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Background: Functional constipation (FC) is one of the most prevalent functional gastrointestinal
disorders, with the most significant negative impact on health-related quality of life. Despite that multiple
systematic reviews and clinical trials have suggested that acupuncture could be effective for FC treatment,
the comparative effectiveness among various acupuncture approaches has remained unknown. This protocol
proposed a plan to assess and rank the effectiveness and safety of different acupuncture methods for patients
with FC.
Methods: We will search 8 bibliographic databases from their inception to 30 June 2021, including
the Cochrane Central Register of Controlled Trials, MEDLINE (via PubMed), EMBASE, Allied and
Complementary Medicine Database, the Chinese Biomedical Literature Database (CBM), Wanfang
Database, VIP Database, and China National Knowledge Infrastructure (CNKI). Randomized controlled
trials (RCT) examining acupuncture methods for FC will be considered. The primary outcome is a
measurement of the weekly stool frequency [including bowel movement (BM), spontaneous bowel
movement (SBM), and complete SBM]. There will be at least 2 reviewers in charge of study selection, data
extraction, risk of bias assessment. Bayesian network meta-analysis will be conducted using ADDIS (Aggregate
Data Drug Information System) V.1.16.8. Meta-regression and subgroup analyses will also be performed,
if feasible, to address the potential causes of inconsistency and heterogeneity. Furthermore, the strength
of evidence will be appraised using the Grading of Recommendations Assessment, Development, and
Evaluation (GRADE) system.
Discussion: In this study, we will provide evidence-based hierarchies for the effectiveness and safety of
acupuncture therapies to manage constipated patients, assisting healthcare providers, physicians, and patients
in making more informed treatment decisions.
Trial registration: This study has been registered at PROSPERO (https://www.crd.york.ac.uk/prospero/)
with a registration number CRD42021227920.
Submitted Apr 05, 2021. Accepted for publication Jun 11, 2021.
doi: 10.21037/apm-21-811
View this article at: https://dx.doi.org/10.21037/apm-21-811
^ ORCID: Junpeng Yao, 0000-0002-0808-8428; Liping Chen, 0000-0002-6063-0261; Ying Li, 0000-0001-7554-0958.
© Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2021;10(7):8300-8309 | https://dx.doi.org/10.21037/apm-21-811
Annals of Palliative Medicine, Vol 10, No 7 July 2021 8301
© Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2021;10(7):8300-8309 | https://dx.doi.org/10.21037/apm-21-811
8302 Yao et al. Protocol of acupuncture methods for functional constipation
optimal acupuncture regimen to improve gastrointestinal embedding, cupping, acupoint injection, blood-letting
symptoms and quality of life in patients with FC? We therapy, and herbal medicine should be excluded due to
present the following article in compliance with the their use of related drugs.
PRISMA-P reporting checklist (available at https://dx.doi.
org/10.21037/apm-21-811). Types of control groups
Treatment methods of non-acupuncture and non-
moxibustion will form the basis of the comparison
Objectives
groups, such as sham acupuncture (invasive/non-invasive),
This network meta-analysis aims to compare the no treatment/waiting list/lifestyle modifications, and
effectiveness and safety of all available acupuncture methods recommended drugs (fiber, stimulant and osmotic laxatives,
in the management of patients with FC. and selective 5-HT4 agonists). Studies comparing different
manipulations of acupuncture or alternate selections of
acupoints will be excluded.
Methods
Types of participants
Secondary outcomes
Adult patients (≥18 years) who have been diagnosed with
FC, irrespective of their ethnic background, gender, or The secondary outcomes will include: (I) stool consistency
initial severity of the condition, will be included. Pediatric assessed with Bristol Stool Form Scale (BSFS) score.
patients will be excluded from this NMA. Diagnosis The BSFS score is a 7-point scale, with scores of 1–2
will be made according to the Rome IV/III/II criteria or indicating constipation, 3–5 indicating normal stool, and
other accepted diagnostic standards (1,2). Patients with 6–7 indicating diarrhea; (II) responder rate, a responder was
constipation co-presenting with irritable bowel syndrome defined as no longer fulfilling the Rome criteria for FC (32);
or secondary constipation (drug-induced, postoperative, or (III) the Patient Assessment of Constipation Quality of Life
attributable to other diseases) should be excluded. questionnaire; and (IV) the incidence and severity of adverse
events (including hematomas, dizziness, or local pain) will
Types of interventions also be measured for safety assessment.
