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ARTICLE: FUNCTIONAL GI DISORDERS

Electroacupuncture vs Prucalopride for Severe Chronic Constipation: A Multicenter, Randomized, Controlled, Noninferiority Trial

Liu, Baoyan MD1; Wu, Jiani MD, PhD1; Yan, Shiyan PhD2; Zhou, Kehua MD, DPT3; He, Liyun MD, PhD2; Fang, Jianqiao MD, PhD4; Fu, Wenbin MD5; Li, Ning MD6; Su, Tongsheng MD7; Sun, Jianhua MD, PhD8; Zhang, Wei MD, PhD9; Yue, Zenghui MD10; Zhang, Hongxing MD, PhD11; Zhao, Jiping MD12; Zhou, Zhongyu MD13; Song, Hujie MD14; Wang, Jian MD, PhD15; Liu, Li'an MD, PhD16; Wang, Linpeng MD17; Lv, Xiaoying MD2; Yang, Xiaofang MD, PhD18; Liu, Yan MD19; Sun, Yuanjie MD1; Wang, Yang MD, PhD1; Qin, Zongshi MD1; Zhou, Jing MD, PhD1; Liu, Zhishun MD, PhD1

Author Information
The American Journal of Gastroenterology: May 2021 - Volume 116 - Issue 5 - p 1024-1035
doi: 10.14309/ajg.0000000000001050

Abstract

INTRODUCTION

Chronic constipation is a disorder characterized by infrequent bowel movements, hard stools, excessive straining, and abdominal bloating or pain for no less than 3 months. It affects around 16% of the global population (1) and accounts for most clinic visits for functional gastrointestinal disorders (2). Severe chronic constipation (SCC), which features ≤2 complete spontaneous bowel movements (CSBMs) per week (3–5), is associated with decreased quality of life at a degree comparable with hypertension, diabetes, heart disease, or depression (6). Nearly 50% of patients are not completely satisfied with conventional treatments (7,8), and patients with SCC respond poorly to laxatives, since they do not address the underlying pathophysiology of constipation and may not relieve associated symptoms other than infrequent defecation (9).

Prucalopride, a high-affinity selective 5-hydroxytryptamine 4 receptor (5-HT4) agonist with potent enterokinetic effects, can accelerate gastric emptying, induce giant migrating contractions, and promote proximal colonic motility in both healthy volunteers (10,11) and patients with SCC (3–5,12). Originally recommended by the World Gastroenterology Organization, prucalopride has now been approved by the European Medicines Agency and the US Food and Drug Administration (FDA) for the treatment of SCC. Among the available drugs for constipation, prucalopride is the most effective treatment at 12 weeks to achieve ≥3 CSBMs per week or an increase of ≥1 CSBM per week for the treatment of SCC in adults in whom laxatives failed to provide adequate relief (13). Nonetheless, prucalopride causes nausea (13.6%), diarrhea (11.8%), abdominal pain (13.7%), and headache (17.5%) (14,15).

Acupuncture has been used for various gastrointestinal disorders, especially in eastern Asian countries. Findings from various meta-analyses indicated that acupuncture might be effective for chronic constipation (16,17). Our previous trial indicated that 8-week electroacupuncture treatment was superior to sham electroacupuncture in increasing CSBMs in patients with SCC (18) with an excellent safety profile and sustainable effects (19). As to the comparison of acupuncture with medical therapies for chronic constipation, the results were inconclusive based on the limited research evidence (17,20). This study aimed to investigate the effectiveness and safety of electroacupuncture compared with prucalopride. Our hypothesis is that electroacupuncture is noninferior to prucalopride in increasing the proportion of participants with ≥3 mean weekly CSBMs over weeks 3–8.

METHODS

Study design

We conducted a randomized, noninferiority trial (NCT02047045) at 14 hospitals in China between April 2014 and August 2016 (Figure 1). The study protocol was approved by the institutional review board at each site, and participants signed informed consent before study participation. The trial was performed according to the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice E6 Guidance for Good Clinical Practice.

Figure 1.
Figure 1.:
Study design.

Study population

Participants were recruited through posters, hospital websites, newspapers, and advertisements from communities. At their first visit, participants were informed that they would receive either electroacupuncture or prucalopride at an equal chance of 50%, if eligible; they could withdraw from the trial at any time. Eligible participants were diagnosed with functional constipation according to the Rome III diagnostic criteria (21) and had fewer than 3 defecations per week for the last 3 months with symptom onset at least 6 months. Physicians in the gastroenterology or anorectal departments were responsible for the diagnosis.

