Shi-Meng Li,Jie Wang,Lu-Fan Xu,Xian-Cheng Zheng,Zhi-Yuan Hui,Jun Wang

1.Beijing University of Chinese Medicine,Beijing 100029,China

2.Department of Acupuncture,Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine,Beijing 100700,China

Keywords:Back-Shu point Chronic fatigue syndrome Intradermal needle Simultaneous regulation on both body constituents and spirits Clinical trial

ABSTRACT Objective:To observe the effect of intradermal needle therapy on back-shu points of five zang organs in treating chronic fatigue syndrome (CFS) and provide evidence for the usage of unilateral back-shu point.Methods:Patients were randomly divided into bilateral backshu point group,unilateral back-shu point group and non-acupoint group,remove shedding cases,each group remaining 30 patients.In bilateral back-shu point group,both sides of backshu points of five zang organs were selected.In unilateral back-shu point group,only one side was selected,left or right alternately.The location where non-acupoint group inserted by intradermal needles were outward from the back-shu points,left or right alternately.Fatigue Scale-14 (FS-14) was used to evaluate the fatigue level and the scores’ improvement of physical fatigue and mental fatigue revealed the therapeutic effect on body constituents and spirits of CFS patient.Results:After the 8-week intradermal needle therapy,the total effective rate was 83.33% in the bilateral back-shu point group,which was 76.67% in the unilateral back-shu point group and 50.00% in the non-acupoint group.The curative effects of the two groups whose back-shu points of five zang organs were inserted by intradermal needles were better than the non-acupoint group(P＜0.05).There was no significant difference in clinical efficacy between the bilateral back-shu point group and the unilateral back-shu point group (P＞0.05).There were statistical differences in FS-14 questionnaires including total,physical and mental scores between before and after the treatment in both the two back-shu point groups(P＜0.05).Only the scores of total and physical fatigue in decreased in non-acupoint group(P＜0.05),which means it couldn’t help to alleviate mental fatigue statistically(P＞0.05).Conclusions:(1) The intradermal needle therapy on back-shu points of five zang organs for CFS has a satisfying clinical efficacy in curing tiredness.It can help to reduce both physical and mental fatigue for the patients.Hence,it can regulate both body constituents and spirits simultaneously.(2) Needling the unilateral acupoints can get similar clinical efficacy to the bilateral points.It reveals that we can cut cost by reducing the consumption of the amount of intradermal needles used on one side.(3) Both the groups of back-shu points get better clinical efficacy than the non-acupoint group dramatically.The reason of why the intradermal needle can treat CFS maybe that back-shu points of five zang organs can regulate the functions of five zang organs characteristically.

1.Introduction

Chronic fatigue syndrome (CFS) is a group of syndromes in which chronic fatigue is the main manifestation and persists over a long period of time,accompanied by physical symptoms such as sore throat,headache,muscle pain,hypothermia,insomnia and psychological symptoms such as anxiety and depression [1].The age of onset is between 30 and 50 years,with a predominance of women [2,3].According to research,CFS is particularly prevalent in brain workers such as cadres,researchers and office workers [4,5].The disease seriously impairs the quality of life of patients [6],hinders economic and social development,and causes problems for individuals,families and the country.Because its etiology and pathogenesis have not been fully elucidated,its clinical manifestations are complex and diverse,and it is highly non-specific,it is difficult for various pharmacological and non-pharmacological treatments to take into account both the physical and psychological fatigue of patients,and clinical outcomes are not very satisfactory [7,8].Although its pathogenesis is complex,it is always based on the dysfunction of the five internal organs.The results are as follows

2.Clinical Data

2.1 General data

All 102 cases were CFS patients who attended the outpatient clinic of the Department of Acupuncture and Moxibustion at Dongzhimen Hospital,Beijing University of Chinese Medicine from April 2019 to January 2020.12 subjects who could not adhere to the treatment were excluded,and finally 30 valid cases were included in each of the bilateral back-shu point group,unilateral back-shu point group and back non-acupuncture point group.There were 12 males and 18 females in the bilateral dorsal acupuncture point group,aged between 24 and 57 years;13 males and 17 females in the unilateral dorsal acupuncture point group,aged between 23 and 55 years;and 13 males and 17 females in the non-dorsal acupuncture point group,aged between 25 and 56 years.After statistical analysis,there were no statistical differences in age,gender,duration of CFS,total FS-14 levels before treatment and levels of physical and mental fatigue among the three groups (P>0.05),which were comparable.