Studies reporting on the use of acupuncture therapy as a
primary intervention will be included. We will define the
Search methods for identification of studies
acupuncture approaches as needle stimulation of acupoints,
including MA, EA, auricular acupuncture/acupressure, Electronics searches
WNA, FA, and moxibustion. Therefore, acupoint catgut This study will search, both electronically and manually,
© Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2021;10(7):8300-8309 | https://dx.doi.org/10.21037/apm-21-811
Annals of Palliative Medicine, Vol 10, No 7 July 2021 8303
#3 (chronic severe constipation or chronic severe functional constipation or slow transit constipation or idiopathic constipation or
functional gastrointestinal disorder or functional defecatory disorder or constipation): ti.ab.
#4 #1 OR #2 OR #3
#6 acupuncture. MeSH.
#8 #5 OR #6 OR #7
#11 randomized.ti.ab.
#12 randomly.ti.ab.
#13 placebo.ti.ab.
#14 trial.ti.
for all RCTs involving acupuncture methods for FC, Searching other resources
regardless of publication status. The following bibliographic Any relevant ongoing or unpublished clinical study will be
databases will be searched up to 30 June 2021: Cochrane obtained from the World Health Organization (WHO)
Central Register of Controlled Trials, MEDLINE (via International Clinical Trials Registry Platform, the National
PubMed), EMBASE, Allied and Complementary Medicine Institutes of Health (NIH) clinical registry, and the
Database, the Chinese Biomedical Literature Database Chinese clinical registry. The reference lists of the selected
(CBM), Wanfang Data, VIP Database, and China National studies and published systematic reviews will be screened
Knowledge Infrastructure (CNKI). The search strategy for additional literature. Moreover, a manual search will
will be structured by Medical Subject Headings (MeSH) be performed for grey literature, including conference
and free-text terms, such as functional constipation OR proceedings. Experts in the field will also be consulted to
constipation AND acupuncture therapy OR acupuncture obtain potential studies and the most recent clinical data
OR electroacupuncture OR acupuncture-moxibustion AND not available by the previously mentioned methods.
randomized. The detailed search strategy for PubMed is
as described in Table 1. Based on the characteristics of each
Selection of studies
database, this search strategy will be adjusted to individual
database constraints. During the study selection process, search results will be
© Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2021;10(7):8300-8309 | https://dx.doi.org/10.21037/apm-21-811
8304 Yao et al. Protocol of acupuncture methods for functional constipation
Identification
(n= ) (n= )
Records excluded
Records screened
Not related to FC (n= )
(n= )
Not related to acupuncture (n= )
(n= ) (n= )
imported from the original databases to Endnote X9, and form by the 2 reviewers (SZ and YY): (I) details of the study
the software will filter repetitive studies. Then, 2 reviewers (publication year, first author, nationality, study design); (II)
(JY and LC) will independently screen all the retrieved patient demographics (sample size, age, gender, ethnicity,
records by reading the title, abstract, and keywords to diagnosis, constipation duration); (III) intervention and
determine which studies meet the inclusion criteria. The full comparator (types of acupuncture, selected acupoints,
text will be obtained and checked independently by the 2 treatment duration/frequency/session, follow-up period);
reviewers (JY and LC), where a study is potentially eligible. (IV) outcomes [types of outcomes, definition of outcome,
Notably, studies excluded after reading the full text will be time points for each assessment, related statistics such as
recorded and explained. The detailed process of selection mean ± standard deviation (SD) and P value]; (V) adverse
is shown in Figure 1. Any disagreement will be resolved by reactions; (VI) main conclusion and funding sources. If the
consensus, and further conflicts will be arbitrated by a third original trials had more than 2 groups, the data would be
reviewer (LZ). extracted separately. When the mean and SD are not offered
directly in the study, we will attempt to obtain them through
a calculation based on our previous study or by contacting
Data extraction and management
the corresponding authors (19). Any discrepancy noticed
The following data will be independently extracted from during the process of data extraction will be resolved through
the eligible studies using a self-designed data acquisition discussion or suggestions from a third reviewer (YL).
© Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2021;10(7):8300-8309 | https://dx.doi.org/10.21037/apm-21-811
Annals of Palliative Medicine, Vol 10, No 7 July 2021 8305
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8306 Yao et al. Protocol of acupuncture methods for functional constipation
used to generate the network diagram and compare each Assessment of reviewer agreement
outcome (38). For each specific outcome, we will sequence
To achieve perfect consistency (at least 80%) between
the effects of different acupuncture methods to determine
the 2 reviewers who conducted the study selection, data
the most effective surface under the cumulative ranking
extraction, and quality assessment, a pilot study will be
curve and mean ranks alongside their 95% CI.
conducted before these processes are implemented. A
Kappa index will be utilized during the pilot study to
Assessment of heterogeneity
assess the inter-rater agreement between the reviewers.
