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Efficacy and safety of acupuncture on the treatment of functional constipation: Study protocol for a randomized controlled trial
World Journal of Acupuncture – Moxibustion 29 (2019) 145–152
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Efficacy and safety of acupuncture on the treatment of functional constipation: Study protocol for a randomized controlled trial Ping YIN () a, Ning-yang GAO () b, Bo DONG () a, Hui-min ZHENG () a, Ze-qin CHEN () a, Xuan YIN () a, Jun-yi WU () a, Yan CAO () a, Shi-fen XU () a,∗ Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of TCM, Shanghai 200071, China (, 200071, ) b Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China (, 201203, ) a
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Article history: Available online 17 May 2019 Keywords: Acupuncture Functional constipation Randomized controlled trial (RCT) Protocol
a b s t r a c t Objective: This trial is aimed at evaluating the efficacy and safety of acupuncture on treating FC. Methods: We describe the protocol for a randomized, patient-assessor-blinded, sham controlled trial. Seventy-two eligible patients will be randomly assigned to the intervention group (acupuncture) or the control group (sham acupuncture). All treatment will be given 26 sessions of acupuncture or sham acupuncture over 8 weeks (5 times per week in the first 2 weeks, 3 times per week during weeks 3–6, and 2 times per week during weeks 7 and 8). Each treatment will last for 20 min. The primary outcome is the change in mean complete spontaneous bowel movements (CSBMs) per week. The secondary outcomes are patient assessment of constipation quality of life questionnaire (PAC-QOL), self-rating anxiety scale (SAS), and the dosage of the medication. All adverse events will be recorded in detail and managed by corresponding researchers as quickly as possible. Outcomes will be evaluated at baseline (1 week before treatment), 2 weeks after intervention begins, 6 weeks after intervention begins, 8 weeks after intervention begins, 4 weeks follow-up, and 12 weeks follow-up. Discussion: The results of this study will provide the evidence of the efficacy and safety of acupuncture as a traditional treatment methods for functional constipation. Trial registration: Chinese Clinical Trial Registry, ChiCTR-INR-17011472. Registered on 23 May 2017. © 2019 World Journal of Acupuncture Moxibustion House. Published by Elsevier B.V. All rights reserved.
Introduction Functional constipation (FC) is one of the most common diseases in the clinic. It may be the primary or secondary cause for the decline of quality of life [1]. FC, no obvious organic lesions, characterized by a group of syndrome including reduced bowel movements and the amount of manure, dry stool, and defecation [2]. It is defined by the Rome III diagnostic criteria and can be further divided into normal transit constipation, slow transit constipation, and outlet constipation [3,4]. With the change of diet structure, quickening of life rhythm and social psychological factors, the prevalence of constipation is on the rise [5]. It has been become a major public health problem worldwide [2]. According to the epidemiological survey, it has a prevalence of 14% in the general population [6], 17.1% of people in
∗
Corresponding author. E-mail address: [email protected] (S.-f. XU).
Europe [7], 12–19% of those in North America [8]. In Asia, it affects 15–23% of women and about 11% of men [9]. Constipation symptoms seriously affect the quality of life of patients, mentally and physically [7,10]. In addition, the direct cost of chronic FC for each patient ranges from $1912 to $7522 per year [11]. At present, treatments for FC mainly include fiber supplements, bio-feedback, osmotic and stimulant laxatives, sacral nerve stimulation or surgery [12]. The clinical treatment of FC includes a variety of ways, but the most curative effect is different. Although the use of certain drugs has been deemed safe, there is no clear evidence of their short-term and long-term effects. Therefore, effect of the treatment is not entirely satisfactory [13]. Acupuncture, as a widely recognized alternative therapy in clinical practice, has been used to treat FC for a long time. Acupuncture can regulate the bowel movements and improve the symptoms in patients with constipation. Some studies have confirmed the effectiveness of acupuncture in the treatment of FC [14–18]. The multicenter trial has showed that electroacupuncture (EA) alleviated symptoms and improved the quality of life
https://doi.org/10.1016/j.wjam.2019.05.001 1003-5257/© 2019 World Journal of Acupuncture Moxibustion House. Published by Elsevier B.V. All rights reserved.
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P. YIN, N.-y. GAO and B. DONG et al. / World Journal of Acupuncture – Moxibustion 29 (2019) 145–152 Table 1 Trail process chart.
Patients Enrollment Sign informed consent Medical history Randomization Intervention Primary outcomes CSBMs Secondary outcomes PAC-QOL SAS Time and Dosage Adverse events
Baseline
Treatment phase
Week-1
Week 0
Follow-up phase
Week 2
Week 6
Week 8
Week 4
Week 12
×
×
×
×
×
×
×
×
×
× × ×
× × × ×
× × × ×
× × × ×
× × ×
× × ×
× × × ×
CSBMs: Complete Spontaneous Bowel Movements; PAS–QOL: Patient Assessment of Constipation Quality of Life questionnaire; SAS: Self-Rating Anxiety Scale.
in patients with chronic severe functional constipation (CSFC) during the 8-week treatment. This shows that eight weeks of EA treatment can increase complete spontaneous bowel movements (CSBMs), and the treatment of CSFC is safe and effective [16]. The meta-analysis reported that the EA treatment and deepneedling effectively increases the frequency of spontaneous bowel movements [14]. Although the studies of acupuncture treatment of FC have increased year by year, there are only a few articles of high-quality. Many reports have different problems, including problems with randomization, lack of sample size estimation, blinding issues, no mention of acupuncturist certification, and no use of the intentionto-treat (ITT) analysis [14]. In order to solve the current design problems of acupuncture clinical research and evaluate the effectiveness of acupuncture for FC, we designed this single-center, patient-assessor-blinded, randomized controlled trial with 8 weeks treatment and 12 weeks follow-up period. In order to objectively evaluate the effectiveness of acupuncture treatment for FC, we rationally set the control group to eliminate the placebo effect of the acupuncture.
Methods/design Study design This study is a single-center, patient-assessor-blinded, randomized controlled trial of acupuncture for functional constipation, which will be conducted in the Acupuncture Department of Shanghai Municipal Hospital of Traditional Chinese Medicine in Shanghai. We will recruit 72 eligible patients and randomly assign them to the intervention group and the control group at a ratio of 1:1. After one week of baseline assessment period, patients will accept 20 weeks of observation (Table 1). All treatments will be given into 26 sessions of acupuncture or sham acupuncture over 8 weeks (5 times per week in the first 2 weeks, 3 times per week during weeks 3–6, and 2 times per week during weeks 7 and 8). Patients will be assessed at 6 different times, the baseline (1 week before treatment), 2 weeks after intervention begins, 6 weeks after intervention begins, 8 weeks after intervention begins, and follow-up at 4 and 12 weeks after the end of treatment. All patients will complete the assessments by the CSBMs, patient assessment of constipation quality of life questionnaire (PAC–QOL), self-rating anxiety scale (SAS) and the drug dosage (including medication time, drug name and dosage). Procedure of the trial will strictly follow the standards for reporting interventions in clinical trials of acupuncture (STRICTA) [19]. (Fig. 1 is a flowchart of the study.)
