Journal of Traditional Chinese Medical Sciences (2016) 3, 9e21

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Electroacupuncture for treatment ofdiabetic peripheral neuropathy: Asystematic review of randomized controlledtrials

Wenjing Xiong, Xue Feng, Jianping Liu **, Wei Chen*

Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029,China

Received 3 June 2016; accepted 4 June 2016Available online 5 July 2016

KEYWORDSElectroacupuncture;Diabetic peripheralneuropathy;Systematic review;Meta-analysis

* Corresponding author. Tel.: þ86 01** Corresponding author. Tel.: þ86 01

E-mail addresses: jianping_l@hotmPeer review under responsibility o

http://dx.doi.org/10.1016/j.jtcms.202095-7548/ª 2016 Beijing University oCC BY-NC-ND license (http://creative

Abstract Objective: To assess the effectiveness and safety of electroacupuncture for thetreatment of diabetic peripheral neuropathy (DPN). Clinical studies in China have shown thebeneficial effect of electroacupuncture compared with conventional medicine. However,the effectiveness of electroacupuncture has not been well acknowledged internationally.Methods: We searched the following databases from their inception through February 2016:MEDLINE, the Cochrane Central Register of Controlled Trials (April, 2015), SinoMed, China Na-tional Knowledge Infrastructure, VIP, Wanfang Database, Chinese Important Conference Pa-pers Database, and the Chinese Dissertation Database. Randomized controlled trials (RCTs)were included if they compared electroacupuncture to conventional medicine, placebo, orno treatment on DPN patients. RevMan 5.3 software was used for data analysis, with effect es-timate presented as relative risk (RR) and mean difference (MD) with a 95% confidence interval(CI).Results: Eleven RCTs involving 837 participants were included. The methodological quality ofincluded RCTs was generally poor in terms of sequence generation, allocation concealment,blinding, incomplete outcome data, and selective outcome reporting. Meta-analysis showedthat electroacupuncture had a better effect on global symptom improvement than methylco-balamin (RR Z 1.29; 95% CI: 1.14e1.46) and vitamin B (RR Z 1.60; 95% CI: 1.33e1.94). Onlytwo RCTs reported adverse events.

0 64286757.0 64286757.ail.com (J. Liu), chenweibucm@163.com (W. Chen).f Beijing University of Chinese Medicine.

16.06.002f Chinese Medicine. Production and hosting by Elsevier B.V. This is an open access article under thecommons.org/licenses/by-nc-nd/4.0/).

10 W. Xiong et al.

Conclusions: Because of the high risk of bias of included trials, we cannot make a conclusion onthe effectiveness of electroacupuncture for DPN. More rigorously designed and conductedmulticenter double-blind RCTs are needed to support the use of electroacupuncture for DPN.ª 2016 Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V. This isan open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Diabetes mellitus is the seventh leading cause of deathworldwide, causing 1.4 million deaths in 2011 (about 2.6%of total global deaths for that year).1 Diabetic peripheralneuropathy (DPN) is one of the most common chroniccomplications of diabetes mellitus, and is among the maincauses of disability.2 Studies in America have shown that32.7% of people with diabetes mellitus3 have evidence ofDPN and multicenter studies in Europe have shown that 28%of people with diabetes mellitus have evidence of DPN.4

The incidence of DPN in worldwide diabetic patientsranges from 5% to 80%, and is still increasing.5

DPN involves sensory, motor, and autonomic nerve le-sions, with sensory neuropathy most frequently experi-enced.6 The principle clinical features of DPN areprogressive loss of sensation and movement in the distallimbs, manifesting as intense limb numbness, severe pain,muscle weakness and atrophy, and weakening or completeloss of tendon reflexes, ultimately leading to foot ulcers,gangrene, and even amputation.7,8 These symptoms resultin a huge disease burden in terms of disability and depletionof health care resources.9e11

The etiology and pathogenesis of DPN have not beenfully elucidated. For this reason, ideal drugs have stillnot been developed.12 Glycemic control is fundamentalin the prevention and treatment of DPN. Medical thera-pies that are part of the DPN drug arsenal includemethylcobalamin (vitamin B12) l to repair nerves, thiocticacid (alpha-lipoic acid) for oxidative stress, prosta-glandin E2 to improve microcirculation, aldose reductaseinhibitors, such as epalrestat to attenuate morphologicabnormality of the nerves. For symptomatic treatmentwith anticonvulsants, antidepressants and acesodyne arealso used for DPN.13e16 Existing pharmaceutical drugsusually have side effects and are costly. Thus, the overallfinancial burden of DPN and its complications has beenestimated at more than four billion USD in one year inAmerica alone.17 Therefore, better therapy options forDPN are needed.

