Liu Hong-hua (劉紅華),Zhang Guo-shan (張國(guó)山),Liu Hui-juan (劉惠娟),LiDuo-duo(李朵朵),Liu M i(劉密),Chang Xiao-rong (常小榮),Liu Mai-lan (劉邁蘭)

Hunan University of ChineseMedicine,Changsha 410208,China

Abstract

Keywords:Acupuncture Therapy;Point Selection,Meridian;Point Selection Based on Syndrome Differentiation;Dyspepsia; Random ized Controlled Trial

Functional dyspepsia(FD)is a group of symptoms characterized by the main clinical manifestations of persistent or recurrent postprandial satiety, early satiety,upper abdominal pain and/or upper abdom inal burning sensation,excluding the organic,metabolic and system ic diseases that may cause the sim ilar symptoms.It is a common functional gastrointestinal disease[1].According to statistics, the global incidence of FD is 5%to 40%[2], and the prevalence of FD in China is 23.5%,which accounts for about 20% to 40% of the digestive tract diseases[3]. The disease recurrently or persistently attacks, w ith a long course and is difficult to cure[4].More and more clinical trials have proved that acupuncture therapy has a significant effect on FD, and the effect is not weaker than that of conventional drug treatment[5-7]. Therefore,FD pertains to gradeⅠof disease spectrum of acupuncture[8].

Acupuncture w ith point selection based on syndrome differentiation along the meridians was applied in this study for FD,compared with acupuncture at nonmeridian and non-acupoint points.Nepean dyspepsia index (NDI) and Leeds dyspepsia questionnaire (LDQ)were used to assess the clinical efficacy.

1 Clinical Materials

1.1 Diagnostic criteria

This study referred the diagnostic criteria of FD in theRome Ⅲ[9]. For at least 3 months in the past 6 months,one or more symptoms such as early satiety,postprandial satiety,upper abdom inal burning sensation and upper abdom inal pain occurred,meanwhile without any evidence of organic disease that could explain the above symptoms (including the diagnosis of upper gastrointestinal endoscopy).

1.2 Inclusion criteria

Those who met the above FD diagnostic criteria ofRome Ⅲ; aged 18-65 years old; no gastro-kinetic agent w ithin 15 d before this visit;had not participated in other clinical trial; patients or the lineal consanguinity agreed to participate in this clinical trial and signed informed consent.

1.3 Exclusion criteria

Those who were unable to express the subjective symptoms;unconscious or psychotic;combined w ith infection or bleeding; patients with malignant tumors or other severe consumptive diseases; those w ith severe primary diseases of cardiovascular,liver,kidney,digestive or hematopoietic systems; those who were planning for pregnancy in 6 months;women during pregnancy or breastfeeding.

1.4 Elim ination and dropout criteria

Those who were enrolled by m istakes;w ith poor compliance; reluctant to join in this trial; receiving other therapies that were forbidden in this trial; those who changed treatment by themselves;those presenting w ith severe adverse events and/or complications and were unsuitable to continue the trial.

1.5 Statistical methods

All data were statistically analyzed by the SPSS version 22.0 statistical software.Chi-square test was applied for data of gender. Measurement data such as age, duration of disease, and LDQ and NDI scores were first tested for normality and homogeneity of variance.Those in normal distribution and w ith homogeneous variance were expressed as mean ± standard deviation(±s). Independent samplet-test was applied to the comparison between groups. Repetitive measurement and analysis of variance was applied to the intra-group comparison.Data in non-normal distribution and not meeting homogeneous variance were expressed as median (lower quartile, upper quartile) [M (QL, QU)]. If data did not meet Mauchly's test of sphericity,multivariate variance was used for correction.P＜0.05 was considered to indicate statistical significant.