Table 2 The Rome III criteria for FC. Functional constipation 1. Two or more of the following symptoms: • Straining ≥25% of defecations • Lumpy or hard stools for ≥25% defecations • Sensation of incomplete evacuation for ≥25% of defecations • Sensation of anorectal obstruction/blockage ≥25% of defecations • Manual maneuvers to facilitate ≥25% of defecations • ≤ 3 defecations per week 2. Loose stools are rarely present without use of laxatives 3. Diagnostic criteria for IBS not met Note: Criteria for FC must be fulfilled for the past 3 months, with onset of symptoms at least 6 months prior to diagnosis.
Participants Inclusion criteria Participants meeting the following criteria will be included: meet the diagnosis of RomeⅢcriteria [20] (Table 2), male or female, aged from 18 to 65 years old, FC grading is mild and moderate [21], no medication has been used for at least 2 weeks before enter the test (if the patient do not defecate for three consecutive days and above, allowing the use of a drug of Glycerin with 10 mL for emergency), (5) not participate in other medical clinical trials in recent three months, (6) can understand the various evaluation scale and complete the assessment and can complete the program of treatment, (7) signed the informed consent form. (1) (2) (3) (4)
Exclusion criteria Participants who report any of the following conditions will be excluded: (1) irritable bowel syndrome and the constipation caused by tumor, inflammatory response, endocrine and metabolic diseases, drug-induced, (2) constipation caused by organic disease, (3) liver, kidney, cardiovascular and cerebrovascular diseases, infectious diseases, cancer and mental illness patients, (4) pregnant or lactating patients, (5) during the treatment of taking other drugs and other effects and judgments (except for emergency treatment).
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Fig. 1. Flow chart of the trail.
Recruitment Participants will be recruited by using advertisements on WeChat and bulletin boards of Shanghai Municipal Hospital of TCM. People who interested in the trial can contact the researcher by phone or direct face-to-face consultation. The researcher will explain the details of the trial, the treatment options, and the pros and cons for participants. If the patients are willing to take part in the study, they are invited to consult with the study doctors. Once the patients meet the inclusion criteria, they will be recruited.
All the patients are required to sign the written informed consent form before the intervention begins. Patients have the right to withdraw from the trial at any time. Randomization and blinding A simple randomization method will be applied in this study. An independent researcher, will use the software SPSS 23.0 to generate a random number table with the ratio of 1:1 to divide 72 participants into the intervention group and the control
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¯ aosh ¯ u¯ ( BL22) with deqi sensation only and no retaining Sanji needle after insertion.
Table 3 Acupuncture method for acupoints in intervention group. Number
Acupoint
Needling method
1 2 3 4 5 6
ST25 TE6 ST36 ST37 BL25 BL22
Puncture Puncture Puncture Puncture Puncture Puncture
perpendicularly perpendicularly perpendicularly perpendicularly perpendicularly perpendicularly
Needles for for for for for for
1–1.5 cun 0.5–1 cun 1–1.5 cun 1–1.5 cun 0.8–1 cun 0.8–1 cun
0.3 × 40 0.3 × 40 0.3 × 40 0.3 × 40 0.3 × 40 0.3 × 40
mm mm mm mm mm mm
group. The researcher will then make random allocation cards and seal each card in an opaque envelope. When the participants met the inclusion criteria, another researcher will give the envelop to the acupuncturist. According to the random digital cards in the envelopes, the acupuncturists will arrange the participants into the intervention group or the control group, and give appropriate treatment. Except for the acupuncturists, patients and assessor who measure the outcomes will be blinded to the randomization in this RCT. In order to ensure the successful implementation of the blinding method, each participant will be asked to wear an eye mask during the treatment, and all treatments will be performed in a separate and closed treatment room. All of the researchers will be trained before the trial begins, and strictly implement the principle of separation of the task. Sample size calculation The sample size calculation for our RCT is based on the change in the CSBMs. According to the previous research [22], the change in CSBMs of the treatment group is 2.44 ± 1.07, and the change in CSBMs of the control group is 1.28 ± 1.14, assuming a two-sided alpha of 0.05, a power of 80%, a sample size of 15 participants should be needed for each group. Taking into account the 20% of the dropout rate, each group is 18 cases. In order to increase the reliability of the study, we expanded the sample size to 36 cases per group, so the total of 72 patients will be included. Interventions Participants in two groups will accept 20 weeks of observation and will be given 26 sessions of acupuncture or sham acupuncture treatment over 8 weeks (5 sessions per week in the first 2 weeks, 3 sessions per week during weeks 3–6, and 2 sessions per week during weeks 7 and 8). Treatment will be carried out after skin disinfection and then patients will be asked to wear an eye mask. Each treatment will last for 20 min. All acupuncturists are licensed doctors with more than 5 years of experience in acupuncture treatment. Moreover, the temperature of the treatment room cannot be lower than 25 °C. Considering the psychological state of the participants, 10 mL glycerin will be allowed to use of if the patient has not defecate for more than 3 days, and record the time and dosage of glycerin punctual. The intervention group Participants in the intervention group will receive acupuncture treatment. Acupuncture methods and location of acupoints are respectively shown in Table 3 and Fig. 2. The acupuncturist ¯ ¯ ( SJ6), Zúsanl ¯ ˘ı u¯ ( ST25), Zh¯ıgou will select bilateral Tiansh ( ST36), and Shàngjùxu¯ ( ST37), while the patient lying in supine position. After the needle insertion, lifting-thrusting or rotating manipulation will be applied for deqi sensation. The needles will be retained for 20 min. And then the patient lie in prone position for the needling of bilateral Dàchángshu¯ ( BL25) and
