Nocturnal enuresis (NE) is a worldwide health problem frequently encountered in childhood and is defined as an involuntary voiding of urine during sleep with a frequency of at least twice a week in children, in the absence of congenital or acquired defects of the central nervous system [
Current first-line nocturnal enuresis therapies center on the aforementioned mechanisms; generally accepted treatments are oral pharmacological therapies including desmopressin, tricyclics, or oxybutynin and behavioral therapies [
Complementary and alternative medicine (CAM) is widely advocated to face the increasing demand for nonpharmacological approaches. As a mainstream CAM therapy, acupuncture treatment based on TCM theory has been commonly used to treat nocturnal enuresis in Chinese cultures. Compared to conventional care, its safety and cost effectiveness assure the maintenance of patients’ compliance. Unfortunately, there is little published information to warrant acupuncture therapy as standard treatment of nocturnal enuresis. The aim of this review is to evaluate the efficacy of acupuncture therapy in the treatment of nocturnal enuresis when compared with placebo acupuncture or oral pharmacological treatment based on randomized controlled trials (RCTs).
A comprehensive literature search of the Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Review (CDSR), EMBASE, ISI Web of Science, and PubMed was conducted. We also searched Chinese databases, including China Knowledge Resource Integrated database (CNKI), WanFang Data, VIP, and Chinese Biomedical (CBM) Literature database. In addition, we searched databases that contained registered trials, such as ClinicalTrials.gov (
Inclusion criteria are as follows: (1) research subjects: the enrolled patients had to be diagnosed with NE and no restrictions on race, age, or sex were imposed; (2) study design: the included studies were required to be RCTs in Chinese or English aiming to assess the efficacy of acupuncture therapy for NE; (3) experimental group interventions: experimental group mainly received acupuncture therapy (including needles, moxibustion, acupressure, electroacupuncture, and acupoint injection, among other techniques), either alone or in conjunction with another kind of acupuncture therapy, without differentiating different acupuncture therapy techniques, acupoints selection, or needle materials; (4) control group interventions: control interventions included placebo acupuncture or oral pharmacological treatment; (5) outcome measurements: the outcome measurement had to include overall clinical efficacy, number of wet nights per week, or maximum voided volume.
Exclusion criteria included the following: (1) articles regarding animal experiments, review articles, case reports, or expert experience reports; (2) nonrandomized studies; (3) studies that compared different acupuncture modalities or acupoints selection; (4) experimental groups that accepted complex therapy, while the contributing factor could not be distinguished; (5) studies that were duplicates for retrieving or publishing.
Two reviewers (Zheng-tao Lv and Wen Song) reviewed each article independently and were blinded to the findings of the other reviewer. In accordance with the predetermined inclusion criteria, two reviewers independently performed a rigorous screening to identify qualified articles, and they extracted data independently from these articles using a standardized collection form, which includes first author, year of the study, sample size, nation or region, baseline characteristics, methodological features of the studies, quality of trial design, interventions, main outcome assessments, follow-up time, and withdrawal. If the required information was not available in the included studies, we contacted the original authors by email. Any discrepancies between reviewers were resolved through discussion until a consensus was reached. The third review author (Man Li) was consulted if a consensus could not be reached.
The methodological quality of the included trials was evaluated using the Jadad quality scale [
The meta-analysis and statistical analysis were performed by using RevMan 5.1 analyses software of the Cochrane Collaboration. We extrapolated the odds ratio (OR) and the associated 95% confidence interval (CI) for treatment effect. The chi-squared test and the Higgins
An initial search of RCTs yielded 3580 potential literature citations, including 346 English studies and 3134 Chinese studies, and 1936 duplicated articles were deleted. After screening titles and abstracts, 61 potentially relevant studies were selected and retrieved for a full-text assessment. Of the remaining 61 studies, 17 studies were excluded because they were not RCTs; 6 articles were duplicates; 7 studies took unsuitable intervention; 6 studies accept the complex therapy, for example, combination of two different kinds of acupuncture therapy; 4 studies did not report the suitable outcome. Finally, 21 studies meet our inclusion criteria [
Flowchart of the literature search and study selection.
The characteristics of the 21 trials are summarized in Table
Characteristics and methodological quality of included studies.
