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Abstract
Purpose: Role of genus cassia in the treatment of Constipation
Methods: Methodological analysis, systematic review, and meta-analysis of identified studies using RevMan
Result and Discussion: Cassia fistula was partially effected in treating constipation however there is a need for improvement in the protocol of studies to reduce biases. These results were only limited to one species so it cannot be generalized among all species of Cassia.
Conclusion: Cassia fistula is partially effective in reducing the pain and consistency of stool during constipation among children.
Keywords: Cassia, Cassia fistula, Constipation, Pediatric gastroenterology
Introduction
Constipation is a clinical disorder attributed to ineffectual colonic impulsion and/or increased resistance to the proliferation of colonic matters 1 . Approximately 20% of the world population suffers from chronic constipation 2 . It is one of the most common pediatric problems 3 . It was found to be the second most stated disorder in the field of pediatric gastroenterology. Treatment costs for children with constipation will be around three times higher than children without constipation in the United States 4 . African American children, particularly girls, are greatly affected by constipation, which has been associated with poor hygiene conditions 5 .
Commonly, constipation is treated by Cisapride in children 6 , other treatments include polyethylene glycol 3350 and lactulose, however polyethylene glycol 3350 has been found to be more effective 7 . Supplemented and non-supplemented yogurt helps in reducing abdominal pain and to enhance defecation frequency 8 . It has been observed that different species of Cassia act effective as a laxative such as Cassia fistula, Cassia alata, and Cassia augustifolia 9– 11 . The genus Cassia is well known in alternative medicine as hepatoprotective 12 , laxative, and in the treatment of ringworm infection 13 , skin diseases 14 and leprosy 15 . It has many pharmacological properties including acting as a hypolipidemic agent 16 , anti-microbial 17 , anti-fungal 18 , and anti-cancer agent 19 . Genus Cassia contains a number of bioactive compounds such as anthraquinone 20 , tannin 21 , coumarins 22 , triterpene, volatile oil 23 , phenolic glycoside 24 , flavonoids 25 from different parts of the plant. Different species of Cassia possess laxative properties due to various anthraquinone derivative such as aloe-emodin, rhein, chrysophanol and chrysoobtusin. In this review, we systematically assessed the laxative potential of different species of Cassia.
Methods
Literature search strategy
A systematic literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using the keywords (Senna AND Laxatives AND Clinical trial) (Cassia AND Laxatives AND Clinical trial) (Cassia AND Clinical trial) (Senna AND Clinical trial) and publication range from 01 January 1960 till 31 December 2018 for identification of the records. Table 1 shows the search strategy for PubMed Central. During screening of the records only full-length open access articles were considered. Abstract only or closed access articles were excluded 11 . Only articles involving children aged between 2–15 were included. All review articles, in-vivo studies and those >10 years from the search date were excluded. A preliminary search of the PubMed, CNKI, Scopus, Web of Science, Google Scholar and PsycINFO databases and digital archive such as PubMed Central, yielded 2207 papers published in English from the last ten years. Duplicate and irrelevant articles were removed (n=2203). One article was further removed during screening due to closed access (n=3). One publication was removed because the article did not meet the eligibility criteria (n=2). A PRISMA Flow Diagram is given in Figure 1.
Figure 1. PRISMA flow diagram.
Table 1. Search strategy.
| PubMed Central | |
|---|---|
| (“cassia”[MeSH Terms] OR “cassia”[All Fields])
AND (“clinical trial”[All Fields] OR “clinical trials as topic”[MeSH Terms] OR “clinical trial”[All Fields]) AND (“1960/01/01”[PubDate]: “2018/12/31”[PubDate]) |
((“cassia”[MeSH Terms] OR “cassia”[All Fields]) AND (“laxatives”[All
Fields] OR “laxatives”[MeSH Terms] OR “laxatives”[All Fields])) AND (“clinical trial”[All Fields] OR “clinical trials as topic”[MeSH Terms] OR “clinical trial”[All Fields]) AND (“1960/01/01”[PubDate] : “2018/12/31”[PubDate]) |
| (“Senna”[MeSH Terms] OR “Senna”[All Fields])
AND (“clinical trial”[All Fields] OR “clinical trials as topic”[MeSH Terms] OR “clinical trial”[All Fields]) AND (“1960/01/01”[PubDate]: “2018/12/31”[PubDate]) |
((“senna plant”[MeSH Terms] OR (“senna”[All Fields] AND
“plant”[All Fields]) OR “senna plant”[All Fields] OR “senna”[All Fields]) AND (“laxatives”[All Fields] OR “laxatives”[MeSH Terms] OR “laxatives”[All Fields])) AND (“clinical trial”[All Fields] OR “clinical trials as topic”[MeSH Terms] OR “clinical trial”[All Fields]) AND (“1960/01/01”[PubDate] : “2018/12/31”[PubDate]) |
Literature screening
Identification of articles were performed at level 1 using the search strategy as mentioned in Table 1. Duplicate articles, irrelevant articles such as polyherbal formulation, review articles, or any article other than Cassia or Senna were removed at level 2. Only four 4 articles were identified as being relevant. One record was excluded due to not being a full text article. Abstracts were being reviewed for the following inclusion and exclusion criteria at level 4 and one article was removed for not meeting the eligibility criteria i.e. Randomized, clinical trial on Constipation, full-length open access articles, Pediatric Functional Constipation (age range: 2–15 years).