1.6 General data

A total of 74 PD patients were enrolled from the First Hospital of Hunan University of Chinese Medicine and Hengyang Hospital Affiliated to Hunan University of Chinese Medicine and by social recruitment. They were random ly divided into an observation group and a control group by central random ization, w ith 37 cases in each group.The central random ization and data management were undertaken by Chengdu Mingke Hongneng Clinical Information Management Co.,Ltd.Four cases in the observation group and 2 cases in the control group dropped out during the trial. Therefore,33 cases in the observation group and 35 cases in the control group were included in the final statistical analysis. This study was reviewed and approved by the Ethics Comm ittee of the Affiliated Hospital of Hunan University of Chinese Medicine, and the clinical trial approval number was 2012CB518500.

There were no statistically significant differences in the general data of gender, age and duration of disease between the two groups(allP＞0.05),indicating that they were comparable (Table 1).

Table 1.Com parison of general data between the two groups

2 Treatment Methods

2.1 Observation group

The observation group was treated w ith acupuncture w ith point selection based on syndrome differentiation along the meridians.

Major acupoints: Zusanli (ST 36) and Neiguan (PC 6).

Adjunct acupoints: Neiting (ST 44) and Taichong (LR 3)for excess syndrome,and Yinlingquan(SP 9)and Gongsun (SP 4) for deficiency syndrome.

Methods:The point location referred theNomenclature and Location of Acupuncture Points(GB/T12346-2006)[10]. Acupoints were selected on one side each time, and the acupoints one each side were used alternatively. After routine disinfection, the sterile acupuncture needles of 0.25 mm in diameter and 25-50 mm in length were punctured, and the lifting- thrusting and tw irling manipulation was performed till the arrival of qi.Then,the physician shallow ly punctured at 2 mm proximal end of the point w ith needles of 0.18 mm in diameter and 13 mm in length as the assisted acupuncture. The LH200 Han's point nerve stimulator was connected.The acupoints and the corresponding assisted points were connected to the same pair of electrodes, and the metal surfaces of the two electrode clamps were not touched. ‘Trans-needle'mode was selected,with a sparse-dense wave,at 2 Hz/100 Hz and 0.1-1.0 mA decided by the patient's tolerance. The stimulation lasted for 30 m in.

2.2 Control group

The control group was treated w ith acupuncture at non-meridian and non-acupoint points.

Non-meridian and non-acupoint points:Medial surface of the elbow, the m idpoint of the connecting line between the elbow tip and the axillary fossa; the midpoint of the connecting line between the medial epicondyle of humerus and the w rist end of ulnar, ulnar side;the junction of deltoid and biceps brachii at anteromedial border of the upper limb; 2 cm apart from the level of Zusanli (ST 36), the lateral border of tibia.

Methods: After routine disinfection, the acupuncture was performed, and the lifting-thrusting and twirling manipulation was performed till the arrival of qi. The physician shallow ly punctured at 2 mm proximal end of the point as the assisted acupuncture which was the same way as the observation group. The LH200 Han's point nerve stimulator was connected. The points and the corresponding assisted points were connected to the same pair of electrodes, and the metal surfaces of the two electrode clamps were not touched. The mode,parameter and the time of the stimulation were as same as those in the observation group.

The treatments in both groups were performed once a day w ith a 2-day break after 5 consecutive treatments,which constituted one treatment course. A total of 4 courses were performed. The follow-up was taken every 4 weeks after the end of treatment, for 5 times in total.

3 Observation of Curative Efficacy

3.1 Criteria for curative efficacy

3.1.1 NDI scale[11-12]

NDI scale was used to evaluate the quality of life(QOL) in FD patients. It consists of 25 items, which are divided into 4 fields of control, interference, food and drink, and sleep.

The scoring formula for each field is the same, and the score after conversion = 100 - [(S - M) ÷ R × 100]. S is the sum of the original score of the field, M is the m inimum score of the field, and R is the maximum score of the field. The higher the score, the better the QOL.

3.1.2 LDQ[13]

The improvement of dyspepsia symptoms was evaluated according to the frequency and severity of the 6 symptoms, i.e. postprandial satiety, early satiety,upper abdom inal pain,upper abdom inal burning sensation,postprandial nausea,and belching.The evaluation method referred the grading standard established by the Spleen and Stomach Diseases Branch of China Association of Traditional Chinese Medicine,and was scored according to the 6-point method[14]. The total score was the sum of the points of each symptom.The higher the score, the more severe the symptoms.