Additional inclusion criteria included age between 18 and 75 years, diagnosis of SCC which was defined as ≤2 mean weekly CSBMs in the past 3 months and during 2-week run-in period, and unsatisfactory response to laxatives (3–5). A CSBM was defined as a spontaneous bowel movement (SBM, a bowel movement without aid in the previous 24 hours) with complete evacuation sensation. Main exclusion criteria were irritable bowel syndrome (IBS); constipation secondary to organic diseases, endocrine, metabolic, nervous, postoperative disorders, or drugs; over 1 mushy or watery stool during run-in period; or severe cardiovascular disease (see Supplementary Digital Content 1, http://links.lww.com/AJG/B773). A thorough history and physical examination (including digital rectal examination when necessary) were performed to evaluate the patient's gastrointestinal symptoms, general health, psychological status, use of constipation medications, dietary fiber intake, and other relevant signs and symptoms. Routine chemistry, complete blood cell count, stool analyses, and fecal occult blood tests were performed in all patients; colonoscopy was performed only if alarm features or deemed necessary by the diagnosing physician.

Study treatment

After a 2-week run-in period, eligible participants were randomly assigned to receive either electroacupuncture or prucalopride with variable block sizes through a centralized web/phone randomization system using a 1:1 ratio and site as a stratification factor. An independent third party generated randomization sequences through PROC PLAN program of SAS 9.3 software. The outcome assessors, data managers, and statisticians were blinded to treatment allocation, while acupuncturists and participants were not.

All acupuncturists had an official license and at least 2-year clinical experiences. Participants in the electroacupuncture group received electroacupuncture at bilateral Tianshu (ST25), Fujie (SP14), and Shangjuxu (ST37). Bilateral Zhongliao (BL33) were used for severe straining (based on participants' complaints and stool diaries), and Baihui (DU20) and Shenting (DU24) for anxiety and depression symptoms (without psychiatry consultation), if any (22). Disposable stainless-steel needles (0.30 × 40 mm, 0.30 × 50 mm, and 0.30 × 75 mm, Huatuo, Suzhou Medical Appliance) and SDZ-V electric acupuncture apparatus (Huatuo, Suzhou Medical Appliance) were used. Acupuncture manipulation methods were presented in Supplementary Digital Content 1, http://links.lww.com/AJG/B773. Participants in the electroacupuncture group received a total of 28 sessions of treatments (30 min/session): 5 sessions per week in the first 2 weeks and 3 sessions (ideally every other day) per week in the following 6 weeks.

In the prucalopride group, participants took prucalopride succinate (Janssen Cilag S.p.A., Italy) orally 2 mg (1 tablet) per day before breakfast for 32 consecutive weeks. At week 8, electrocardiogram was performed; participants with significant electrocardiogram changes from baseline could stop prucalopride at any time.

During the study period, all participants maintained their routine diet and lifestyle. Participants were encouraged not to use additional medical therapy other than rescue medicine for constipation, and if used, they were required to make appropriate documentations. Participants with no bowel movements for ≥3 consecutive days could take 1–2 tablets (5–10 mg) of enteric-coated bisacodyl and/or use 110-mL glycerol enema with detailed documentations. However, rescue medicine was forbidden during 48 hours before and after the first treatment.

Assessments and outcomes

Similar to our previous trial (18), participants completed stool diaries (see Supplementary Digital Content 1, http://links.lww.com/AJG/B773) during the baseline assessment (run-in) period, weeks 1–2, 3–8, 11–12, 15–16, 19–20, and 31–32 and the Chinese-version Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire (23) at baseline, weeks 4 and 8.

The primary outcome was the proportion of participants with ≥3 mean weekly CSBMs over weeks 3–8. Weekly CSBMs and changes from baseline over weeks 3–8 were evaluated (post hoc). Overall CSBM responders (≥3 CSBMs/wk and ≥1 increase of CSBM from baseline simultaneously for at least 6 weeks) and sustained CSBM responders (meet the criteria for at least 3 of the last 4 weeks' treatment) during the 8-week treatment period were analyzed (post hoc) (24).