The control group Participants in the control group will receive superficial acupuncture treatment. Location of non-acupoints are respectively shown in Fig. 3. The acupuncturist will select the following sham ¯ acupoints: bilateral acupoints 0.5 cun upper outer of Huang shu¯ ¯ ˘ı ( KI16), bilateral acupoints 0.5 cun upper outer of Jiansh ( PC5), bilateral acuponints 0.5 cun upper outer of Dìj¯ı ( SP8), and bilateral acupoints 0.5 cun upper outer of Y¯ınlíngquán ( SP9), while lying in supine position. Acupuncturists will do no manipulation at each acupoint. The needles will also be retained for 20 min. And then patient lie in prone position, the acupuncturist will puncture shallowly with needles at bilateral ¯ ˘ı points, and acupoints 0.5 cun upper outer of the first Lumbar jiaj ¯ ˘ı bilateral acupoints 0.5 cun upper outer of the fourth lumbar jiaj Points. It will not be required to the needle sensation and the needle retaining. Outcomes All assessments will be conducted at baseline, endpoints (2 weeks after intervention begins, 6 weeks after intervention begins, 8 weeks after intervention begins), and follow-up (4 weeks and 12 weeks after the end of treatment). All questionnaires are in Chinese. Primary outcome The primary outcome of this study is the change in mean CSBMs per week. It is calculated as the total number of CSBMs divided by the number of weeks in the assessment period, during weeks 1–8 (the treatment period) and weeks 9–20 (the follow-up period). The number of CSBMs is recorded every week during the whole process of the study. CSBMs is considered to be clinically meaningful, since it combines a subjective measure of the completeness of evacuation with an objective measure of the number of bowel movements and reflects the relief of chronic constipation. Three or more CSBMs per week is considered to be the low end of the range that defines normal bowel function, it also reflects the normalization of bowel function [23]. Secondary outcomes 1. PAC–QOL, 28 items retained forming four sub-scales (worries and concerns, physical discomfort, psycho social discomfort, and satisfaction) and an overall scale. The PAC–QOL is a brief but comprehensive assessment of the burden of constipation on patients’ everyday functions and well-being. Multinational studies demonstrate that the PAC–QOL is internally consistent, reproducible, valid, and responsive to improvements over time [24]. 2. SAS, allowed participants to score the mental effects of constipation on their daily lives. SAS was developed primarily as a measure of somatic symptoms associated with anxiety responding [25]. Exploratory factor analysis revealed four lower-order SAS factors subsequently: (1) anxiety and panic; (2) vestibular sensations; (3) somatic control; (4) gastrointestinal/muscular sensations. The SAS is demonstrated good reliability. The correlations between the SAS factors and other anxiety variables provide supportive evidence for convergent validity [26]. 3. Dosage diary, the proportion of participants using medicine and dosage for emergency treatment. Throughout this trial, if the patients do not defecate for more than 3 days, they will be allowed to the use of glycerin with at most 10 mL each time, but they must promptly and strictly record the time and dosage of glycerin in the dairy.
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Fig. 2. Location of acupoints in intervention group.
The participants will be asked to record a diary of defecation every day during treatment and follow-up period. The contents of the diary include CSBMs, difficulty in defecation, stool characteristics and using Glycerin of the time and dosage. At the same time, adverse events are recorded and reported to researchers at any time.
Adverse events All participants are asked to report any adverse events (such as syncope, curved needle, subcutaneous hematoma, local infection or diseases occurring during the trial) related to the treatment they are undergoing to the specific researcher in charge of assessing adverse effects. The details of every adverse event will be recorded in detail and the reasons will be analyzed. Adverse events will be managed by acupuncturists within 24 h, the prevention principles and methods will be developed then. If the participants feel unwell, they can either pause or quit the trial at any time.
For patients in the control group who are ineffective in treatment, we will give two courses of free acupuncture treatment after the end of the study. Data collection and quality control The researchers will fill in the case report form (CRF) for each enrolled participant, collect demographic characteristics, baseline symptom, data outcome at each visit (Table 1), and adverse events, etc. Two researchers are responsible for data entry and retention. To ensure the accuracy of the data, two-input methods will be used. We will promptly input data on the ResMan website. To guarantee the quality of the trial, it will be carried out by Shanghai Municipal Hospital of Traditional Chinese Medicine. All the researchers will be trained on patient selection and exclusion, acupuncture in different groups. Moreover, the acupuncturist should hold the qualification of practicing physician for more than 5 years. At the same time, a qualified clinical trial expert will be invited to monitor this study.
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Fig. 3. Location of non-acupoints in control group.
Statistical analysis All the data analyses will be performed on the Intention-ToTreat (ITT) population of all randomized participants. Data analyses will be performed with the use of the statistical software SPSS 23.0. The significance level used for statistical analysis with 2tailed testing will be 5%. P value of less than 0.05 is considered to be statistically significant. Data values will be mainly presented as mean and standard deviation (Mean ± SD). The independent sample t-test will be used to compare the measurement data between two groups. The paired t-test will be used to compare the data of before and after treatments in each group. The rank-sum test will be used for ranked data, while the chi-squared test will be adopted to analyze categorical data. Non-parametric tests will be used for variables which do not follow a normal distribution. Discussion Acupuncture has been used in the treatment of constipation in China for centuries, and more and more researchers have begun to pay attention to the impact of acupuncture on functional constipation [27–29]. Previous study showed that acupuncture can increase the frequency of defecation, improve the symptoms of defecation
difficulties and change the quality of defecation in constipation patients. It has a sustained effect even during the follow-up period [30]. Although there are more and more studies on acupuncture treatment of FC, there are still some problems. For example, previous RCTs about acupuncture for FC had limitations including imperfect blinding method, irrational design or inadequate control groups and so on. By designing this RCT – with a strictly randomized controlled trial, setting control group and applying sham acupoints method – we aim to contribute better evidence for the effectiveness of acupuncture, which is expected to reduce the related symptoms of functional constipation. Furthermore, in order to handle statistical data ITT principle is used to reduce deviation of the RCT. In recent years, there are also high quality researchs about acupuncture treatment of constipation. For example, Liu Z and others [16] reported that electroacupuncture treatment has a definite curative effect for CSFC. Researchers selected ST25, Fùjié ( SP14) and ST37 in EA group with deep needling method and EA at bilateral ST25 and SP14 for 30 min. Compared with the sham acupuncture group, the acupuncture therapy can not only improve CSBMs in patients with CSFC, but also be safe and effective. There are kinds of clinical acupuncture treatments for FC with different