Study | Study design | Sample size ( |
Nation/region | Age (mean or range) | Baseline | EC approval | Jadad score |
---|---|---|---|---|---|---|---|
Dong et al., 2012 [ |
RCT, parallel 2 arms | 120 (60/60) | China | E: 8.61 (5~12) years |
Adequate | Not reported | 1 |
Hong et al., 2011 [ |
RCT, parallel 3 arms | 99 (33/33/33) | China | 5~13 years | Adequate | Not reported | 2 |
Hui et al., 2006 [ |
RCT, parallel 2 arms | 67 (35/32) | China | E: 5~12 years |
Adequate | Not reported | 2 |
Liu, 2007 [ |
RCT, parallel 2 arms | 60 (30/30) | China | 5~12 years | Not reported | Not reported | 1 |
Karaman et al., 2011 [ |
RCT, parallel 2 arms Prospective, randomized, placebo controlled, single-blind study | 83 (57/26) | Turkey | E: 8.5 ± 3.2 years |
Adequate | Yes | 3 |
Ding et al., 2007 [ |
RCT, parallel 2 arms | 80 (42/38) | China | 3~13 years | Adequate | Not reported | 1 |
Tong and Zhan, 2009 [ |
RCT, parallel 2 arms | 60 (30/30) | Guinea-Bissau | 6~20 years | Adequate | Not reported | 2 |
Moursy et al., 2014 [ |
RCT, parallel 3 arms | 186 (62/62/62) | Egypt | 15.7 years (range 10–21 years) | Adequate | Yes | 3 |
Tian and Zhong, 2008 [ |
RCT, parallel 2 arms | 228 (116/112) | China | E: 7.58 ± 2.16 years |
Adequate | Not reported | 3 |
Ling and Chen, 2011 [ |
RCT, parallel 2 arms | 60 (30/30) | China | E: 9.2 (5~16) years |
Adequate | Not reported | 2 |
Radmayr et al., 2001 [ |
RCT, parallel 2 arms | 40 (20/20) | Austria | E: 8.6 (5~16) years |
Adequate | Yes | 2 |
Radvanska et al., 2011 [ |
RCT, parallel 2 arms Prospective, single-blind, randomized, placebo controlled design | 29 (16/13) | Slovakia | E: 8.7 ± 1.4 years |
Adequate | Yes | 4 |
Yang et al., 2012 [ |
RCT, parallel 2 arms | 69 (35/34) | China | 3~15 years | Adequate | Not reported | 1 |
Luo, 2010 [ |
RCT, parallel 2 arms | 40 (20/20) | China | E: 8.5 ± 0.1 years |
Adequate | Not reported | 1 |
Tang et al., 2012 [ |
RCT, parallel 2 arms | 48 (24/24) | China | E: 5~11 years |
Adequate | Not reported | 2 |
Qiu, 2008 [ |
RCT, parallel 2 arms | 56 (31/25) | China | 3~16 years | Not reported | Not reported | 1 |
Zhu et al., 2003 [ |
RCT, parallel 2 arms | 76 (41/35) | China | 4~15 years | Adequate | Not reported | 1 |
Zhang, 2010 [ |
RCT, parallel 2 arms | 80 (40/40) | China | 3~18 years | Adequate | Not reported | 1 |
Chen and Gu, 2003 [ |
RCT, parallel 2 arms | 72 (40/32) | China | 5~14 years | Adequate | Not reported | 1 |
Yuksek et al., 2003 [ |
RCT, parallel 2 arms | 24 (12/12) | Turkey | E: 7.67 ± 2.34 years |
Adequate | No | 1 |
Hong and Zhang, 2009 [ |
RCT, parallel 2 arms | 30 (15/15) | China | 8~21 years | Adequate | Not reported | 1 |
Interventions and outcomes of included studies.
Study | Duration of treatment | Follow-up after treatment | Experimental treatment | Control treatment | Cure rate of intervention group | Cure rate of control group | Outcome measurement |
---|---|---|---|---|---|---|---|
Dong et al., 2012 [ |
5 weeks | 6 months | Acupoint injection with scraping therapy ( |
Western medicine: Meclofenoxate ( |
46/60 (76.67%) | 36/60 (60%) | Cure rate, improvement rate, follow-up at 1 and 6 months |
|
|||||||
Hong et al., 2011 [ |
1 month | Not reported | Moxibustion ( |
Chinese patent medicine ( |
20/33 (60.6%) |
8/33 (24.24%) | Cure rate, improvement rate |
|
|||||||
Hui et al., 2006 [ |
1 month | 1 year | Heat-producing needling ( |
Western medicine: imipramine hydrochloride ( |
20/35 (57.2%) | 14/32 (43.8%) | Cure rate, total effective rate, follow-up at 1 month |
|
|||||||
Liu, 2007 [ |
3 weeks | Not reported | Enuresis patch ( |
Western medicine: Meclofenoxate ( |
18/30 (60%) | 9/30 (30%) | Cure rate, improvement rate |
|
|||||||
Karaman et al., 2011 [ |
4 weeks | 6 months | Laser acupuncture ( |
Placebo therapy: with a nonlaser light source ( |
31/57 (54.4%) | 3/26 (11.5%) | Complete improvement rate, partial improvement rate, mean number of weekly bedwetting episodes: the children were reevaluated 15, 30, 90, and 180 days after treatment |
|
|||||||
Ding et al., 2007 [ |
1 month | 3 months | Enuresis patch ( |
Western medicine: Meclofenoxate ( |