2.2 Diagnostic criteria

The diagnostic criteria for CFS were developed with reference to the 2008 Clinical Research Guidelines on New Chinese Medicines for Chronic Fatigue Syndrome [9] of the Subhealth Branch of the Chinese Society of Traditional Chinese Medicine.

Main symptoms:chronic fatigue that cannot be explained clinically,persisting or recurring for more than 6 months and not relieved by rest;not the result of prolonged exertion,but exacerbated by exertion;severe fatigue symptoms that have a significant impact on work and daily behavioural ability.Exclude other fatigue that can be caused by a primary illness.

At the same time,at least four of the following eight co-morbidities must be present for at least six months,but they should occur later than fatigue:(i) sore throat;(ii) difficulty concentrating or significant memory loss;(iii) swollen neck or axillary lymph nodes;(iv) muscle pain;(v) multi-joint pain without redness or swelling;(vi) a new type of headache with a high degree of severity;(vii) difficulty relieving sleep;(viii) fatigue lasting more than 24 hours after exercise.

2.3 Inclusion criteria

Meet the diagnostic criteria for CFS,have never received acupuncture treatment within the last 30 days,and sign an informed consent form.

2.4 Exclusion criteria

(i) the presence of a primary condition that can explain chronic fatigue,such as hypothyroidism,medically induced fatigue due to drug side effects;(ii) chronic fatigue caused by the persistence of some diseases with a clear clinical diagnosis that are difficult to treat under existing medical conditions,such as patients with hepatitis B virus or hepatitis C virus infection;(iii) past or current primary diagnosis of psychotic-depressive mood disorder or bipolar mood with depressive features disorder,various types of schizophrenia,delusional disorder,dementia,anorexia nervosa or bulimia nervosa;④ body mass index [=weight (kg)/height2 (m)] greater than 45;⑤patients with major diseases such as severe heart,kidney,lung,liver and brain diseases,and severe liver and kidney abnormalities;⑥SCL-90 score higher than 160.

2.5 Exclusion criteria

(i) found not to meet the inclusion criteria after enrollment;(ii)interrupted treatment for more than 7 days;(iii) received other treatment during the course of treatment;(iv) unexpectedly unable to continue regular treatment during the treatment process.

2.6 Discharge criteria

(i) major adverse events,complications or specific physiological changes that make it inappropriate to continue with the trial;(ii)discontinuation of treatment for subjective or objective reasons and loss of contact;(iii) incomplete information that makes it difficult to evaluate effectiveness and safety.

3.Study protocol

3.1 Treatment methods

(1) Bilateral back-shu point group

Acupoints:the backshu points of five zang organs were selected,including bilateral Feishu (肺俞，BL13),Xinshu(心俞，BL15),Ganshu(肝俞，BL18),Pishu(脾俞，BL20),Shenshu(肾俞，BL23),all taken bilaterally.

Operation:CFS subjects were treated with acupuncture in a prone position.The acupuncture point was firstly located on the back,then the skin was disinfected with 75% alcohol and a 0.20mm × 1.5mm disposable intradermal needles of SEIRIN brand (manufactured by Japan co.,LTD.) was inserted into the skin where the acupoint was located and fixed with adhesive tape.The needles were left in place for 48 hours.

Course of treatment:2 times a week for 8 weeks.

(2) Unilateral back-shu point group

Acupoints:the same as the bilateral dorsal points group,taken unilaterally,alternating between left and right.

The operation and course of treatment are the same as for the bilateral back-shu point group.

(3) Non-acupoint group

Acupoints:located on the back-shu point of the five zang organs about 1.5cm to 2cm outwards (about midway between the two lateral lines of the Foot Taiyang Bladder Channel),avoiding the acupoints of the Foot Taiyang Bladder Channel and the positive reaction points of the acupoints.