Secondary outcomes included: the proportion of participants with ≥3 mean weekly CSBMs over other assessment periods; proportion of participants with ≥1 increase in mean weekly CSBMs from baseline; the change from baseline in mean weekly CSBMs, mean weekly SBMs, and mean scores (0–3 indicating not difficult to very difficult) of straining for each SBM; proportions of participants using rescue medicine; changes from baseline in mean scores (1–7 indicating different stool types) of stool consistency for each SBM over weeks 1–2 and 3–8, rated by Bristol Stool Form Scale (25); time to the first CSBM, defined as days from after the first treatment till the occurrence of first CSBM without rescue medicine 48 hours before and after the first treatment; and change from baseline in the scores of PAC-QOL in weeks 4 and 8, with higher scores indicating poorer qualities of life and 0.5 as minimal clinically important differences (26).

Adverse events (AEs) were appropriately assessed, managed, and documented throughout the trial. Acupuncturists and physicians decided if the AEs were treatment-emergent AEs (TEAEs). Acceptance levels toward electroacupuncture were assessed within 5 minutes after the first and tenth treatment, with 0–4 indicating hardly to very acceptable. Compliance was assessed through counting acupuncture sessions received or prucalopride tablets administered (through deducting the number of recycled tablets).

Statistical analysis

The proportion of participants with ≥3 mean weekly CSBMs was 31.67% in the electroacupuncture group in our pilot study (27) and was 30.9% in the prucalopride group in a previous placebo-controlled trial (5). Calculated by PROC POWER in SAS, 560 participants were needed to provide 80% power to detect a difference of −10% (the noninferior margin) between groups in the proportion of participants with ≥3 mean weekly CSBMs over weeks 3–8 at a 1-sided significance level of 5% (28), assuming a 20% loss to follow-up rate. The difference between prucalopride and placebo in the proportions of participants with ≥3 mean weekly CSBMs was around 17.7%–23% in previous trials (4,5,29–31); hence, we set −10%, about half of that difference, as the noninferior margin.

Outcomes were evaluated based on the modified intention-to-treat population, defined as all randomized participants with baseline data. The primary outcome was also assessed based on the per-protocol (PP) population, defined as all randomized population without major protocol violations (see Supplementary Digital Content 1, http://links.lww.com/AJG/B773). The primary outcome was assessed using a 1-tailed test at a significance level of 0.025, while secondary outcomes using a 2-tailed test at a significant level of 0.05, with SAS software, version 9.4. For the proportion of participants with ≥3 mean weekly CSBMs and ≥1 increase in mean weekly CSBMs from baseline, the Cochran-Mantel-Haenszel test, stratified by site, was used to test a hierarchical comparison between 2 groups. For the proportions of overall CSBM responders and sustained CSBM responders over weeks 1–8, the χ2 test was used. For the change from baseline in mean weekly CSBMs and SBMs, a repeated-measures analysis of variance was used, setting group, time, and the interaction between group and time as fixed effects, and baseline CSBMs/SBMs and usage of rescue medicine as covariates. For the change in mean scores of PAC-QOL between groups, the t test was used. For the mean scores of straining and stool consistency, mean dosage of rescue medicine used per week and the time (days) to the first CSBM after treatment, the Wilcoxon rank-sum test was used. The proportions of participants using rescue medicine between groups were compared using χ2 tests. The numbers and proportions of participants with AEs between groups were described and evaluated with the χ2 test.

Missing data for the primary outcome were imputed using the multiple imputation method under the missing at random assumption (32). The results for the PP set were used as the sensitivity analysis. For secondary outcomes, no imputation was used.

This study was approved by the institutional review board of Guang'anmen Hospital, China Academy of Chinese Medical Sciences (2013EC124-01), and then was approved by the ethics committees of all the other 13 centers, including institutional review board of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (ECPJ-BDY-2014-06), Clinical Trials and Biomedical Ethics Committee of West China Hospital of Sichuan University (2014 Clinical Trial [listed] Review No 8), Medical Ethics Committee of the Third Affiliated Hospital of Zhejiang Chinese Medical University (ZSLL-KY-2014-001), Ethics Committee of Hengyang Hospital Affiliated to Hunan University of Chinese Medicine (EC-AF-2014002), Ethics Committee of Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University (2014BL-034-02), Ethics Committee of the Affiliated Hospital of Shandong University of TCM ([2014] Ethical Review No [020]-KY), Ethics Committee of the First Hospital of Hunan University of Chinese Medicine (HN-LL-KY-2014-001-01), Ethics Committee of Hubei Province Hospital of Traditional Chinese Medicine (HBZY2014-C005-01), Ethics Committee of Jiangsu Province Hospital of Traditional Chinese Medicine (2014NL-044-02), Ethics Committee of Shaanxi Province Hospital of Traditional Chinese Medicine ([2014] Ethical Review No [03]), Ethics Committee of Hiser Medical Group (2014-1-2), and Institutional Ethics Committee of Guangdong Province Hospital of Traditional Chinese Medicine (B2014-010-02) (see Supplementary Digital Content 3, http://links.lww.com/AJG/B775). All participants gave written informed consent.