Eligibility criteria
Types of studies. The author has selected studies of randomized open label, prospective, controlled, parallel-group clinical trial for meta-analysis. Baseline characteristics of randomized trials of studies included on pediatric functional constipation are presented in Table 4. Characteristics of the studies included are mentioned in Table 5.
Types of participants. The author included studies involving patients (aged 2–15 years) with Functional constipation. The diagnosis of Functional constipation was according to according to the Rome III criteria 26 . Inclusion and exclusion criteria were based on Study design, participants, intervention, outcome (SPIO) criteria and indicated in Table 2.
Table 2. Study design; participants; intervention; outcome (SPIO) criteria.
| Inclusion Criteria | Exclusion Criteria | |
|---|---|---|
| Study design | Randomized, clinical trial on Constipation, full-length
open access articles, Pediatric Functional Constipation |
All review articles, irrelevant articles, Exclude
abstract only articles, clinical trial on adults. |
| Participants | Children (age range: 2–15 years) | Adults |
| Intervention |
Cassia fistula was delivered to Pediatric with Functional
Constipation |
|
| Outcomes | Role of the
Cassia fistula emulsion in Pediatric Functional
Constipation |
Types of interventions. Included studies were focused on the role Cassia in the treatment of Functional constipation. Unfortunately, there were only two studies identified.
Types of outcomes. Eligible studies included consisted of the following outcomes: improvement in the episodes of fecal incontinence per week, improvement in the episodes of retentive posturing per week, improvement in the average of severity of pain of defecation (by VAS), improvement in defecation frequency per week, patient’s drug compliance and improvement in the average of consistency of stool defecated (by VAS).
Methodological quality assessment (MQ)
Methodological quality assessment was made on the basis of following criteria. 1) Aims and Hypothesis clearly defined, adequate sample representation, patient care quality, ethical approval protocol, outcomes assessment, validity and reliability of outcome measure, attempt to blind researcher, follow-up, appropriate statistical analysis and missing data reported. Ten item defined evaluation of methodological quality (MQ) is presented in Figure 2. Risk of Bias were assessed using Cochrane collaboration’s tool on the basis of the following criteria such as selection bias, performance bias, attrition bias, reporting bias and miscellaneous. Cochrane Collaboration’s tool for assessing the risk of bias was used and the results are presented in Table 6 27 .
Figure 2. Methodological quality assessment of the 2 studies included in the meta-analysis (0=No/not reported, 1=Yes).
Data extraction
The following data were extracted according to study characteristics (e.g., first author, year of publication, search dates, and number of included studies), patient characteristics (functional constipated children, aged between 2–15), sample size, study type (e.g., Randomized open label, prospective, controlled, parallel-group clinical trial study), randomization methods (e.g., “systematic randomization and simple randomization”) and outcome measures/variables (e.g., improvement in defecation frequency per week, improvement in the episodes of fecal incontinence per week, improvement in the episodes of retentive posturing per week, improvement in the average of severity of pain of defecation (by VAS), improvement in the average of consistency of stool defecated (by VAS) and patient’s drug compliance). Data extraction was performed by Muhammad Shazad Aslam. Transcripts were analysed, coded and data was extracted using the demo version of qualitative data analysis software Atlas.ti 8.0. Table 3 represent all the data that was extracted. All the meta-data are available as Dataset 1.