25/42 (59.5%) | 13/38 (34.2%) | Cure rate, improvement rate |
|
|||||||
Tong and Zhan, 2009 [ |
1 month | Not reported | Suspended moxibustion ( |
Chinese patent medicine ( |
17/30 (56.7%) | 10/30 (33.3%) | Cure rate, improvement rate |
|
|||||||
Moursy et al., 2014 [ |
3 months | 6 months | Laser acupuncture ( |
Western medicine: desmopressin ( |
33 /62 (53%) | 35/62 (56.5%) |
Cure rate, improvement rate, mean weekly number of wet nights, MVV (maximum voided volume): the patients were evaluated once every 2 weeks for 3 months and once every 4 weeks for 6 months |
|
|||||||
Tian and Zhong, 2008 [ |
2 weeks | Not reported | Acupuncture ( |
Chinese patent medicine ( |
61/116 (52.59%) | 47/112 (41.96%) | Cure rate, improvement rate |
|
|||||||
Ling and Chen, 2011 [ |
1 month | Not reported | Acupoint injection ( |
Chinese patent medicine ( |
18/30 (60%) | 15/30 (50%) | Cure rate, improvement rate |
|
|||||||
Radmayr et al., 2001 [ |
6 months | Not reported | Laser Acupuncture ( |
Western medicine: desmopressin ( |
13/20 (65%) | 15/20 (75%) | Response rate, partial response rate |
|
|||||||
Radvanska et al., 2011 [ |
5 weeks | Not reported | Laser acupuncture ( |
Placebo therapy: without active laser light but with or without skin contact ( |
Not reported | not reported | Wet nights/wk, voiding frequency, nocturnal urine production on wet nights |
|
|||||||
Yang et al., 2012 [ |
1 month | Not reported | Ear point tapping with medicinal cake-separated moxibustion ( |
Chinese patent medicine ( |
21/35 (60%) | 12/34 (35.3%) | Cure rate, improvement rate |
|
|||||||
Luo, 2010 [ |
3 months | Not reported | Acupuncture-massage ( |
Chinese medicine ( |
14/20 (70%) | 4/20 (20%) | Cure rate, improvement rate |
|
|||||||
Tang et al., 2012 [ |
2 weeks | 1 month | Massage ( |
Chinese medicine ( |
16/24 (66.7%) | 11/24 (45.8%) | Cure rate, improvement rate |
|
|||||||
Qiu, 2008 [ |
1 month | Not reported | Ear point tapping ( |
Chinese medicine ( |
17/31 (54.8%) | 15/25 (60%) | Cure rate, improvement rate |
|
|||||||
Zhu et al., 2003 [ |
3 weeks | 3 months | Acupoint injection ( |
Western medicine: Meclofenoxate ( |
19/41 (46.5%) | 6/35 (17.1%) | Cure rate, improvement rate |
|
|||||||
Zhang, 2010 [ |
1 month | Not reported | Medicinal cake-separated moxibustion with embedded needling ( |
Western medicine: desmopressin ( |
22/40 (55%) | 6/40 (15%) | Cure rate, improvement rate |
|
|||||||
Chen and Gu, 2003 [ |
2 weeks | Not reported | Acupoint injection ( |
Chinese medicine ( |
36/40 (90%) | 14/32 (43.7%) | Cure rate, improvement rate |
|
|||||||
Yuksek et al., 2003 [ |
6 months | Not reported | Acupressure ( |
Western medicine: oxybutynin ( |
10/12 (83.3%) | 7/12 (58.3%) | Complete improvement rate, partial improvement rate, follow-up at 15 days and 1, 3, and 6 months |
|
|||||||
Hong and Zhang, 2009 [ |
1 month | Not reported | Needle warming moxibustion ( |
Chinese medicine ( |
13/15 (86.7%) | 5/15 (33.3%) | Cure rate, improvement rate |
The mean Jadad score of these 21 studies was 1.7, ranging from 1 to 4 points (Table
The 21 included RCTs adopted in consistent interventions and different reported outcomes, with no unified efficacy standard. To reach a consistent understanding of the therapeutic effect of acupuncture therapy for nocturnal enuresis, intervention therapies for control group were further refined. We limited the control group methods to western or traditional Chinese medicine alone, as two studies used placebo treatment or sham-acupuncture as control group [
Three studies reported mean weekly number of wet nights [
The results of heterogeneity tests indicated that
Forest plot of comparison: the clinical effective rate.
Our meta-analysis of ten studies [
The same findings applied to other ten studies [
A subgroup analysis was conducted to further evaluate the clinical effect of acupuncture therapy and identify the heterogeneity within western medicine group. The western medicine group was divided into four groups according to the medication types. Four studies used Meclofenoxate as control intervention [
Subgroup analysis: acupuncture therapy versus Meclofenoxate.