RESULTS

Populations and baseline characteristics

Among 799 participants screened, 560 (280 in each group) were randomized (Figure 2). A total of 33 (5.89%) participants dropped out: 5 (electroacupuncture, n = 3; prucalopride, n = 2) withdrew informed consents and had no baseline data and 28 participants (electroacupuncture, n = 12; prucalopride, n = 16) dropped out after baseline assessment. Proportions of participants who completed ≥80% treatment were similar between groups (electroacupuncture vs prucalopride: 93.50% [259/277] vs 91.01% [253/278], P = 0.272). For the primary outcome, diary data were imputed in 3.62% and 5.40% of the participants in the electroacupuncture and prucalopride groups; 94.6% and 93.53% of the participants in the electroacupuncture and prucalopride groups completed stool diaries throughout 34 weeks; 94.6% participants considered electroacupuncture treatment acceptable (see Appendix Table 6, Supplementary Digital Content 2, http://links.lww.com/AJG/B774). Baseline characteristics were similar between groups (Table 1).

Figure 2.
Figure 2.:
Trial flowchart. MITT set was defined as all the randomized participants with baseline data; PP set was composed of the intention-to-treat population without major protocol violations; *2 of the 6 participants dropped out completed stool diary in week 3. †Participants in the prucalopride group were administrated prucalopride for additional 24 weeks. MITT, modified intention-to-treat; PP, per-protocol.
Table 1.
Table 1.:
Baseline characteristicsa

Treatment outcomes

The proportion of participants with ≥3 mean weekly CSBMs over weeks 3–8 was 36.2% in the electroacupuncture group vs 37.8% in the prucalopride group (difference: −1.6%; 95% confidence interval [CI], −8% to 4.7%, P < 0.001 for noninferiority; 90% CI, −6.6% to 3.3%); similar results were found in the PP population (difference −0.15%; 95% CI, −6.52% to 6.21%, P < 0.001 for noninferiority; 90% CI, −5.10% to 4.80%). The differences were within the prespecified noninferiority margin of −10%, demonstrating the noninferiority of electroacupuncture to prucalopride (Figure 3a, see Appendix Table 1, Supplementary Digital Content 2, http://links.lww.com/AJG/B774). The changes from baseline in mean weekly CSBMs over weeks 3–8 were 1.96 in the electroacupuncture group and 1.97 in the prucalopride group (difference: −0.01; 95% CI, −0.17 to 0.15, P = 0.910). No between-group differences were found in the proportions of overall CSBM responders (electroacupuncture vs prucalopride: 24.91% vs 25.54%, difference: −0.63% [95% CI, −7.86% to 6.60%], P = 0.864, see Appendix Table 2, Supplementary Digital Content 2, http://links.lww.com/AJG/B774) or the proportions of sustained CSBM responders (electroacupuncture vs prucalopride: 24.91% vs 24.46%, difference: 0.45% [95% CI, −6.73% to 7.62], P = 0.902 (see Appendix Table 3, Supplementary Digital Content 2, http://links.lww.com/AJG/B774).