DPN has been treated using acupuncture for 2000years.18 There are many types of acupuncture used inChina, including auricular, manual, scalp, electro-acupuncture, needle tapping, acupoint injection, bloodpricking, warm needling, and moxibustion. Electro-acupuncture is one of the most widely applied therapies forDPN to ameliorate symptoms, improve quality of life (QoL),and prevent other complications. In recent years, manyclinical trials and animal experiments have shown thebenefit of electroacupuncture in the treatment ofDPN.19e26

Electroacupuncture for DPN is based on the theory oftraditional Chinese medicine (TCM), in which DPN is dueto decreases in the body of the fundamental substancesof yin and essence, which lead to endogenous drynessthat eventually damages the qi and yin. Because of theinterdependence of yin and yang, impairment of yinaffects yang, and results in deficiency of both yin andyang.27 Deficiency of yin and the resulting dry-heat willdry the body fluids, allowing pathogenic qi to enter thechannels. These two conditions can lead to the stasis ofblood and stagnation in the channels such that yang qicannot reach the ends of the four limbs. The sinews andvessels lack the nourishment provided by qi and blood,which eventually results in DPN.28e30 As DPN is causedby qi and yin deficiency, blood stasis, and stagnation,the treatment principle involves replenishing qi andnourishing yin, dissolving stasis and unblocking thechannels.

This systematic review aimed to evaluate the potentialbeneficial and harmful effects of electroacupuncture forthe treatment of DPN. Information from this review mayprovide the foundation for formulating guidelines on elec-troacupuncture for DPN therapy and prevention.

Materials and methods

Data sources and searches

The following electronic databases were searched fromtheir inception through February 2016: MEDLINE (Table 1),the Cochrane Central Register of Controlled Trials (CEN-TRAL) (April 2015), SinoMed, Chinese Network KnowledgeInfrastructure (CNKI), Chinese Scientific Journals Database(VIP), and Wanfang Database. The Chinese Important Con-ference Papers Database and the Chinese DissertationDatabase were searched for gray literature.

English search terms included: “acupuncture,”“acupuncture therapy,” “needling,” “electro-acupuncture,” “diabetic neuropathy,” “diabetic peripheralneuropathy,” “DPN,” “clinical trial,” and “randomizedcontrolled trial.” The Chinese search terms were “zhen ci,”“zhen jiu,” “dian zhen,” “tang niao bing shen jing bingbian,” “tang niao bing zhou wei shen jing bing bian,” “linchuang shi yan,” and “sui ji.” The search terms were usedindividually or in combination. Reference lists of all rele-vant studies were also hand-searched.

Two authors (WJX, XF) independently conducted theliterature search, study selection and data extraction.Disagreement was resolved by discussion, and consensuswas reached through discussion with a third party (WC).

Table 1 MEDLINE search strategy of RCTs of electroacupuncture for treatment of diabetic peripheral neuropathy.

Strategy Search specification Articles returned

#1 (Diet, Diabetic [Mesh]) OR (Diabetic Diets) OR(Diets, Diabetic) OR (Diabetic Diet)

15339

#2 (Peripheral Nervous System Diseases [Mesh]) OR(Peripheral Nervous System Disease) OR (PNS Diseases)OR (PNS Disease) OR (Peripheral Neuropathies) OR (Neuropathy,Peripheral) OR (Peripheral Neuropathy) OR (PNS (PeripheralNervous System) Diseases) OR (Peripheral Nerve Diseases)OR (Nerve Disease, Peripheral) OR (Nerve Diseases, Peripheral)OR (Peripheral Nerve Disease) OR (Peripheral Nervous System Disorders)

154749

#3 #1 AND #2 365#4 (Diabetic Neuropathies [Mesh]) 18395#5 (Diabetic peripheral neuropathy) OR DPN 16554#6 #3 OR #4 OR #5 21917#7 (Acupuncture [Mesh]) OR (acupuncture therapy

[Mesh]) OR acupuncture OR needling OR electroacupuncture25225

#8 Randomized controlled trial [pt] 407385#9 Controlled clinical trial [pt] 492669#10 Randomized [tiab] 371389#11 Randomly [tiab] 249387#12 Random* 1027473#13 Placebo [tiab] 173944#14 Trial [tiab] 423017#15 Groups [tiab] 1581281#16 #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 2549334#17 Animal OR rat OR mouse OR mice OR dog OR rabbit OR duck [ti] 6106896#18 #6 AND #7 AND #16 NOT #17 18

Electroacupuncture for treatment of diabetic peripheral neuropathy 11

Inclusion and exclusion criteria

Parallel randomized controlled trials (RCTs) were includedif they involved electroacupuncture for DPN, regardless ofpublication status.