The curative efficacy was evaluated by a third party who did not know the grouping situation. In the data summary stage, blinding was used, and the researcher,operator and statistician were separated.

3.2 Safety evaluation

The adverse reactions related to acupuncture intervention during the trial,and the treatment methods related to adverse reactions were recorded in details.

3.3 Results

3.3.1 Comparison of the NDI score

There was no significant difference in the NDI score between the two groups before treatment (P＞0.05),indicating that they were comparable. The NDI scores in the observation group after treatment and at the 5 time points during follow-up were higher than that before treatment (allP＜0.01), indicating that acupuncture with point selection based on syndrome differentiation along the meridians had certain short-term and long-term effects on FD. The NDI scores in the control group after treatment and at the 5 time points during follow-up were statistically different from that before treatment(allP＜0.05). The NDI scores after treatment and each time point during follow-up in the observation group were significantly higher than those in the control group(allP＜0.01),indicating that acupuncture w ith point selection based on syndrome differentiation along the meridians had better short-term and long-term effects than acupuncture at non-meridian and non-acupoint points in the treatment of FD (Table 2).

3.3.2 Comparison of the total and component LDQ scores between the two groups

There were no significant differences in each symptom score and the total score of LDQ between the two groups before treatment (allP＞0.05),indicating that they were comparable. In the observation group,the 6 component and total LDQ scores after treatment and at the 5 time points during follow-up were significantly lower than those before treatment (allP＜0.01),indicating that acupuncture with point selection based on syndrome differentiation along the meridians had certain short-term and long-term effects on FD. The total LDQ score in the control group after treatment and at the 5 time points during follow-up significantly decreased compared w ith before treatment (P＜0.05). The total LDQ score and scores of upper abdom inal pain, postprandial satiety and upper abdom inal burning sensation after treatment and at each time point during follow-up in the observation group were significantly lower than those in the control group (P＜0.01 orP＜0.05), indicating that acupuncture w ith point selection based on syndrome differentiation along the meridians had better short-term and long-term effects than acupuncture at non-meridian and non-acupoint points in the treatment of FD. The comparison of total LDQ score between the two groups is shown in Table 3,and the comparison of each symptom score is shown in Table 4-Table 9.

Table 2.Com parison of the NDI score between the two groups (±s, point)

Table 2.Com parison of the NDI score between the two groups (±s, point)

Note:Compared with the same group before treatment,1) P＜0.01,2) P＜0.05;compared with the control group at the same time point,3) P＜0.01

Group n tr B ea etfmo reen t treAat fmt eer nt 4 w tre eaetkms eanf tt e r 8 w tre eaetkms eanf tt e r 12 twre eaet m ks e a n ftt er 16 twre eaet m ks e a n ftt er 20 twre eaet m ks e a n ftt e r Observation 33 296.2±54.0 347.3±45.61)3) 354.5±41.11)3) 359.4±40.41)3) 361.1±37.11)3) 366.1±36.71)3) 368.6±34.81)3) Control 35 294.8±49.1 310.7±48.62) 316.3±47.62) 320.9±43.92) 320.8±44.62) 317.3±48.02) 330.9±59.02)

Table 3. Comparison of the total LDQ score between the two groups ( ±s, point)

Table 3. Comparison of the total LDQ score between the two groups ( ±s, point)

Note:Compared w ith the same group before treatment,1) P＜0.01,2) P＜0.05;compared w ith the control group at the same time point,3) P＜0.01

Observation 33 8.10±3.56 3.58±3.681)3) 2.87±3.081)3) 2.65±2.921)3) 2.39±2.761)3) 2.42±2.731)3) 1.71±2.261)3) Control 35 7.68±3.74 6.35±2.852) 5.97±2.912) 5.76±2.912) 5.94±3.382) 5.68±2.952) 5.62±3.142)