Table 3. Data extraction.
| Characteristics | Seyyed Ali Mozaffarpur | Mohammad Reza Esmaeilidooki |
|---|---|---|
| Publication Year | 2012 | 2016 |
| Type of Study | Randomized, clinical trial | This randomized open label, prospective, controlled, parallel-
group clinical trial study |
| Age | Age between 4–13 years | Aged between 2 – 15 years |
| Randomization | systematic randomization | Simple randomization |
| Total Sample Size | 81 | 51 |
| Variables | Frequency of defecation, consistency
of stools, and severity of pain during defecation, retentive posturing and fecal incontinence per week |
Improvement in defecation frequency per week,
improvement in the episodes of fecal incontinence per week, improvement in the episodes of retentive posturing per week, improvement in the average of severity of pain of defecation (by VAS), improvement in the average of consistency of stool defecated (by VAS) and patient’s drug compliance |
| Length of each contact
with the participant/ caregivers |
Clinical efficacy and tolerance were
assessed using weekly sheets, parents completed every night. They were given three sheets (included seven questions in seven columns) to complete them daily for 3 weeks. |
During the study, we had regular phone calls with the
parents to check the probable complications, treatment (taking the prescribed drugs) and data filling process. If there were any serious questions or problems, we visited the child. At the end of 4 weeks of treatment, the children were visited and the filled out forms were taken and evaluated. |
| Blinding of Experiment | The investigators, the children and
their parents were aware of the study group assignment. |
Fortunately, due to the developing socioeconomic conditions
of the people in these regions in recent years, we were able to keep in touch with all the patients during the study period by phone call. |
| Diagnosis | Rome III criteria of functional
constipation |
Rome III criteria of functional constipation |
| Diagnostic test | Paraclinics like anorectal manometry,
thyroid function tests, anti-tTG, and other laboratory tests |
thyroid function tests, anti-tTG, and etc. If it remained any
doubt, barium study and anorectal manometry would be performed |
Table 4. Baseline characteristics of randomized trials of studies included in pediatric functional constipation.
| Variable in Treatment (T) | Mozaffarpur,
2012 (T) |
Esmaeilidooki,
2016 (T) |
Mozaffarpur,
2012 (C) |
Esmaeilidooki,
2016 (C) |
Variable in Control (C) |
|---|---|---|---|---|---|
| Sample size in Treatment (N) | 41 | 52 | 40 | 57 | Sample size in Control (N) |
| Age, months, Mean(±SD) | 69.4(±24.3) | 64.6(±25.2) | 65.9(±19.1) | 55.2(±31.2) | Age, months, Mean(±SD) |
| Sex, Male, (n) (%) | 29(70.7%) | 33 | 23(57.5%) | 30 | Sex, Male, (n) (%) |
| Weight, Kg Mean(±SD) | 21.7 (±7.2) | 20.5(±7.2) | 20.7(±7.8) | 18.5(±8.9) | Weight, Kg(±SD) |
|
Duration of constipation,
months, Mean(±SD) |
34.2(±25.9) | 31.1(±24.6) | 30.8(±22.8) | 23.5(±21.8) |
Duration of constipation,
months, Mean(±SD) |
|
Defecation ≤ 2 per week, n
(%) |
32(78%) | 41 | 30(75%) | 52 |
Defecation ≤ 2 per week, n
(%) |
| Incontinence, n (%) | 31(75.6%) | 34 | 27(67.5%) | 37 | Incontinence, n (%) |
|
History of previous
treatment, n (%) |
32 (78%) | 43 | 28(70%) | 51 |
History of previous
treatment, n (%) |
| Retentive posturing, n (%) | 32(78%) | 40 | 29(72.5%) | 37 | Retentive posturing, n (%) |
Table 5. Study characteristics.
| Author, year | Study Design | Hypothesis | Statistical analysis | Software | Outcomes |
|---|---|---|---|---|---|
| Mozaffarpur, 2012 | Randomized,
clinical trial |
The author
hypothesized that Cassia fistula emulsion (CFE) would be as effective or better than Mineral oil (MO) in treating FC. |
The statistical analyses included
the determination of means and Standard deviation (SDs), t test, χ2 test, ANOVA repeated measures and Fisher’s exact test, with significance accepted at the 5% level. |
SPSS (version
17), |
CFE was most effective
than MO in the 3-week treatment of children with FC. |
|
Esmaeilidooki,
2016 |
Randomized,
clinical trial |
N/A | The statistical analyses included
the determination of means and SDs, t test, χ2 test, ANOVA repeated measures and Fisher’s exact test, with significance accepted at the 5% level. |
SPSS IBM20
and STATA 11.2 |
Significant
improvement when compared with the control group however unable to find substantial evidence of the role of identified bioactive compounds due to limitation as it requires further investigation |
Table 6. Cochrane Collaboration’s tool for assessing risk of bias.
| Study (author,
year) |
Selection
bias |
Performance
bias |
Detection
bias |
Attrition
bias |
Reporting
bias |
Other
bias |
|---|---|---|---|---|---|---|
| Mozaffarpur, 2012 | Unclear | Yes | Yes | No | No | Unclear |
|
Esmaeilidooki,
2016 |
Unclear | Yes | Yes | No | No | Unclear |
Statistical analysis
Meta-analysis was conducted using the Review Manager (RevMan) 5.3 software 28 . The summary measures were reported as odds ratios (ORs) or as a standard mean difference (SMD) with 95% confidence intervals (CI). The presence of heterogeneity among trials was assessed using the Chi-square test, and the extent of the inconsistency was measured by I2 statistics. Output file from RevMan is available as Underlying data 29 .