The definition of DPN must have met the followingdiagnostic criteria: met international diabetes mellitus andDPN criteria, such as the WHO criteria31 or the AmericanDiabetes Association (ADA)32; participants had predomi-nantly distal symmetrical sensorimotor polyneuropathy ofthe limbs. Other causes of multiple sensorimotor neuropa-thy were excluded.

Our operational definition of electroacupuncture waspuncturing the body with acupuncture needles at specificpoints on the corresponding channel based on TCM syn-drome pattern differentiation and treatment, followedby application of electric current through theneedles.33,34

The control intervention included conventional treat-ment, sham acupuncture, placebo, or no treatment. RCTsevaluating acupuncture therapy combined with other in-terventions compared with those other interventions alonewere also included.

Primary outcome was global symptom improvementmeasured by corroborative methods, such as the visualanalog scale or by other criteria defined by the in-vestigators. Secondary outcomes included changes in nerveconduction velocity measured by a corroborant instru-mentation, QoL, health economics, and adverse events.

Quality assessment

Two authors (WJX, XF) independently assessed the qualityof included RCTs according to the Cochrane risk of biastool.35 The following types of bias were assessed: randomsequence generation (selection bias), allocation conceal-ment (selection bias), blinding of participants andpersonnel (performance bias), blinding of outcome assess-ment (detection bias), incomplete outcome data (attritionbias), selective outcome reporting (reporting bias), andbaseline imbalance (other bias). Disagreement wasresolved by discussion, and consensus was reached throughdiscussion with a third party (WC).

Data analysis

RevMan 5.3 software was used to conduct the data analysis.Data were presented as relative risk (RR) with 95% confi-dence intervals (CI) for dichotomous outcomes, and meandifference (MD) with 95% CI for continuous outcomes. Meta-analysis was planned if the included RCTs had acceptablehomogeneity regarding study design, participants, in-terventions, controls, and outcome measures. We testedheterogeneity using the I2 statistic with significance set at�50%, and the chi-square statistic significance set atP < 0.10. If we identified significant heterogeneity, therandom-effects model would be used. If we identifiedenough RCTs, we planned to assess possible sources ofheterogeneity by subgroup and sensitivity analyses, and to

12 W. Xiong et al.

assess the effect of small sample RCTs on results and pub-lication bias using funnel plots.

Results

Description of included studies

A total of 1306 articles were identified through primaryretrieval (Fig. 1). After reading the titles and abstracts,1143 articles were excluded because of duplication orinconformity of titles or abstracts. This resulted in 163 ar-ticles for further assessment. Of these, 151 articles wereexcluded because they did not meet our inclusion criteria:inconformity of study type, participants, intervention,control, or outcomes; lack of diagnostic criteria; and

Fig. 1 Flow chart of

duplicate studies. Ultimately, 12 RCTs were included,36e47

one of which was a three-armed trial.44 We determinedthat the studies Li37 and Li38 reported different parts of thesame RCT, so we combined their data into 1 trial that wereferred to as Li YF 2003 (2000). Thus, 11 trials from 12publications were included in our final analyses.

Characteristics of included RCTs are presented inTable 2, and treatments performed are presented inTable 3. All included RCTs were conducted and publishedin China. Total number of participants was 837, with anaverage of 76 participants per trial. Age of participantsranged from 37 to 80 years. No RCT reported sample sizecalculation. Treatment duration ranged from 14 days to 2months. With respect to the diagnostic criteria of dia-betes, 1 trial47 used the ADA guideline, 10 tri-als36e38,40e47 used the WHO criteria, and 3 trials37e39,41

selection process.

Table 2 Characteristics of included trials.