The procedure and treatment are the same as for the bilateral backshu point group.

3.2 Observation indicators

3.2.1 Efficacy indicators.

Fatigue Scale-14 (FS-14) score:The FS-14 is a tool to assess the level of fatigue in subjects and is widely used in epidemiological and symptomatological studies of fatigue for adults aged 16 years and above.It consists of a total of 14 questions that reflect the severity of fatigue in terms of both physical and mental fatigue,and is generally regarded as a reliable and valid method of clinical outcome assessment for CFS.

In this study,subjects completed the FS-14 before and after treatment based on the last two weeks,and the scores for all questions were added to obtain a total score,which was positively correlated with their total level of fatigue.Within this form,questions 1 to 8 are proportional to the level of physical fatigue of the subject and questions 9 to 14 are proportional to the level of mental fatigue of the person being surveyed.

3.2.2 Safety observation indicators

(i) General information:basic information,duration of illness,condition,past history and allergy history of the patients at the time of inclusion were recorded.(ii) All adverse events that may have occurred during the treatment process were observed and recorded in detail.

3.3 Adverse event recording and management

From the time patients are screened for entry into the clinical study,any possible adverse events are monitored and assessed at all times throughout the course of treatment,and the time of occurrence,duration,extent and management of each symptom are recorded in detail.

3.4 Statistical methods

SPSS 20.0 statistical software was used for statistical analysis.The measurement data conforming to normal distribution were described by () and t-test was used for comparison of 3 groups.For non-normally distributed measurement data,median (M) and interquartile spacing (P25-P75) were applied to describe the data and rank sum test was used for comparison of 3 groups,χ2test was used for comparison of 3 groups for count data and rank sum test was used for comparison of 3 groups for rank data.Differences were considered statistically significant atP<0.05.

4.Study results

4.1 Criteria for judging efficacy

The efficacy index was calculated using the nimodipine method with reference to the relevant criteria in the Clinical Research Guidelines for the Treatment of Chronic Fatigue Syndrome with New Chinese Medicines [9]:efficacy index=(pre-treatment score -post-treatment score)/ pre-treatment score 100%,and the efficacy criteria of this study were judged as follows:①cured:efficacy index 95%;② significant effective:70% efficacy index <95%;③effective:30% efficacy index <70%;④ ineffective:efficacy index<30%.

4.2 Comparison of the total FS-14 scores of the three groups

The difference was statistically significant (P<0.05).There was no significant difference between the bilateral back-shu point group and the unilateral back-shu point group in reducing the total FS-14 score of CFS patients (P>0.05) (Table 1).

Table 1 Comparison of total FS-14 scores (points;n=30)

4.3 Comparison of somatic fatigue scores among the three groups

After treatment,the somatic fatigue scores in all three groups were significantly lower than before treatment in this group,and the differences were all statistically significant (P<0.05).The degree of reduction in somatic fatigue scores:bilateral dorsal acupuncture point group >unilateral dorsal acupuncture point group >nondorsal acupuncture point group,the efficacy of the bilateral dorsal acupuncture point group and the unilateral dorsal acupuncture point group was significantly better than that of the non-dorsal acupuncture point group (P<0.05);there was no significant difference between the bilateral dorsal acupuncture point group and the unilateral dorsal acupuncture point group in reducing the somatic fatigue scores of CFS patients (P>0.05) (Table 2).

4.4 Comparison of mental fatigue scores in the three groups

The mental fatigue scores in the bilateral back-shu point group and the unilateral back-shu point group were both significantly lower after treatment than before treatment in this group,and the difference was statistically significant (P<0.05),while the non-acupoint group could reduce the patients' mental fatigue to some extent,but the difference was not statistically significant (P>0.05).There was no significant difference between the bilateral back-shu point group and the unilateral back-shu point group in reducing mental fatigue scores in patients with CFS (P>0.05) (Table 3).