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acupoints selection and operating methods. Each method has its own benefits and risks. The main goal of our trial is to present a well-designed trial to study the therapeutic effect of acupuncture on patients with FC. First of all, we promote the acupuncture method with the principle of “regulating triple energizer and activating functions of six-fu organs” in this trial. The optimized acupoints selection of acupuncture in treating FC is an important part in this study. The TCM theory about the specificity of acupoints is one of the most mysterious questions mentioned by the acupuncture researchers. The triple energizer is the passage of qi, and FC was always caused by qi movement stagnation or the abnormal circulation of qi in triple energizer. When the qi of the triple energizers run smoothly, yinyang balance and the symptoms of FC will be improved. We applied fu-mu and back-shu combined acupoint prescription strategy because they can directly regulate the function of viscera. Therefore, except for these acupoints including ST36, ST25, ST37 and BL25 which are commonly used in the clinical practice to treat FC [31]. We also choose SJ6 and BL22 as the main acupoints. Secondly, deqi often plays a key role in the effectiveness of acupuncture treatment. In this study, the lifting-thrusting manipulation and rotating manipulation will be applied for deqi. When patients are lying in prone position, the acupuncturist will just only manipulate the acupuncture needles to achieve the deqi and no needle retention will be performed. Finally, the regime with decreasing treatment frequency adapted in the study is for the purpose of observing whether acupuncture treatment can achieve a certain therapeutic effect by maintaining the minimum therapeutic dose, and exploring whether it can exert a long-term efficacy. And the SAS scale is used for observing the patient’s mental state during this trial, and also for further analysis of the correlation between constipation and anxiety. There are also some limitations in this research. For example, it is hard to make the study double-blinded. The participants, the assessor, the statistics and the scholars will be blinded in our study, however, it will be impossible to blind the acupuncturists who know the group assignment in the trial. In addition, the sample size is relatively small and there is only a single center in this study. In the future, in order to provide a more reliable evidence for acupuncture treatment of FC and remedy the defects of clinical research designs in acupuncture clinical trials, we will launch a multi-center trial, expand the sample size and other methods for in-depth study. Competing interests The authors declare that they have no competing interests. Funding This study is supported by the Shanghai Municipal Commission of Health and Family Planning (Grant No. 2016LQ015). Acknowledgements Shi-fen XU (the head of the Acupuncture Department) in Shanghai Municipal Hospital of Traditional Chinese Medicine provided general support, and was responsible for the designation of this clinical trial as well as protocol modifications communication to relevant parties. We also would like to express our thanks to the people who have helped us in this trial. Authors’ contributions Ping YIN, Shi-fen XU conceived the design of the trial. Bo DONG and Ze-qin CHEN participated in the design of the statistical
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analysis. Hui-min ZHENG, Xuan YIN, Jun-yi WU and Yan CAO helped in the design of the treatment methods. Ping YIN, Ningyang GAO and Shi-fen XU helped draft the paper. Ping YIN and Ning-yang GAO made equal contributions to this paper. All authors approved the final manuscript and consented for publication. Ethics approval and consent to participate The trial has been approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine (2016SHLKY-16) on 7 December 2016. And it has been registered in Chinese Clinical Trials Registry (ChiCTR-INR-17011472) on 23 May 2017. All of the patients will be asked to sign the written informed consent before entering the trial. Consent for publication All authors read and approved the final manuscript. References [1] Bassotti G, Villanacci V. A practical approach to diagnosis and management of functional constipation in adults. Intern Emerg Med 2013;8(4):275–82. [2] Zheng Q, Zheng H, Lu L, Leng J, Zhou S, Zheng H, et al. Acupuncture for functional constipation: protocol of an individual patient data meta-analysis. BMJ Open 2015;5(5):e007137. [3] Jamshed N, Lee ZE, Olden KW. Diagnostic approach to chronic constipation in adults. Am Fam Phys 2011;84(3):299–306. [4] Drossman DA, Dumitrascu DL. Rome III: new standard for functional gastrointestinal disorders. J Gastrointestin Liver Dis 2006;15(3):237–41. [5] Group China Medical Association Society of Surgery Colorectal and Anal Surgery Guidelines for the diagnosis and treatment of chronic constipation in China (2013, Wuhan). Chin J Gastroen 2013;18(10):605–12. [6] Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol 2011;106(9):1582–91. [7] Peppas G, Alexiou VG, Mourtzoukou E, Falagas ME. Epidemiology of constipation in Europe and Oceania: a systematic review. BMC Gastroenterol 2008;8(1):5. [8] Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 2004;99(4):750–9. [9] Gwee KA, Ghoshal UC, Gonlachanvit S, Chua AS, Myung SJ, Rajindrajith S, et al. Primary care management of chronic constipation in Asia: the ANMA chronic constipation tool. J Neurogastroenterol Motil 2013;19(2):149–60. [10] Belsey JD, Geraint M, Dixon TA. Systematic review and meta analysis: polyethylene glycol in adults with non-organic constipation. Int J Clin Pract 2010;64(7):944–55. [11] Nellesen D, Yee K, Chawla A, Lewis BE, Carson RT. A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation. J Manag Care Pharm 2013;19(9):755–64. [12] Basilisco G, Coletta M. Chronic constipation: a critical review. Dig Liver Dis 2013;45(11):886–93. [13] Serrano-Falcón B, Rey E. The safety of available treatments for chronic constipation. Expert Opin Drug Safety 2017;16(11):1243–53. [14] Zhou SL, Zhang XL, Wang JH. Comparison of electroacupuncture and medical treatment for functional constipation: a systematic review and meta-analysis. Acup Med 2017;35(5):324. [15] Wu J, Liu B, Li N, Sun J, Wang L, Wang L, et al. Effect and safety of deep needling and shallow needling for functional constipation: a multicenter, randomized controlled trial. Medicine (Baltimore) 2014;93(28):e284. [16] Liu Z, Yan S, Wu J, He L, Li N, Dong G, et al. Acupuncture for chronic severe functional constipation: a randomized trial. Ann Intern Med 2016;165(11):761–9. [17] Zhang T, Chon TY, Liu B, Do A, Li G, Bauer B, et al. Efficacy of acupuncture for chronic constipation: a systematic review. Am J Chin Med 2013;41(4):717–42. [18] Xue QM, Li N, Liu ZS, Wang CW, Lu JQ. Efficacy of electroacupuncture in the treatment of functional constipation: a randomized controlled pilot trial. Chin J Integr Med 2015;21(6):459–63. [19] MacPherson H, Altman DG, Hammerschlag R, Youping L, Taixiang W, White A, et al. Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement. J Evid Based Med 2010;3(3):140–55. [20] Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130(5):1377–90. [21] Gastroenterology Chinese Society of Guidelines for the diagnosis and treatment of chronic constipation. Chin J Digest 2004;24(1):39–40. [22] Shi J, Qin LH, Liu ZH, Gu G, Pan B, Wang DL, et al. Therapeutic effect of electroacupuncture on severe functional constipation. J Anhui Univer Chin Med 2015;34(1):42–5.