Study ID Sample size: No.(M/F) Sample age (year) Intervention Outcomes

I C I C

Li36 31 (18/13) 30 (20/10) 48 49 T: Electroacupuncture Global symptom improvementC: Inositol

Li37,38 48 36 63.03 � 9.84 T: Electroacupuncture Global symptom improvementC: Methylcobalamin MNCV in left and right median,

tibial and ulnar nerve, and SNCVin left and right median andsural nerve

Liu39 40 (13/27) 40 (18/22) 57.35 � 9.32 57.65 � 9.45 T: Electroacupuncture þmethylcobalamin

Global symptom improvement

C: Methylcobalamin MNCV in common peroneal andmedian nerve, SNCV in commonperoneal and median nerve

Wang40 30 (18/12) 30 (17/13) 59.20 � 9.56 57.90 � 7.29 T: Electroacupuncture Global symptom improvementC: Methylcobalamin MNCV in common peroneal nerve

and SNCV in tibial nerveXue41 34 34 63.03 � 9.84 T: Electroacupuncture Global symptom improvement

C: Methylcobalamin MNCV and SNCV in median andtibial nerve

Yang42 36 (20/16) 36 (19/17) NA NA T: Electroacupuncture Global symptom improvementC: Vitamin B12 Adverse events

Ye43 30 (14/16) 36 (19/17) 61.8 � 9.48 58.70 � 8.85 T: Electroacupuncture Global symptom improvementC: Methylcobalamin MNCV in common peroneal and

median nerve, and SNCV in medianand sural nerve

Zhao44 120 NA NA T1: Electroacupuncture Global symptom improvementT2:Electroacupuncture þthioctic acid injection

MNCV in left median, right tibialand left ulnar nerve, SNCV in leftmedian, right sural and leftulnar nerve

C: Thioctic acid injectionZhao45 40 (22/18) 40 (20/20) 52 � 8 51 � 7 T: Electroacupuncture þ

methylcobalaminGlobal symptom improvement

C: Methylcobalamin MNCV in left median, right tibialand left ulnar nerve, SNCV inleft median, right tibial andleft ulnar nerve

Zhang46 30 (17/13) 30 (19/11) 61.8 � 7.8 NA T: Electroacupuncture þthioctic acid injection

Adverse events

C: Thioctic acid injectionZhang47 46 (24/22) 46 (24/22) 59.1 � 7.4 59.5 � 7.2 T: Electroacupuncture Global symptom improvement

C: Vitamin B1 and B12 MNCV and SNCV in commonperoneal and median nerve

Abbreviations: C, control group; F, female; I, intervention group; M, male; MNCV, motor nerve conduction velocity; NA, not available;SNCV, sensory nerve conduction velocity.

Electroacupuncture for treatment of diabetic peripheral neuropathy 13

used the Chinese Diabetic Peripheral Neuropathy Diag-nostic Criteria.48e50 Control interventions included B vi-tamins (B1, B6, B12, and methylcobalamin), inositol, andthioctic acid (alpha-lipoic acid) injection. No trial usedsham acupuncture, placebo, pharmaceutical drugs or notreatment as a control. Hypoglycemic therapy, includingoral hypoglycemic agents, insulin, diabetes education,and exercise, was used as a basic therapy in all exceptone trial.47

All included trials except one46 reported global symptomimprovement and 8 trials37e41,43e45,47 reported changes in

the motor/sensory nerve conduction velocity. However, forglobal symptom improvement, the classification anddemarcation points of the hierarchical outcomes of theimprovement were quite different. For the convenience ofanalyzing them as dichotomous data, we merged the“cure,” “markedly effective,” and “effective” outcomesinto a single positive category, and merged “ineffective”outcomes into a negative category. Measurements ofchanges in nerve conduction velocity were also quitedifferent. Only 2 trials42,46 reported adverse events, and notrial evaluated QoL or health economics.

Table 3 Treatments in included trials.

Study ID Intervention Control

Li36 Electroacupuncture: Acupoints were BL 13 (Feishu), BL 18(Ganshu), BL 20 (Pishu), BL 23 (Shenshu), Yishu, ST 36 (Zusanli),SP 6 (Sanyinjiao). EA applied using continuous wave for 30 minonce daily, 10 days as 1 treatment course, total of 3 courses.

Inositol, orally, 0.5 g, TID, 10 days as 1treatment course, 3 courses total.