Statistical heterogeneity among studies will be assessed
We interpreted thresholds for the Kappa index as greater
using the Q test and I² statistics. According to the Cochrane
than 0.75, reflecting perfect agreement, 0.4–0.75 indicating
Handbook, the thresholds for the interpretation of the I²
moderate agreement, and a Kappa index less than 0.4
statistics are as follows: 0–40%, might not be important;
indicating a low level of consistency (42).
30–60%, may reflect moderate heterogeneity; 50–90%,
may indicate substantial heterogeneity; 75–100%,
represents considerable heterogeneity (41). After statistical Ethics and informed consents
heterogeneity is established, the researchers will search
for possible sources from the clinical and methodological Given that the data is not individualized, formal ethical
perspective then perform subgroup or sensitivity analysis to approval is not required. All analyzed trials will have
detect the possible causes of heterogeneity. followed the Declaration of Helsinki (as revised in 2013)
and current ethical standards. Additionally, the findings
Meta-regression, subgroup analysis and sensitivity from this study will be published in a peer-reviewed journal.
analysis We also plan to disseminate this study, including pilot
Meta-regression and subgroup analysis will also be results, through the conference presentations.
performed, whenever feasible, to detect the possible sources
of inconsistency and heterogeneity. Meta-regression will Discussion
be conducted with the following covariates: (I) initial
severity of the disease; (II) sample size; (III) average age; Multiple acupuncture therapies have been reported as
and (IV) the duration, frequency, and course of acupuncture effective for FC; however, there is high variability among
methods. Subgroup analyses will be employed based on the clinicians in using these acupuncture methods. Our previous
different comparators and various forms of acupuncture standard pairwise meta-analyses that combined evidence
methods. from 30 RCTs indicated that acupuncture was superior
Multiple sensitivity analyses for the analyzed outcomes to laxatives in terms of stool frequency and improving
will be performed to assess the findings’ robustness and the quality of daily life (19). Based on the previous work,
examine if any particular study accounted for a large this Bayesian network meta-analysis will compare the
proportion of heterogeneity. The analyses will be based on effectiveness of all available acupuncture therapies and
different statistical models and qualities of methodology. rank the probability of acupuncture methods concerning
The meta-analysis will be repeated, and more inferior each domain of FC. We expect that our findings will help
quality studies will be excluded. healthcare providers, physicians, and patients to make more
precise treatment decisions. Moreover, the results of this
study will also apply to informing evidence-based guidelines
Assessment of publication bias
for FC treatment. Any deviations from the procedures
A comparison-adjusted funnel plot will be used to inspect described in this protocol will be updated in PROSPERO
reported bias and small-scale effects visually. If a sufficient and, therefore, report the rationale for and the date of these
number of included studies (more than 10 trials) are amendments in the final report.
available, the funnel plot will be used to assess the reported
bias (19). If the funnel plot is found to be asymmetrical,
Strengths and limitations
Egger’s regression test will be used to analyze the causes of
asymmetry. All eligible trials, regardless of the quality of This study will also have several strengths and limitations.
their methodologies, will be included. Firstly, this will be the first Bayesian network meta-analysis
© Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2021;10(7):8300-8309 | https://dx.doi.org/10.21037/apm-21-811
Annals of Palliative Medicine, Vol 10, No 7 July 2021 8307
attempted to establish evidence-based hierarchies for the Open Access Statement: This is an Open Access article
effectiveness and safety of all acupuncture therapies for distributed in accordance with the Creative Commons
the management of constipated patients. The results of Attribution-NonCommercial-NoDerivs 4.0 International
this study will assist healthcare providers, physicians, and License (CC BY-NC-ND 4.0), which permits the non-
patients in making more accurate treatment decisions. commercial replication and distribution of the article with
Secondly, 2 or more researchers will independently conduct the strict proviso that no changes or edits are made and the
the study selection, data extraction, and quality assessment original work is properly cited (including links to both the
to ensure that all relevant studies will be collected without formal publication through the relevant DOI and the license).
personal bias. Regarding limitations, our proposed See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
methodology will focus on acupuncture methods, and less
emphasis will be placed on the analysis of specific details
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Annals of Palliative Medicine, Vol 10, No 7 July 2021 8309
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© Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2021;10(7):8300-8309 | https://dx.doi.org/10.21037/apm-21-811