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World Journal of Acupuncture – Moxibustion journal homepage: www.elsevier.com/locate/wjam
Efficacy and safety of acupuncture on the treatment of functional constipation: Study protocol for a randomized controlled trial Ping YIN () a, Ning-yang GAO () b, Bo DONG () a, Hui-min ZHENG () a, Ze-qin CHEN () a, Xuan YIN () a, Jun-yi WU () a, Yan CAO () a, Shi-fen XU () a,∗ Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of TCM, Shanghai 200071, China (, 200071, ) b Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China (, 201203, ) a
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Article history: Available online 17 May 2019 Keywords: Acupuncture Functional constipation Randomized controlled trial (RCT) Protocol
a b s t r a c t Objective: This trial is aimed at evaluating the efficacy and safety of acupuncture on treating FC. Methods: We describe the protocol for a randomized, patient-assessor-blinded, sham controlled trial. Seventy-two eligible patients will be randomly assigned to the intervention group (acupuncture) or the control group (sham acupuncture). All treatment will be given 26 sessions of acupuncture or sham acupuncture over 8 weeks (5 times per week in the first 2 weeks, 3 times per week during weeks 3–6, and 2 times per week during weeks 7 and 8). Each treatment will last for 20 min. The primary outcome is the change in mean complete spontaneous bowel movements (CSBMs) per week. The secondary outcomes are patient assessment of constipation quality of life questionnaire (PAC-QOL), self-rating anxiety scale (SAS), and the dosage of the medication. All adverse events will be recorded in detail and managed by corresponding researchers as quickly as possible. Outcomes will be evaluated at baseline (1 week before treatment), 2 weeks after intervention begins, 6 weeks after intervention begins, 8 weeks after intervention begins, 4 weeks follow-up, and 12 weeks follow-up. Discussion: The results of this study will provide the evidence of the efficacy and safety of acupuncture as a traditional treatment methods for functional constipation. Trial registration: Chinese Clinical Trial Registry, ChiCTR-INR-17011472. Registered on 23 May 2017. © 2019 World Journal of Acupuncture Moxibustion House. Published by Elsevier B.V. All rights reserved.
Introduction Functional constipation (FC) is one of the most common diseases in the clinic. It may be the primary or secondary cause for the decline of quality of life [1]. FC, no obvious organic lesions, characterized by a group of syndrome including reduced bowel movements and the amount of manure, dry stool, and defecation [2]. It is defined by the Rome III diagnostic criteria and can be further divided into normal transit constipation, slow transit constipation, and outlet constipation [3,4]. With the change of diet structure, quickening of life rhythm and social psychological factors, the prevalence of constipation is on the rise [5]. It has been become a major public health problem worldwide [2]. According to the epidemiological survey, it has a prevalence of 14% in the general population [6], 17.1% of people in
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Corresponding author. E-mail address: [email protected] (S.-f. XU).
Europe [7], 12–19% of those in North America [8]. In Asia, it affects 15–23% of women and about 11% of men [9]. Constipation symptoms seriously affect the quality of life of patients, mentally and physically [7,10]. In addition, the direct cost of chronic FC for each patient ranges from $1912 to $7522 per year [11]. At present, treatments for FC mainly include fiber supplements, bio-feedback, osmotic and stimulant laxatives, sacral nerve stimulation or surgery [12]. The clinical treatment of FC includes a variety of ways, but the most curative effect is different. Although the use of certain drugs has been deemed safe, there is no clear evidence of their short-term and long-term effects. Therefore, effect of the treatment is not entirely satisfactory [13]. Acupuncture, as a widely recognized alternative therapy in clinical practice, has been used to treat FC for a long time. Acupuncture can regulate the bowel movements and improve the symptoms in patients with constipation. Some studies have confirmed the effectiveness of acupuncture in the treatment of FC [14–18]. The multicenter trial has showed that electroacupuncture (EA) alleviated symptoms and improved the quality of life
https://doi.org/10.1016/j.wjam.2019.05.001 1003-5257/© 2019 World Journal of Acupuncture Moxibustion House. Published by Elsevier B.V. All rights reserved.
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P. YIN, N.-y. GAO and B. DONG et al. / World Journal of Acupuncture – Moxibustion 29 (2019) 145–152 Table 1 Trail process chart.
Patients Enrollment Sign informed consent Medical history Randomization Intervention Primary outcomes CSBMs Secondary outcomes PAC-QOL SAS Time and Dosage Adverse events
Baseline
Treatment phase
Week-1
Week 0
Follow-up phase
Week 2
Week 6
Week 8
Week 4
Week 12
×
×
×
×
×
×
×
×
×
× × ×
× × × ×
× × × ×
× × × ×
× × ×
× × ×
× × × ×
CSBMs: Complete Spontaneous Bowel Movements; PAS–QOL: Patient Assessment of Constipation Quality of Life questionnaire; SAS: Self-Rating Anxiety Scale.
in patients with chronic severe functional constipation (CSFC) during the 8-week treatment. This shows that eight weeks of EA treatment can increase complete spontaneous bowel movements (CSBMs), and the treatment of CSFC is safe and effective [16]. The meta-analysis reported that the EA treatment and deepneedling effectively increases the frequency of spontaneous bowel movements [14]. Although the studies of acupuncture treatment of FC have increased year by year, there are only a few articles of high-quality. Many reports have different problems, including problems with randomization, lack of sample size estimation, blinding issues, no mention of acupuncturist certification, and no use of the intentionto-treat (ITT) analysis [14]. In order to solve the current design problems of acupuncture clinical research and evaluate the effectiveness of acupuncture for FC, we designed this single-center, patient-assessor-blinded, randomized controlled trial with 8 weeks treatment and 12 weeks follow-up period. In order to objectively evaluate the effectiveness of acupuncture treatment for FC, we rationally set the control group to eliminate the placebo effect of the acupuncture.
Methods/design Study design This study is a single-center, patient-assessor-blinded, randomized controlled trial of acupuncture for functional constipation, which will be conducted in the Acupuncture Department of Shanghai Municipal Hospital of Traditional Chinese Medicine in Shanghai. We will recruit 72 eligible patients and randomly assign them to the intervention group and the control group at a ratio of 1:1. After one week of baseline assessment period, patients will accept 20 weeks of observation (Table 1). All treatments will be given into 26 sessions of acupuncture or sham acupuncture over 8 weeks (5 times per week in the first 2 weeks, 3 times per week during weeks 3–6, and 2 times per week during weeks 7 and 8). Patients will be assessed at 6 different times, the baseline (1 week before treatment), 2 weeks after intervention begins, 6 weeks after intervention begins, 8 weeks after intervention begins, and follow-up at 4 and 12 weeks after the end of treatment. All patients will complete the assessments by the CSBMs, patient assessment of constipation quality of life questionnaire (PAC–QOL), self-rating anxiety scale (SAS) and the drug dosage (including medication time, drug name and dosage). Procedure of the trial will strictly follow the standards for reporting interventions in clinical trials of acupuncture (STRICTA) [19]. (Fig. 1 is a flowchart of the study.)