Table 4. Com parison of the score of upper abdom inal pain between the two groups ( ±s, point)

Table 4. Com parison of the score of upper abdom inal pain between the two groups ( ±s, point)

Note:Compared w ith the same group before treatment,1) P＜0.01,2) P＜0.05;compared w ith the control group at the same time point,3) P＜0.01, 4) P＜0.05

Group ntr Be a etfmo ree nt treAat fmt eer nt 4w tre eaetkms e anf tt e r 8w tre eaetkms e anf tt e r 12 twre eaet m ks e a n ftt er 16 twre eaet m ks e a n ftt er 20 twre eaet m ks e anftt er Observation 33 1.67±1.16 0.82±1.011)4) 0.67±0.891)4) 0.67±0.851)3) 0.64±0.821)3)0.55±0.791)3) 0.36±0.601)3) Control 35 1.77±1.22 1.43±1.072) 1.37±0.942)1.31±0.932) 1.37±1.002)1.37±0.972) 1.31±0.992)

Table 5. Com parison of the score of postprandial satiety between the two groups ( ±s, point)

Table 5. Com parison of the score of postprandial satiety between the two groups ( ±s, point)

Note:Compared with the same group before treatment,1)P＜0.01,2) P＜0.05;compared with the control group at the same time point,3)P＜0.01

Observation 33 2.30±0.85 1.15±1.091)3) 0.97±0.881)3) 0.79±0.861)3) 0.82±0.851)3)0.79±0.781)3)0.70±0.771)3) Control 35 2.23±1.11 1.97±0.952)1.89±0.932) 1.89±0.932) 1.83±0.992)1.83±0.922)1.77±0.912)

Table 6. Com parison of the score of early satiety between the two groups ( ±s, point)

Note:Compared w ith the same group before treatment,1) P＜0.01;compared w ith the control group at the same time point, 2) P＜0.05

Group n trBea etfmo ree nt treAat fmt eer nt 4 w tre eaetkms eanf tt e r 8w tre eaetkms e anf t t er 12 twre eaet mkseanftt er 16 twre eaet mkseanftt er 20 twre eaet mkseanftt er Observation 33 1.21±1.14 0.61±0.931) 0.42±0.791) 0.45±0.791) 0.45±0.791) 0.45±0.791) 0.39±0.751)2) Control 35 1.09±1.12 0.86±0.97 0.83±0.99 0.83±0.92 0.83±0.86 0.77±0.91 0.83±0.92

Table 7. Com parison of the score of upper abdom inal burning sensation between the two groups ( ±s, point)

Table 7. Com parison of the score of upper abdom inal burning sensation between the two groups ( ±s, point)

Note:Compared w ith the same group before treatment,1) P＜0.01;compared w ith the control group at the same time point,2) P＜0.01,3)P＜0.05

Group ntr Be a etfmo ree nt treAat fmt eer nt 4w tre eaetkms e anf t t er 8w tre eaetkms e anf t t er 12 twre eaet m ks e a n ftt er 16 twre eaet m ks e anftt er 20 twre eaet m ks e anftt er Observation 33 0.73±1.07 0.18±0.471)3)0.18±0.471)2) 0.18±0.471)3) 0.09±0.291)2)0.12±0.331)3)0.09±0.291)2)Control 35 0.86±1.09 0.77±1.09 0.71±1.07 0.66±1.03 0.60±0.98 0.63±1.03 0.57±0.95

Table 8.Com parison of the score of postprandial nausea between the two groups ( ±s, point)

Table 8.Com parison of the score of postprandial nausea between the two groups ( ±s, point)

Note:Compared with the same group before treatment,1) P＜0.01;compared w ith the control group at the same time point, 2) P＜0.05