Figure 3.
Figure 3.:
Primary outcome and the weekly CSBMs. (a) Between-group difference of the proportion of participants with ≥3 mean weekly CSBMs over weeks 3–8. The plot showed the proportion of participants with ≥3 mean weekly CSBMs over weeks 3–8 in the electroacupuncture and prucalopride groups in analysis of the MITT population and PP population. To test noninferiority, 95% CIs were calculated (as shown in dotted line), and 90% CIs were also provided (as shown in full line). CIs in gray areas are noninferior with −10% points as noninferior margin (as shown as Δ). The exact numbers of the primary outcome were shown in Appendix Table 1 (see Supplemental Digital Content 2, http://links.lww.com/AJG/B774). (b) Weekly CSBMs during the whole study period. Data are observed values of weekly CSBMs with error bars representing 95% CI. The electroacupuncture group experienced >2 weekly CSBMs through weeks 3–32, and the prucalopride group experienced >2 mean weekly CSBMs through weeks 1–32. For the group difference of weekly CSBMs through week −2 to 32, a repeated-measures analysis of variance was used, setting group, time, and the interaction of group and time as the fixed effects; besides, the baseline CSBM data and usage of rescue medicine were set as covariates. No significant differences between the 2 groups in weeks 5, 6, 11, 12, 15, 16, 20, 31, and 32 were found. *Two of the 6 participants dropped out completed stool diary in week 3. CSBMs, complete spontaneous bowel movements; CI, confidence interval; MITT, modified intention-to-treat; PP, per-protocol.

In the electroacupuncture group, the number of weekly CSBMs increased gradually, reached >2 at week 3, peaked at week 8, and remained above 2 during the 24-week follow-up period. Notably, the mean weekly CSBMs with electroacupuncture was significantly higher than prucalopride in weeks 7 and 8 (P < 0.05 for both, see Appendix Table 4, Supplementary Digital Content 2, http://links.lww.com/AJG/B774). The therapeutic effects (weekly CSBMs>2) of prucalopride began at week 1 and remained stable throughout the 32-week period (Figure 3b).

The prucalopride group had significantly better results in the majority of secondary outcomes over weeks 1–2, including the proportion of participants with ≥3 mean weekly CSBMs, the proportion of participants with ≥1 increase in mean weekly CSBMs, change from baseline in mean weekly CSBMs, and mean score for straining and stool consistency. Prucalopride also showed better results in mean weekly SBMs across all assessment periods and the proportions of participants using rescue medicine over weeks 1–2 and weeks 19–20 (Table 2).

Table 2.
Table 2.:
Secondary outcomesa
Table 2-A.
Table 2-A.:
Secondary outcomesa

Adverse Events

AEs occurred less frequently in the electroacupuncture group (49/277, 17.69%) than the prucalopride group (123/278, 44.24%). Common TEAEs were hematoma around the needling site (16.61%) in the electroacupuncture group and abdominal pain (13.67%), diarrhea (12.95%), and headache (12.23%) in the prucalopride group. No major electrocardiograph changes occurred at week 8 in participants taking prucalopride (Table 3). One non-treatment-related serious AE (myocardial infarction) was reported in the electroacupuncture group (see Appendix Table 5, Supplementary Digital Content 2, http://links.lww.com/AJG/B774).

Table 3.
Table 3.:
Treatment-emergent AEsa

DISCUSSION

This trial provided the first large scale, rigorously designed, head-to-head comparison between electroacupuncture and prucalopride in patients with SCC. In this trial, electroacupuncture was noninferior to prucalopride for increasing the proportion of participants with ≥3 mean weekly CSBMs over weeks 3–8, but with sustained effects and a better safety profile.

This trial used a clinically meaningful outcome measurement of CSBM as primary outcome. Although the diagnosis of constipation is based on <3 defecations (SBMs in Rome IV) per week in Rome III, CSBM may be a better measure of constipation (33), especially for patients with SCC. CSBM identifies bowel movements that fully relieves the subjective discomfort of constipation on top of the objective measure of bowel movement frequency (5,24). Three CSBMs per week is regarded as normalization of bowel function. Reasonably, overall CSBM responder has been recommended by the US FDA as the primary efficacy endpoint in clinical trials for chronic idiopathic constipation (14). Other strengths of this trial include a design based on our previous trial, a prespecific protocol, and high compliance and low drop-out rates.

Electroacupuncture could improve gastrointestinal motility, promote contractility of distal colon, and accelerate whole gut transit in both healthy and constipated rats (34,35). Acupuncture may not only regenerate the lost enteric neurons and regulate the inhibitory and excitatory activities in the enteric nervous system (36,37) but also modulate serum motilin, ghrelin, gastrin, and bile acid levels (38). To investigate the mechanism of the sustaining effects of acupuncture, functional magnetic resonance imaging studies were performed in healthy adults (39,40). Acupuncture could induce sustained increase or decrease in the connectivity of different parts of the brain default mode network (39), gradually increased centrality in parahippocampal and middle temporal gyri; these effects were sustained during follow-up (40). In addition, MacPherson et al. (41) found that enhanced self-efficacy may partially explain the long-term benefits of acupuncture.