Table 2 The Rome III criteria for FC. Functional constipation 1. Two or more of the following symptoms: • Straining ≥25% of defecations • Lumpy or hard stools for ≥25% defecations • Sensation of incomplete evacuation for ≥25% of defecations • Sensation of anorectal obstruction/blockage ≥25% of defecations • Manual maneuvers to facilitate ≥25% of defecations • ≤ 3 defecations per week 2. Loose stools are rarely present without use of laxatives 3. Diagnostic criteria for IBS not met Note: Criteria for FC must be fulfilled for the past 3 months, with onset of symptoms at least 6 months prior to diagnosis.
Participants Inclusion criteria Participants meeting the following criteria will be included: meet the diagnosis of RomeⅢcriteria [20] (Table 2), male or female, aged from 18 to 65 years old, FC grading is mild and moderate [21], no medication has been used for at least 2 weeks before enter the test (if the patient do not defecate for three consecutive days and above, allowing the use of a drug of Glycerin with 10 mL for emergency), (5) not participate in other medical clinical trials in recent three months, (6) can understand the various evaluation scale and complete the assessment and can complete the program of treatment, (7) signed the informed consent form. (1) (2) (3) (4)
Exclusion criteria Participants who report any of the following conditions will be excluded: (1) irritable bowel syndrome and the constipation caused by tumor, inflammatory response, endocrine and metabolic diseases, drug-induced, (2) constipation caused by organic disease, (3) liver, kidney, cardiovascular and cerebrovascular diseases, infectious diseases, cancer and mental illness patients, (4) pregnant or lactating patients, (5) during the treatment of taking other drugs and other effects and judgments (except for emergency treatment).
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Fig. 1. Flow chart of the trail.
Recruitment Participants will be recruited by using advertisements on WeChat and bulletin boards of Shanghai Municipal Hospital of TCM. People who interested in the trial can contact the researcher by phone or direct face-to-face consultation. The researcher will explain the details of the trial, the treatment options, and the pros and cons for participants. If the patients are willing to take part in the study, they are invited to consult with the study doctors. Once the patients meet the inclusion criteria, they will be recruited.
All the patients are required to sign the written informed consent form before the intervention begins. Patients have the right to withdraw from the trial at any time. Randomization and blinding A simple randomization method will be applied in this study. An independent researcher, will use the software SPSS 23.0 to generate a random number table with the ratio of 1:1 to divide 72 participants into the intervention group and the control
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¯ aosh ¯ u¯ ( BL22) with deqi sensation only and no retaining Sanji needle after insertion.
Table 3 Acupuncture method for acupoints in intervention group. Number
Acupoint
Needling method
1 2 3 4 5 6
ST25 TE6 ST36 ST37 BL25 BL22
Puncture Puncture Puncture Puncture Puncture Puncture
perpendicularly perpendicularly perpendicularly perpendicularly perpendicularly perpendicularly
Needles for for for for for for
1–1.5 cun 0.5–1 cun 1–1.5 cun 1–1.5 cun 0.8–1 cun 0.8–1 cun
0.3 × 40 0.3 × 40 0.3 × 40 0.3 × 40 0.3 × 40 0.3 × 40
mm mm mm mm mm mm
group. The researcher will then make random allocation cards and seal each card in an opaque envelope. When the participants met the inclusion criteria, another researcher will give the envelop to the acupuncturist. According to the random digital cards in the envelopes, the acupuncturists will arrange the participants into the intervention group or the control group, and give appropriate treatment. Except for the acupuncturists, patients and assessor who measure the outcomes will be blinded to the randomization in this RCT. In order to ensure the successful implementation of the blinding method, each participant will be asked to wear an eye mask during the treatment, and all treatments will be performed in a separate and closed treatment room. All of the researchers will be trained before the trial begins, and strictly implement the principle of separation of the task. Sample size calculation The sample size calculation for our RCT is based on the change in the CSBMs. According to the previous research [22], the change in CSBMs of the treatment group is 2.44 ± 1.07, and the change in CSBMs of the control group is 1.28 ± 1.14, assuming a two-sided alpha of 0.05, a power of 80%, a sample size of 15 participants should be needed for each group. Taking into account the 20% of the dropout rate, each group is 18 cases. In order to increase the reliability of the study, we expanded the sample size to 36 cases per group, so the total of 72 patients will be included. Interventions Participants in two groups will accept 20 weeks of observation and will be given 26 sessions of acupuncture or sham acupuncture treatment over 8 weeks (5 sessions per week in the first 2 weeks, 3 sessions per week during weeks 3–6, and 2 sessions per week during weeks 7 and 8). Treatment will be carried out after skin disinfection and then patients will be asked to wear an eye mask. Each treatment will last for 20 min. All acupuncturists are licensed doctors with more than 5 years of experience in acupuncture treatment. Moreover, the temperature of the treatment room cannot be lower than 25 °C. Considering the psychological state of the participants, 10 mL glycerin will be allowed to use of if the patient has not defecate for more than 3 days, and record the time and dosage of glycerin punctual. The intervention group Participants in the intervention group will receive acupuncture treatment. Acupuncture methods and location of acupoints are respectively shown in Table 3 and Fig. 2. The acupuncturist ¯ ¯ ( SJ6), Zúsanl ¯ ˘ı u¯ ( ST25), Zh¯ıgou will select bilateral Tiansh ( ST36), and Shàngjùxu¯ ( ST37), while the patient lying in supine position. After the needle insertion, lifting-thrusting or rotating manipulation will be applied for deqi sensation. The needles will be retained for 20 min. And then the patient lie in prone position for the needling of bilateral Dàchángshu¯ ( BL25) and
