such as enemas. Lactulose plus paraffin uses a different galenic formulation compared to lactulose used in previous studies and was found to be non-inferior compared to PEG when used for treatment period of 28 days. Moving forward, long term RCTs comparing PEG and lactulose plus paraffin are needed to identify if this treatment is as effective (or more effective) and well tolerated when used for chronic constipation. An economic study might also be helpful to identify if one of these treatment options is associated with reduced cost.