Prucalopride is the only available highly selective prokinetic agents for the treatment of SCC with strong evidence support; its use in SCC has now been approved by both the European Medicines Agency and the US FDA. Prucalopride can help regain normal bowel function, increase 1 or more CSBMs/wk from baseline, and decrease symptoms and improve quality of life in patients with SCC who were unsatisfactory to laxatives (3–5). In this study, the overall CSBM responder was 25.54% with prucalopride, within the range of 11%–28% reported in previous trials (14); 44.24% of the participants in the prucalopride group reported TEAEs, within the range of 35.9%–57.2% reported in the Asia-specific population (30,42).

The present trial also demonstrated some unique properties of electroacupuncture and prucalopride. With a better safety profile, the effects of electroacupuncture accumulated with treatment sessions, temporarily exceeded prucalopride at weeks 6–8, peaked at week 8, and remained at a similar level to prucalopride through the follow-up period, whereas prucalopride had rapid onset: Its effects occurred in the first 2 weeks and remained stable throughout the trial with 2-mg once-daily administration (Figure 3b). As for the stable sustained effects of electroacupuncture on SCC, the proportions of participants with ≥3 CSBMs/wk in this study were 36.2% during treatment and 37.6% during follow-up; these results were consistent with our previous trial (31.3% and 37.7% over treatment and follow-up periods) (18). Electroacupuncture was comparable with prucalopride in increasing CSBMs, but also improving quality of life, and relieving discomforts such as straining in SCC. In a recent trial comparing acupuncture vs medical therapies in patients with IBS, Pei et al. (43) found that acupuncture may be more effective in relieving symptoms of IBS as a whole; however, for the IBS-constipation subtype, no difference was detected between acupuncture and the osmotic laxative of polyethylene glycol, the first-line therapy recommended for constipation by American Gastroenterological Association (44). These results lend further support to the findings of the present noninferiority trial of acupuncture vs a pharmaceutic agent, although the 2 trials differ in study disease and stimulus procedure. However, Pei et al. (43) evaluated the primary outcome by IBS Symptom Severity Score on the domains of abdominal pain, distention, subjective satisfaction with bowel habits, and general well-being (45), whereas the effects of acupuncture on the characteristic features of constipation, such as defecation frequency, complete evacuation sensation, stool consistency, and excessive straining, were not assessed. In addition, polyethylene glycol was administered for 6 weeks, while prucalopride was taken for 32 consecutive weeks in this study, in which condition the sustained effects of acupuncture after the completion of the treatment can be compared with the effects of prucalopride on continuous medication directly. The trial by Pei et al. (43) used manual acupuncture, whereas the present trial used electroacupuncture. By attaching a microcurrent close to the bioelectricity of the human body on the needle, electroacupuncture combines electric stimulation with manual acupuncture and thus poses additional properties of transcutaneous neuromodulation, which were reported to reduce colonic transit time (46). Overall, our trial indicates that electroacupuncture can serve as a promising alternative for the management of SCC.

Notably, electroacupuncture might function well to relieve the incomplete evacuation sensation in SCC. Although, during weeks 3–32, electroacupuncture largely differs from prucalopride in the change from baseline in mean weekly SBMs (difference range: −0.47 to −0.74); this difference became dismal for the change from baseline in mean weekly CSBMs (SBMs with complete evacuation sensation; difference range: −0.01 to −0.14). Subjective feelings are a major component of CSBM and participants in the present trial were not blinded. Consequently, the relief from complete evacuation sensation might be due to nonspecific effects of acupuncture, such as intense patient-practitioner interactions and greater expectations from acupuncture treatment (47,48). However, unlike pharmaceutical agents, in which the material entity can be physically separated from other aspects of the intervention and is often causally responsible for the outcome, the nonspecific effects of procedural interventions such as acupuncture are intertwined with and integral to the their characteristic effects (48). In addition, Zhongliao (BL33), which locates in the S3 foramina (22), was used for patients with severe straining. This could possibly stimulate the autonomic fibers from the pelvic nerves (49), conferring the complete evacuation sensation increasing CSBMs. Maeda et al. (50) reported that sacral neuromodulation provided long-term relief for intractable constipation in a small number of patients.