The control group Participants in the control group will receive superficial acupuncture treatment. Location of non-acupoints are respectively shown in Fig. 3. The acupuncturist will select the following sham ¯ acupoints: bilateral acupoints 0.5 cun upper outer of Huang shu¯ ¯ ˘ı ( KI16), bilateral acupoints 0.5 cun upper outer of Jiansh ( PC5), bilateral acuponints 0.5 cun upper outer of Dìj¯ı ( SP8), and bilateral acupoints 0.5 cun upper outer of Y¯ınlíngquán ( SP9), while lying in supine position. Acupuncturists will do no manipulation at each acupoint. The needles will also be retained for 20 min. And then patient lie in prone position, the acupuncturist will puncture shallowly with needles at bilateral ¯ ˘ı points, and acupoints 0.5 cun upper outer of the first Lumbar jiaj ¯ ˘ı bilateral acupoints 0.5 cun upper outer of the fourth lumbar jiaj Points. It will not be required to the needle sensation and the needle retaining. Outcomes All assessments will be conducted at baseline, endpoints (2 weeks after intervention begins, 6 weeks after intervention begins, 8 weeks after intervention begins), and follow-up (4 weeks and 12 weeks after the end of treatment). All questionnaires are in Chinese. Primary outcome The primary outcome of this study is the change in mean CSBMs per week. It is calculated as the total number of CSBMs divided by the number of weeks in the assessment period, during weeks 1–8 (the treatment period) and weeks 9–20 (the follow-up period). The number of CSBMs is recorded every week during the whole process of the study. CSBMs is considered to be clinically meaningful, since it combines a subjective measure of the completeness of evacuation with an objective measure of the number of bowel movements and reflects the relief of chronic constipation. Three or more CSBMs per week is considered to be the low end of the range that defines normal bowel function, it also reflects the normalization of bowel function [23]. Secondary outcomes 1. PAC–QOL, 28 items retained forming four sub-scales (worries and concerns, physical discomfort, psycho social discomfort, and satisfaction) and an overall scale. The PAC–QOL is a brief but comprehensive assessment of the burden of constipation on patients’ everyday functions and well-being. Multinational studies demonstrate that the PAC–QOL is internally consistent, reproducible, valid, and responsive to improvements over time [24]. 2. SAS, allowed participants to score the mental effects of constipation on their daily lives. SAS was developed primarily as a measure of somatic symptoms associated with anxiety responding [25]. Exploratory factor analysis revealed four lower-order SAS factors subsequently: (1) anxiety and panic; (2) vestibular sensations; (3) somatic control; (4) gastrointestinal/muscular sensations. The SAS is demonstrated good reliability. The correlations between the SAS factors and other anxiety variables provide supportive evidence for convergent validity [26]. 3. Dosage diary, the proportion of participants using medicine and dosage for emergency treatment. Throughout this trial, if the patients do not defecate for more than 3 days, they will be allowed to the use of glycerin with at most 10 mL each time, but they must promptly and strictly record the time and dosage of glycerin in the dairy.
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Fig. 2. Location of acupoints in intervention group.
The participants will be asked to record a diary of defecation every day during treatment and follow-up period. The contents of the diary include CSBMs, difficulty in defecation, stool characteristics and using Glycerin of the time and dosage. At the same time, adverse events are recorded and reported to researchers at any time.
Adverse events All participants are asked to report any adverse events (such as syncope, curved needle, subcutaneous hematoma, local infection or diseases occurring during the trial) related to the treatment they are undergoing to the specific researcher in charge of assessing adverse effects. The details of every adverse event will be recorded in detail and the reasons will be analyzed. Adverse events will be managed by acupuncturists within 24 h, the prevention principles and methods will be developed then. If the participants feel unwell, they can either pause or quit the trial at any time.
For patients in the control group who are ineffective in treatment, we will give two courses of free acupuncture treatment after the end of the study. Data collection and quality control The researchers will fill in the case report form (CRF) for each enrolled participant, collect demographic characteristics, baseline symptom, data outcome at each visit (Table 1), and adverse events, etc. Two researchers are responsible for data entry and retention. To ensure the accuracy of the data, two-input methods will be used. We will promptly input data on the ResMan website. To guarantee the quality of the trial, it will be carried out by Shanghai Municipal Hospital of Traditional Chinese Medicine. All the researchers will be trained on patient selection and exclusion, acupuncture in different groups. Moreover, the acupuncturist should hold the qualification of practicing physician for more than 5 years. At the same time, a qualified clinical trial expert will be invited to monitor this study.
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Fig. 3. Location of non-acupoints in control group.
Statistical analysis All the data analyses will be performed on the Intention-ToTreat (ITT) population of all randomized participants. Data analyses will be performed with the use of the statistical software SPSS 23.0. The significance level used for statistical analysis with 2tailed testing will be 5%. P value of less than 0.05 is considered to be statistically significant. Data values will be mainly presented as mean and standard deviation (Mean ± SD). The independent sample t-test will be used to compare the measurement data between two groups. The paired t-test will be used to compare the data of before and after treatments in each group. The rank-sum test will be used for ranked data, while the chi-squared test will be adopted to analyze categorical data. Non-parametric tests will be used for variables which do not follow a normal distribution. Discussion Acupuncture has been used in the treatment of constipation in China for centuries, and more and more researchers have begun to pay attention to the impact of acupuncture on functional constipation [27–29]. Previous study showed that acupuncture can increase the frequency of defecation, improve the symptoms of defecation
difficulties and change the quality of defecation in constipation patients. It has a sustained effect even during the follow-up period [30]. Although there are more and more studies on acupuncture treatment of FC, there are still some problems. For example, previous RCTs about acupuncture for FC had limitations including imperfect blinding method, irrational design or inadequate control groups and so on. By designing this RCT – with a strictly randomized controlled trial, setting control group and applying sham acupoints method – we aim to contribute better evidence for the effectiveness of acupuncture, which is expected to reduce the related symptoms of functional constipation. Furthermore, in order to handle statistical data ITT principle is used to reduce deviation of the RCT. In recent years, there are also high quality researchs about acupuncture treatment of constipation. For example, Liu Z and others [16] reported that electroacupuncture treatment has a definite curative effect for CSFC. Researchers selected ST25, Fùjié ( SP14) and ST37 in EA group with deep needling method and EA at bilateral ST25 and SP14 for 30 min. Compared with the sham acupuncture group, the acupuncture therapy can not only improve CSBMs in patients with CSFC, but also be safe and effective. There are kinds of clinical acupuncture treatments for FC with different