Li37,38 Electroacupuncture: Primary acupoints were CV 4(Guanyuan), CV 6 (Qihai), ST 40 (Fenglong), SP 6 (Sanyinjiao) BL20 (Pishu), BL 23 (Shenshu), GB 30 (Huantiao), BL 58 (Feiyang).Secondary points added based on site of neuralgia. EA appliedto acupoints at site innervated by damaged nerve usingcontinuous wave for 30 min, once every other day, 3 times perweek, 2 months as 1 treatment course, total of 1 course.

Methylcobalamin, orally, 500 mg, TID, 2 monthsas 1 course of treatment, total of 1 course.

Liu39 Electroacupuncture D oral methylcobalamin: Acupointswere LI 11 (Quchi), TE 5 (Waiguan), LI 4 (Hegu), ST 40(Fenglong), GB 34 (Yanglingquan), ST 36 (Zusanli), SP 6(Sanyinjiao), LR 3 (Taichong). EA applied using for 30 min oncedaily, 10 days as 1 treatment course, total of 3 courses, with 3days’ rest between courses. Methylcobalamin administeredsame as control group.

Methylcobalamin, orally, 0.5 mg, TID, 10 daysas 1 course, 3 courses total with 3 days’ restbetween courses.

Wang40 Electroacupuncture: Acupoints were BL 20 (Pishu), BL 23(Shenshu), GB 30 (Huantiao), GB 34 (Yanglingquan), ST 36(Zusanli), SP 6 (Sanyinjiao), KI (Taixi), LI 11 (Quchi), TE 5(Waiguan), LI 4 (Hegu). EA applied using dilatational wave for30 min once daily, 6 times per week, 4 weeks as 1 treatmentcourse, total of 1 course.

Methylcobalamin, IM, 500 mg/mL, QD, 4 weeksas 1 course, total of 1 course.

Xue41 Electroacupuncture: Primary acupoints were CV 12(Zhongwan), LI 4 (Hegu), LI 11 (Quchi), PC 6 (Neiguan), ST 36(Zusanli), ST 40 (Fenglong), SP 6 (Sanyinjiao), SP 10 (Xuehai),Yanglingquan (GB34). Secondary points added based on site ofneuralgia. EA applied to acupoints at site innervated bydamaged nerve using continuous wave for 30 min, once daily, 5times per week, 2 months as 1 treatment course, total of 1course.

Methylcobalamin, orally, 500 mg, TID, 2 monthsas 1 treatment course, total of 1 course.

Yang42 Electroacupuncture: Acupoints were ST 36 (Zusanli), KI 1(Yongquan). Electrodes impregnated with herbal ingredients(danshen) were affixed to acupoints, followed by EA at 3wavelengths for 15 min each. Treatment was once daily, 2weeks as 1 treatment course, total of 1 course.

Vitamin B12, IM, 500 mg/mL, QD, 2 weeks as 1course, total of 1 course.

Ye43 Electroacupuncture: Acupoints were LI 4 (Hegu), LR 3(Taichong) LI 11 (Quchi), KI (Taixi), ST 36 (Zusanli) KI 1(Yongquan). EA applied using discontinuous wave for 30 minonce daily, every other day, 28 days as 1 treatment course,total of 1 course.

Methylcobalamin, IM, 0.5 mg/mL, QD, 4 weeksas 1 course, total of 1 course.

Zhao44 Tx group 1: Electroacupuncture; Tx group 2:

Electroacupuncture D thioctic acid IV infusion. Tx1:Acupoints were CV 4 (Guanyuan), CV 6 (Qihai), LI 4 (Hegu), SI 3(Houxi), KI 1 (Yongquan), ST 41 (Jiexi), SP 6 (Sanyinjiao) BL 20(Pishu), BL 23 (Shenshu), BL 58 (Feiyang), GB 30 (Huantiao).Secondary points added based on site of neuralgia and/orsyndrome pattern differentiation. EA applied using continuouswave, once daily, 2 weeks as 1 treatment course, total was 2courses, with 1 day’s rest between courses. Tx2 combined Tx1and the control group.

Thioctic acid, IV infusion, 600 mg/250 mL over30 min, QD, 2 weeks as 1 course, 2 coursestotal.

Zhao45 Electroacupuncture D oral methylcobalamin: Acupointswere BL 20 (Pishu), BL 23 (Shenshu), CV 6 (Qihai), CV 4(Guanyuan), ST 36 (Zusanli), SP 6 (Sanyinjiao). Secondarypoints added based on site of neuralgia and syndrome patterndifferentiation. EA applied using continuous wave for 30 min

Methylcobalamin, orally, 0.5 mg, TID, 15 daysas 1 course, 2 courses total, with 1 day’s restbetween courses.