Group ntr Be a etfmo reen t treAat fmt eer nt 4w tre eaetkms e anf t t er 8 w tre eaetkms eanf tt e r 12 twre eaet m ks e anftt er 16 twre eaet m ks e anftt er 20 twre eaet m ks e anftt er Observation 33 1.12±1.39 0.48±0.831)0.39±0.751) 0.33±0.651) 0.27±0.571)0.27±0.571)0.18±0.391)2)Control 35 0.83±1.22 0.57±1.04 0.57±1.07 0.63±1.06 0.66±1.06 0.54±0.98 0.57±1.00

Table 9.Comparison of the score of belching between the two groups ( ±s, point)

Table 9.Comparison of the score of belching between the two groups ( ±s, point)

Note:Compared w ith the same group before treatment,1) P＜0.01,2) P＜0.05

Group ntr Be a etfmo ree nt treAat fmt eer nt 4w tre eaetkms e anf tt e r 8w tre eaetkms e anf t t er 12 twre eaet m ks e a n ftt er 16 twre eaet m ks e anftt er 20 twre eaet m ks e a n ftt er Observation 33 1.30±1.13 0.70±0.881) 0.58±0.751)0.52±0.711) 0.42±0.661) 0.45±0.791)0.58±1.371) Control 35 1.06±1.11 0.83±0.952) 0.71±0.862)0.57±0.742) 0.74±0.892) 0.63±0.842)0.80±1.492)

4 Discussion

There are mainly two options for non-meridian and non-acupoint point selection at home and abroad. One is to select beside meridian point,between the two meridians. Another is to select 4 fixed positions on the upper and lower limbs: medial surface of the elbow, the midpoint of the connecting line between the elbow tip and the axillary fossa; the m idpoint of the connecting line between the medial epicondyle of humerus and the w rist end of ulnar, ulnar side; the junction of deltoid and biceps brachii at the anteromedial border of upper limb; 1-2 cm apart from the level of Zusanli (ST 36), the lateral border of tibia. In this study, the second option was applied as the non-meridian and non-acupoint point selection for the comparison[23].The results suggested that some symptoms in the control group,such as upper abdom inal pain and postprandial fullness were also improved to some extent, which m ight be related to the acupuncture effect of placebo- acupuncture itself,or the psychological effect of the patient after receiving acupuncture,that is,placebo effect,and the placebo effect could also cause physiological changes and play a certain role[24].

In the previous clinical studies, acupuncture for FD was mostly observations on immediate effect or short-term effect. In this study, the follow-up time was 20 weeks. During the 20-week follow-up, the symptoms in the patients in the observation group were significantly improved compared to those before treatment,and the clinical efficacy and QOL were significantly superior to those in the control group,indicating that acupuncture with point selection based on syndrome differentiation along the meridians not only could relieve clinical symptoms in FD patients, but also improve the QOL,with confirmative long-term effect and m inor adverse reactions,this method is worth clinical application and promotion.

Conflict of Interest The authors declare that there is no potential conflict of interest in thisarticle.Acknow ledgments This work was sponsored by National Basic Research Program of China (973 Program,國(guó)家重點(diǎn)基礎(chǔ)研究發(fā)展計(jì)劃項(xiàng)目,No.2015CB554502);Opening Fund Project of Domestic First-class Discipline Construction of Traditional Chinese Medicine of Hunan University of Chinese Medicine (湖南中醫(yī)藥大學(xué)中醫(yī)學(xué)一流學(xué)科開放基金項(xiàng) 目,No.2018ZYX04); General Project of Hunan Province Administration of Traditional Chinese Medicine (湖南省中醫(yī)藥管理局一般項(xiàng)目,No.2017165);Cultivating Plan (Beanstalk Plan)Fund for Outstanding Teachers of Hunan University of Chinese Medicine[湖南中醫(yī)藥大學(xué)優(yōu)秀青年教師培養(yǎng)對(duì)象(青苗計(jì)劃)];2019 Training Program for Excellent Young Innovators of Changsha (2019年長(zhǎng)沙市杰出創(chuàng)新青年培養(yǎng)計(jì)劃).Statement of Informed Consent Informed consent was obtained from the guardians of the recruited children in this study.

Received:22 January 2020/Accepted:20 February 2020