Subgroup analysis: acupuncture therapy versus desmopressin.
Two studies used placebo treatment or sham-acupuncture as control group [
Three studies reported mean weekly number of wet nights [
Two studies reported maximum voided volume (MVV) [
We conducted a funnel plot analysis of the aforementioned 19 studies [
Funnel plot of randomized controlled trials.
The present study analyzed data from 21 RCTs involving 1590 individuals that featured to assess the efficacy of acupuncture therapy to treat NE. Based on the findings in our systematic review and meta-analysis, acupuncture therapy can significantly improve the clinical efficacy in enuretic children when compared with placebo acupuncture or TCM. In contrast to western medicine, acupuncture therapy was more effective than Meclofenoxate. Conclusions regarding the safety of acupuncture therapy cannot be drawn due to the paucity of evidence provided by the included trials. However, the drawn conclusion should be interpreted cautiously owing to low methodological qualities of included studies.
The pathogenesis of nocturnal enuresis is multifactorial; several factors such as psychosocial, developmental, hormonal, and genetic factors have been proven to be involved in nocturnal enuresis. Nocturnal polyuria, nocturnal detrusor overactivity, and high arousal thresholds are main pathogenesis of NE. To date, increasing evidence suggests that all three mechanisms can be attributed to brainstem disturbance. The locus coeruleus (LC) has axonal connections with the hypothalamic cells that produce vasopressin and also plays an important role in arousal from sleep [
Acupuncture points were selected in order to influence the spinal micturition centers as well as the parasympathetic innervation to the urinary tract [
In TCM theory, the generation and discharge of urine are associated with lung, kidney, spleen, and bladder. The pathogenesis of nocturnal enuresis is Qi deficiency of lung, spleen, and kidney; bladder is not controlled by Qi as well. Through different forms of stimulation on meridian points or specific parts of body, imbalance and instability between Zangfu organs are corrected to improve symptoms of NE and maintain the stability of inner state [
In 2005, a systematic review reported that acupuncture in combination with another therapy could further significantly reduce the number of wet nights when compared to acupuncture therapy alone, and, regarding the comparison of acupuncture therapy with antidiuretic medication, the results showed that the outcome favored medication but was not significantly better than acupuncture therapy [
Based on the studies included in our meta-analysis, the methodological qualities were judged to be generally poor, which might limit the value of conclusions about clinical efficacy of acupuncture therapy for treating NE. The vast majority of the included trials failed to describe detailed information about randomization and allocation concealment. Lack of blinding procedures in RCTs can also exaggerate the conclusions of these trials. Further assessment of acupuncture therapy needs to be taken by large-scale clinical studies which employ rigorous methodologies.
The diagnosis and therapeutic evaluation standards employed by studies, that are performed in China, are mainly in accordance with “Standards for Diagnosis of Syndromes or Diseases of TCM and Evaluation of the Therapeutic Effect” issued by the State Administration of TCM in 1994 [
The utilization of different acupuncture techniques by different investigator can greatly affect curative effect of acupuncture therapy [
In contrast to TCM, acupuncture therapy could further improve the clinical effect in treating nocturnal children; no subgroup analysis was made in this group because the acupuncture modalities and Chinese medicine types varied from studies to studies. The data extracted from these studies suggested an overall efficacy trend; the standardization of acupuncture techniques is one problem to be solved in need. In the subgroup analysis conducted in western medicine group, acupuncture therapy was more effective than Meclofenoxate while no significant difference could be detected between acupuncture and imipramine hydrochloride, desmopressin, or oxybutynin. Types and doses of administered drugs might affect the results of experiment to a certain extent. Given that the evidence from China occupies a large proportion, further rigorous experiments within western context are required. Considering all these above factors, the appearance of heterogeneity could be reasonably explained.
The included studies in our systematic review comprise various methodological deficiencies, and the findings of the present review are somewhat limited due to low methodological qualities. Future randomized controlled trials should employ improved methodologies and reporting specifications as follows: (1) all clinical studies of acupuncture should be registered and comply with the revised standards for reporting interventions in clinical trials of acupuncture (STRICTA) [
In summary, the results of this study suggest that acupuncture therapy demonstrate better clinical efficacy than pharmacological treatment or placebo treatment in treating NE. Due to the low methodological qualities of included trials, the findings of current study should be interpreted with caution. Therefore, to further assess the potential beneficial effect of acupuncture therapy for NE, additional RCTs with rigorous experimental design, large-scale high quality methodological control, long follow-ups, and strict reporting specification are required.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Zheng-tao Lv and Wen Song contributed equally to this paper.
This work was supported by Grants from the National Natural Science Foundation of China (no. 81473768; no. 81101927) and Grants from Wuhan Science and Technology Bureau no. 2013060602010280.