Results and discussion
Both of the selected studies were not blinded during intervention and outcome assessment that will result in performance bias and detection bias respectively. These biases occur where the investigators know about the participant's treatment group. Performance bias can also refer to the fact that participants can change their responses or behaviour if they know which group they are allocated in. Blinding of outcome assessment may decrease the risk of the investigator or participant being aware of the treatment that a patient is receiving. If the participants and the caregivers are aware of the intervention and outcome that may affect the behavior of the participants, these behavioral changes may affect the performance of the treatment. Clinical trials on adults were also excluded, such as a randomized clinical trial of a phytotherapeutic compound containing Pimpinella anisum, Foeniculum vulgare, Sambucus nigra, and Cassia augustifolia for chronic constipation 9 . Results of both included studies were non-significant when comparing their baseline characteristics of pediatric functional constipation as presented in Table 5. During analysis of study characteristics, it was found that both of studies demonstrated Cassia fistula is helping to treat constipation among the children as shown in Table 3, but there is a risk of bias according to Cochrane Collaboration’s tool ( Table 6). Moreover, both studies found were from one country (Iran). During a methodological assessment, many flaws were identified such as inadequate patient care, attempt to blind the researcher and missing data ( Figure 2). During meta-analysis, the comparison was made before and after treatment among different variables such as defaecation, fecal incontinence, retentive posturing, the severity of pain, and consistency of stool. All the variable (before and after treatment) were found to be symmetrical when plotted on a funnel plot as shown in Figure 4, Figure 6, Figure 8, Figure 10, Figure 12, and Figure 14 respectively. The overall effect for some variables is statistically insignificant (P=0.11, P=0.49, P=0.24) such as fecal incontinence, retentive posturing, and acceptance, tolerance respectively. High heterogeneity was found in two variables i.e severity of pain (90%) and consistency of stool (77%). All the forest plot of defaecation, fecal incontinence, retentive posturing, severity of pain, consistency of stool and acceptance and tolerance are represented in Figure 3, Figure 5, Figure 7, Figure 9, Figure 11 and Figure 13 respectively.
Figure 6. Funnel plot showing overall standardized mean difference in fecal incontinence before and after treatment.
Figure 8. Funnel plot showing overall standardized mean difference in retentive posturing before and after treatment.
Figure 10. Funnel plot showing overall standardized mean difference in severity of pain before and after treatment.
Figure 12. Funnel plot showing overall standardized mean difference in consistency of stool before and after treatment.
Figure 14. Funnel plot showing overall standardized mean difference in acceptance and tolerance after treatment.
Figure 3. Forest plot in defaecation before and after treatment.
Figure 5. Forest plot in fecal incontinence before and after treatment.
Figure 7. Forest plot in retentive posturing before and after treatment.
Figure 9. Forest plot in severity of pain before and after treatment.
Figure 11. Forest plot in consistency of stool before and after treatment.
Figure 13. Forest plot in acceptance and tolerance after treatment.
Figure 4. Funnel plot showing overall standardized mean difference in defaecation before and after treatment.
Conclusion
After evaluation of results, it was found that Cassia fistula was not completely effective. It was partly effective in reducing the pain and consistency of stool during constipation. However, these results cannot be generalized among all population. A well designed, expert validated protocol is required in the future. There is a need to develop an instrument that will be free from bias. Moreover, the results cannot be generalized among all species of Cassia as the studies available are only for one species. There is a need to isolate identified bioactive compounds from different species of Cassia and evaluate the effect of different factors such as duration of constipation, defecation, incontinence or retentive posturing under clinical trial.
Declarations
Data availability
Underlying data. Open Science Framework: Application of genus Cassia in the treatment of Constipation: A systematic review. https://doi.org/10.17605/OSF.IO/PKR4N 29
This project contains the following underlying data:
-
-
Cassia Senna for Constipation.rm5 (study RevMan file)
-
-
Quotation Manager.xlsx (study characteristics of citations included in this study)
Reporting guidelines
Open Science Framework: PRISMA diagram and flowchart for the study “Application of genus Cassia in the treatment of constipation: A systematic review”. https://doi.org/10.17605/OSF.IO/PKR4N 29
Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).
Funding Statement
This research was supported by Xiamen University Malaysia.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[version 2; peer review: 2 approved
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