As for limitations of the trial, first, using Rome III criteria to differentiate IBS from functional constipation in patients taking laxatives was remarkably difficult (21,51) and some participants in the trial might actually have IBS. Second, the subtypes of normal-transit, slow-transit, or evacuation disorder were not differentiated and certain type(s) may have preferential responses to electroacupuncture. Third, a widely accepted noninferiority margin for SCC in clinical trials remains to be established. Forth, participants and clinicians were not blinded. However, a large bias is not possible attached to our result since the primary outcome of bowel movement frequency was objective, although the bias to the subjective outcome of complete evacuation sensation cannot be completely ruled out. Fifth, previous treatment history was limited to 2 weeks before the run-in period, and history of acupuncture treatment was unknown. Previous acupuncture exposure can influence the blinding process (52), which is not applicable in this trial. However, it might also impact the magnitude of placebo effects by influencing participants' expectations and beliefs. Procedural interventions such as acupuncture may have enhanced placebo effects compared with pharmaceuticals (53); thus, sixth, the degree to which participants' expectations and beliefs interfere with the results was not evaluated. Seventh, the 28 sessions of electroacupuncture might be burdensome for some patients.

In conclusion, electroacupuncture was noninferior to prucalopride in increasing the proportion of participants ≥3 CSBMs/wk over weeks 3–8, but with a better safety profile. Electroacupuncture and prucalopride had similar effects in relieving discomforts and improving quality of life in patients with SCC. The effects of electroacupuncture could accumulate with 8-week treatments and sustain for 24 weeks after treatment. Electroacupuncture provides a promising noninferior alternative for SCC.

Data sharing study protocol, informed consent form, and statistical analysis plan are in the supplementary digital files ( see Supplementary Digital Content 1, http://links.lww.com/AJG/B773). For statistical code and data sets, proposals should be directed to [email protected], and requestors need to sign a data access agreement, if approved. The data will be available with publication in the next 6 months.

CONFLICTS OF INTEREST

Guarantor of the article: Baoyan Liu, MD, and Zhishun Liu, MD, PhD.

Specific author contributions: B.L. and Z.L. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Z.L. Acquisition, analysis, or interpretation of data: B.L., J.Wu, S.Y., L.H., X.L., J.F., W.F., N.L., T.S., J.S., J.Wang, Z.Y., H.Z., W.Z., J.Z., Z.Z., L.L., L.W., Y.L., Y.W., Z.Q., J.Z., Y.S., H.S., and X.Y. Drafting of the manuscript: J.Wu, Z.L., S.Y., Y.S., and K.Z. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: S.Y. Obtained funding: B.L. and Z.L. Administrative, technical, or material support: B.L., J.Wu, S.Y., L.H., J.F., W.F., N.L., T.S., J.S., J.Wang., Z.Y., H.Z., W.Z., J.Z., Z.Z., L.L., L.W., X.L., Y.L., Y.W., J.Z., Z.Q., H.S., and X.Y. Supervision: B.L. and Z.L. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. All authors have read and approved the final draft of the manuscript.

Financial support: This study was supported and funded by the Twelfth Five-Year National Science and Technology Pillar Program (grant 2012BAI24B01) from the Ministry of Science and Technology of the People's Republic of China. The funder of the study had no role in the design and conduct of study, the collection, analysis and interpretation of data, or writing of the report. The corresponding author had full access to all data in the study and the final responsibility for the decision to submit for publication.

Potential competing interests: None to report.

Study Highlights

WHAT IS KNOWN

  • ✓ Severe chronic constipation (SCC) is associated with decreased colonic motility and transit and responds poorly to laxatives.
  • ✓ Prucalopride is a novel gastrointestinal prokinetic agent recommended for SCC, but side effects including gastrointestinal symptoms and headaches are common.
  • ✓ Electroacupuncture has proven efficacy for SCC with an excellent safety profile and sustainable effects.
  • ✓ The benefits of electroacupuncture as compared to prucalopride remained unknown.

WHAT IS NEW HERE

  • ✓ Electroacupuncture was noninferior to prucalopride in increasing the proportion of participants with ≥3 mean weekly CSBMs over weeks 3–8.
  • ✓ Electroacupuncture and prucalopride had similar effects in improving gastrointestinal discomforts and quality of life of SCC.
  • ✓ AEs were less frequent with electroacupuncture than prucalopride.
  • ✓ The effects of electroacupuncture could sustain 24 weeks after 8 weeks' treatment.
  • ✓ Effects of electroacupuncture were slower onset as compared with prucalopride.

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