4.5 Comparison of the overall efficacy of the three groups

Of the 30 cases in the bilateral dorsal acupuncture point group,1 case was cured,9 cases showed efficacy,15 cases were effective,5 cases were ineffective,25 cases were effective,with a total effective rate of 83.33%;of the 30 cases in the unilateral dorsal acupuncture point group,0 cases were cured,7 cases showed efficacy,16 cases were effective,7 cases were ineffective,23 cases were effective,with a total effective rate of 76.67%;of the 30 cases in the back nonacupuncture point group,0 cases were cured,1 case showed efficacy,14 cases were effective,15 cases were ineffective,with a total effective rate of 50.00%.The total effective rate was 50.00%.The clinical efficacy of both the bilateral dorsal acupuncture point group and the unilateral dorsal acupuncture point group was significantly better than that of the non-dorsal acupuncture point group (P <0.01),while the difference in efficacy between the bilateral dorsal acupuncture point group and the unilateral dorsal acupuncture point group was not statistically significant (P >0.05) (Table 4).

Table 2 Comparison of somatic fatigue scores (score;n=30)

Table 3 Comparison of brain fatigue scores (score;n=30)

Table 4 Comparison of clinical efficacy

4.6 Safety evaluation

During the course of this study,there were no adverse events and therefore intradermal needle therapy can be regarded as a safe treatment for CFS.

5.Discussion

The high and increasing incidence of CFS not only leads to physical fatigue but also to psychological fatigue,which seriously affects the quality of life of patients and causes a huge economic burden and social pressure.Its pathogenesis may be related to psychosocial factors,immune imbalance,pathogenic infections,metabolic abnormalities,neuroendocrine system dysregulation and genetic factors [10].There is a wealth of research on the pathogenesis of CFS at home and abroad,but the findings remain limited,with a significant proportion of CFS patients with unknown pathogenesis,limited modern medical treatments,uncertain efficacy and poor patient compliance [11-13].

Previous studies have shown that acupuncture has satisfactory efficacy in the treatment of CFS.Zhao J et al [14] used acupuncture to treat 29 CFS patients with qi-deficiency by Center-Supplementing and Qi-Boosting Decoction,selecting acupoints Bai Hui (百会,DU 20),Tai Yuan (太渊,LU 9),Zhong Wan (中脘,RN 12),Qi Hai (气海,RN 6),Zu San Li (足三里,ST 36) and San Yin Jiao (三阴交,SP 6).After 4 weeks of treatment,the MOS item short from health survey (SF-36) scores of pain,energy,physical function and social function improved in the experimental group (P<0.05) and were all better than those of the non-acupuncture control group (P<0.05).In addition,FS-14 scores,Beck Depression Inventory (BDI) scores,and Somatic and Psychological Health Report (SPHERE) scores were generally lower (P<0.05) and better than the latter group (P<0.05).Luo Mei-ting [15] selected the acupoints of Chi Ze (尺泽,LU 5),Zu San Li (足三里,ST 36),Tai Chong (太冲,LV 3),Zu Lin qi (足临泣,GB 41),Tai Bai (太白,SP 3),Bai Hui (百会,DU 20),Dan Zhong (膻中,RN 17),Zhong Wan (中脘,RN 12) and Qi Hai (气海,RN 6)based on the theory of ascending and descending of qi movement,and treated 30 patients with CFS of liver constraint and qi stagnation with acupuncture.After 5 weeks,the fatigue severity score and symptom score decreased and were lower than those of the Chinese medicine oral control group,and the overall clinical efficiency was better (P<0.05).After 4 weeks,the patients' FS-14,SPHERE and Pittsburgh Sleep Quality Index (PSQI) scores were reduced (P<0.05,P<0.01);serum interleukin-6 and interferon-gamma levels decreased(P<0.01),and the above scores and serum index levels in this group were generally lower than those in the control group of basic treatment combined with basic treatment of glutathione and vitamin B1 orally (P<0.05,P<0.01).