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acupoints selection and operating methods. Each method has its own benefits and risks. The main goal of our trial is to present a well-designed trial to study the therapeutic effect of acupuncture on patients with FC. First of all, we promote the acupuncture method with the principle of “regulating triple energizer and activating functions of six-fu organs” in this trial. The optimized acupoints selection of acupuncture in treating FC is an important part in this study. The TCM theory about the specificity of acupoints is one of the most mysterious questions mentioned by the acupuncture researchers. The triple energizer is the passage of qi, and FC was always caused by qi movement stagnation or the abnormal circulation of qi in triple energizer. When the qi of the triple energizers run smoothly, yinyang balance and the symptoms of FC will be improved. We applied fu-mu and back-shu combined acupoint prescription strategy because they can directly regulate the function of viscera. Therefore, except for these acupoints including ST36, ST25, ST37 and BL25 which are commonly used in the clinical practice to treat FC [31]. We also choose SJ6 and BL22 as the main acupoints. Secondly, deqi often plays a key role in the effectiveness of acupuncture treatment. In this study, the lifting-thrusting manipulation and rotating manipulation will be applied for deqi. When patients are lying in prone position, the acupuncturist will just only manipulate the acupuncture needles to achieve the deqi and no needle retention will be performed. Finally, the regime with decreasing treatment frequency adapted in the study is for the purpose of observing whether acupuncture treatment can achieve a certain therapeutic effect by maintaining the minimum therapeutic dose, and exploring whether it can exert a long-term efficacy. And the SAS scale is used for observing the patient’s mental state during this trial, and also for further analysis of the correlation between constipation and anxiety. There are also some limitations in this research. For example, it is hard to make the study double-blinded. The participants, the assessor, the statistics and the scholars will be blinded in our study, however, it will be impossible to blind the acupuncturists who know the group assignment in the trial. In addition, the sample size is relatively small and there is only a single center in this study. In the future, in order to provide a more reliable evidence for acupuncture treatment of FC and remedy the defects of clinical research designs in acupuncture clinical trials, we will launch a multi-center trial, expand the sample size and other methods for in-depth study. Competing interests The authors declare that they have no competing interests. Funding This study is supported by the Shanghai Municipal Commission of Health and Family Planning (Grant No. 2016LQ015). Acknowledgements Shi-fen XU (the head of the Acupuncture Department) in Shanghai Municipal Hospital of Traditional Chinese Medicine provided general support, and was responsible for the designation of this clinical trial as well as protocol modifications communication to relevant parties. We also would like to express our thanks to the people who have helped us in this trial. Authors’ contributions Ping YIN, Shi-fen XU conceived the design of the trial. Bo DONG and Ze-qin CHEN participated in the design of the statistical
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analysis. Hui-min ZHENG, Xuan YIN, Jun-yi WU and Yan CAO helped in the design of the treatment methods. Ping YIN, Ningyang GAO and Shi-fen XU helped draft the paper. Ping YIN and Ning-yang GAO made equal contributions to this paper. All authors approved the final manuscript and consented for publication. Ethics approval and consent to participate The trial has been approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine (2016SHLKY-16) on 7 December 2016. And it has been registered in Chinese Clinical Trials Registry (ChiCTR-INR-17011472) on 23 May 2017. All of the patients will be asked to sign the written informed consent before entering the trial. Consent for publication All authors read and approved the final manuscript. References [1] Bassotti G, Villanacci V. A practical approach to diagnosis and management of functional constipation in adults. Intern Emerg Med 2013;8(4):275–82. [2] Zheng Q, Zheng H, Lu L, Leng J, Zhou S, Zheng H, et al. Acupuncture for functional constipation: protocol of an individual patient data meta-analysis. BMJ Open 2015;5(5):e007137. [3] Jamshed N, Lee ZE, Olden KW. Diagnostic approach to chronic constipation in adults. Am Fam Phys 2011;84(3):299–306. [4] Drossman DA, Dumitrascu DL. Rome III: new standard for functional gastrointestinal disorders. J Gastrointestin Liver Dis 2006;15(3):237–41. [5] Group China Medical Association Society of Surgery Colorectal and Anal Surgery Guidelines for the diagnosis and treatment of chronic constipation in China (2013, Wuhan). Chin J Gastroen 2013;18(10):605–12. [6] Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol 2011;106(9):1582–91. [7] Peppas G, Alexiou VG, Mourtzoukou E, Falagas ME. Epidemiology of constipation in Europe and Oceania: a systematic review. BMC Gastroenterol 2008;8(1):5. [8] Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 2004;99(4):750–9. [9] Gwee KA, Ghoshal UC, Gonlachanvit S, Chua AS, Myung SJ, Rajindrajith S, et al. Primary care management of chronic constipation in Asia: the ANMA chronic constipation tool. J Neurogastroenterol Motil 2013;19(2):149–60. [10] Belsey JD, Geraint M, Dixon TA. Systematic review and meta analysis: polyethylene glycol in adults with non-organic constipation. Int J Clin Pract 2010;64(7):944–55. [11] Nellesen D, Yee K, Chawla A, Lewis BE, Carson RT. A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation. J Manag Care Pharm 2013;19(9):755–64. [12] Basilisco G, Coletta M. Chronic constipation: a critical review. Dig Liver Dis 2013;45(11):886–93. [13] Serrano-Falcón B, Rey E. The safety of available treatments for chronic constipation. Expert Opin Drug Safety 2017;16(11):1243–53. [14] Zhou SL, Zhang XL, Wang JH. Comparison of electroacupuncture and medical treatment for functional constipation: a systematic review and meta-analysis. Acup Med 2017;35(5):324. [15] Wu J, Liu B, Li N, Sun J, Wang L, Wang L, et al. Effect and safety of deep needling and shallow needling for functional constipation: a multicenter, randomized controlled trial. Medicine (Baltimore) 2014;93(28):e284. [16] Liu Z, Yan S, Wu J, He L, Li N, Dong G, et al. Acupuncture for chronic severe functional constipation: a randomized trial. Ann Intern Med 2016;165(11):761–9. [17] Zhang T, Chon TY, Liu B, Do A, Li G, Bauer B, et al. Efficacy of acupuncture for chronic constipation: a systematic review. Am J Chin Med 2013;41(4):717–42. [18] Xue QM, Li N, Liu ZS, Wang CW, Lu JQ. Efficacy of electroacupuncture in the treatment of functional constipation: a randomized controlled pilot trial. Chin J Integr Med 2015;21(6):459–63. [19] MacPherson H, Altman DG, Hammerschlag R, Youping L, Taixiang W, White A, et al. Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement. J Evid Based Med 2010;3(3):140–55. [20] Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130(5):1377–90. [21] Gastroenterology Chinese Society of Guidelines for the diagnosis and treatment of chronic constipation. Chin J Digest 2004;24(1):39–40. [22] Shi J, Qin LH, Liu ZH, Gu G, Pan B, Wang DL, et al. Therapeutic effect of electroacupuncture on severe functional constipation. J Anhui Univer Chin Med 2015;34(1):42–5.
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