Chinese medicine theory emphasizes that the human body is centered on the five zang organ,which govern the five body constituents and and harbor the five spirits.The physical and mental symptoms involved in CFS are closely related to the dysfunction of the five zang organ.Previous clinical studies [17] have demonstrated that acupuncture of the back-shu point of five zang organs can effectively relieve both somatic and mental fatigue in the treatment of CFS,with reliable efficacy and low recurrence rate.In this study,the theoretical guidance of the theory of Visceral Manifestation and the principle of "those who treat five zang organs treat their backshu points" were used to select acupuncture points,and the simple and popular intradermal needle therapy was used as the treatment method.The aim is to explore the therapeutic effects of acupuncture on CFS under the guidance of the Chinese medicine theory of Visceral Manifestation,and to optimise the operation protocol to form a standard of practice,so as to facilitate its application and provide a new option for the general improvement of the physical quality of the population.This will provide a new option for the general improvement of the physical quality of the population.

As one of the characteristic Chinese medicine treatments combining the acupuncture theory of the cutaneous regions and acupoints,intradermal needle therapy takes the meaning of "static to stay for a long time,good at treating long-term diseases",promoting the body's qi and blood to produce benign regulation of the body,thus preventing and treating diseases,and has the advantages of less pain,faster onset and longer lasting effect than traditional acupuncture intradermal needle therapy,and is therefore widely used in clinical practice.This is particularly effective in the treatment of pain and chronic visceral diseases [18-26].Based on the pathogenesis of CFS and its non-specific pain symptoms such as muscle pain,sore throat and headache,which are consistent with the characteristics and application of intradermal needle,intradermal needle can be considered as an effective treatment for CFS.In one study [27],alternating the use of back-shu points with tonic acupoints,the overall effective rate of the intradermal needle group (94%) was more desirable than that of the conventional acupuncture group(85%),with statistical significance (P<0.05),and the FS-14 and depression scale scores were also significantly superior to those of the conventional acupuncture group (P<0.05).

The intradermal needle therapy on back-shu points of five zang organs for CFS had a obvious clinical efficacy,and the unilateral and bilateral acupoints were comparable in terms of efficacy,both having significant advantages over the non-acupoint group.All three treatments helped to alleviate the fatigue manifestations of CFS patients,with significant improvements in their overall level of fatigue and somatic fatigue.In terms of mental fatigue,only the bilateral back-shu points and the unilateral back-shu points were treated with intradermal needle to reduce it.After 8 weeks of intradermal needle treatment,the three groups of CFS patients showed significant differences in FS-14 levels due to the different acupoint selection protocols.There was no statistical difference between the overall level of fatigue and the levels of somatic and mental fatigue in the bilateral back-shu point group compared to the unilateral back-shu point group,and both groups were better than the non-acupoint group in all three aspects.Therefore,it can be concluded that the intradermal needle therapy on back-shu points of five zang organs for CFS is reliable in improving the fatigue of patients,and can improve both somatic fatigue and mental fatigue of patients,with the effect of harmonizing the form and the spirit.The comparable efficacy of unilateral and bilateral acupoints confirms the concept of holism in Chinese medicine,in which the human being is an organic whole and the channel qi from acupoints travels through the meridians like a ring,linking left and right.Therefore,unilateral acupoint can be used for therapeutic purposes if the disease mechanism is identified.The results of this study show that the intradermal needle therapy on back-shu points of five zang organs is safe and effective in the treatment of CFS,and is a convenient treatment option.It also provides clinical data for the enrichment of the classical acupuncture theories such as "acupuncture to regulate qi","Visceral Manifestation theory","those who treat five zang organs treat their back-shu points" and " the unity of spirit and form".Besides,it helps to lay the foundation for the further popularisation of the clinical application of intradermal needle,and to provide new options to improve the physical and mental health of the nation.It also provides clinical ideas for the application of unilateral backshu points,and provides experimental support for saving medical resources.

Author contributions:Experimental design by corresponding author (Wang Jun),experimental implementation by first author (Li Shimeng),second author (Wang Jie) and third author (Xu Lufan),experimental evaluation by fourth author (Zheng Xiancheng) and fifth author (Hui Zhiyuan),written by first author (Li Shimeng) and reviewed by corresponding author (Wang Jun).