14 W. Xiong et al.

Table 3 (continued )

Study ID Intervention Control

once daily, 2 weeks as 1 treatment course, total was 2 courses,with 1 day’s rest between courses. Methylcobalamin wasadministered the same as the control group.

Zhang46 Electroacupuncture D thioctic acid infusion: Acupoints wereLI 15 (Jianyu), LI 11 (Quchi), PC 6 (Neiguan), LI 4 (Hegu), ST 36(Zusanli), SP 6 (Sanyinjiao), SP 10 (Xuehai), BL 17 (Geshu), BL40 (Weizhong), GB 34 (Yanglingquan). EA was applied withcontinuous wave for 30 min, once daily, 5 times per week, 1week as 1 course, total was 3 courses, with 2 days’ restbetween courses. Thioctic acid was administered the same asthe control group.

Thioctic acid, IV infusion, 600 mg/250 mL over30 min, QD, 3 weeks as 1 course, total of 1course.

Zhang47 Electroacupuncture: Acupoints were LI 4 (Hegu), LI 10(Shousanli), LI 11 (Quchi), TE 5 (Waiguan), SP 6 (Sanyinjiao), SP10 (Xuehai), ST 36 (Zusanli), ST 40 (Fenglong), LR 3 (Taichong)GB 34 (Yanglingquan). EA was applied with continuous wave for30 min once daily, 30 days as 1 treatment course, total of 1course.

Vitamins B1 (100 mg/mL) and B12 (500 mg/mL),both IM and QD, 30 days as 1 course, total of 1course.

Abbreviations: BID, 2 times daily; EA, electroacupuncture; QD, once daily; TID, 3 times daily.

Electroacupuncture for treatment of diabetic peripheral neuropathy 15

Quality assessment

Although all included trials mentioned “random alloca-tion,” only 5 trials37e39,44e46 described the method ofrandom sequence generation such as using a randomnumber table (Figs. 2 and 3). No trial mentioned allo-cation concealment or blinding. For incomplete outcomedata, no trial provided information on drop-outs such asnumber of missing cases and the reason for the deletion.No trial reported intention-to-treat (ITT) analysis. Withregard to selective reporting, we classified all includedtrials as unclear risk of bias because the study protocolswere unattainable. No trial reported sample calculation,and 1 RCT42 did not report whether the baseline char-acteristics of the treatment and the control group werecomparable.

Fig. 2 Risk of

Effect estimates

The effect estimates of electroacupuncture are shown inTable 4.

Effect on global symptom improvementTen trials36e45,47 reported global symptom improvementoutcomes (Fig. 4). Results showed that electroacupuncturehad a better curative effect than methylcobalamin (RR1.29; 95% CI 1.14 to 1.46) and vitamin B (RR 1.60; 95% CI1.33 to 1.94). Electroacupuncture plus methylcobalaminversus methylcobalamin alone (RR Z 1.20; 95% CI:1.03e1.40) and electroacupuncture plus thioctic acid in-jection versus thioctic acid injection alone (RR Z 1.23; 95%CI: 1.02e1.47) also showed a better curative effect onglobal symptom improvement. Subgroup and sensitivity

bias graph.

Fig. 3 Risk of bias summary graph.

16 W. Xiong et al.

analyses were not performed because of the low hetero-geneity (I2 Z 33%).

Effect on changes in nerve conduction velocityEight trials37e41,43e45,47 reported the outcomes of changesin nerve conduction velocity. A total of 21 kinds of nerveconduction velocity tests of 6 different nerves weremeasured. Six trials39e41,43,45,47 indicated that electro-acupuncture had a beneficial effect on nerve conductionvelocity, while 2 trials37,38,44 did not. The combined trial ofLi37,38 found that methylcobalamin had a better therapeu-tic effect than electroacupuncture on motor nerve con-duction velocity in the left median and tibial nerves, and onmotor nerve conduction velocity in the right median, tibialand ulnar nerves. Another trial44 found that thioctic acid

injection had a better effect than electroacupuncture onchanges in motor nerve conduction velocity in the left ulnarnerve, and on sensory nerve conduction velocity in the leftmedian nerve.

Adverse events

In the 2 trials42,46 that reported adverse events, no seriousuntoward events occurred. The remaining trials did notreport adverse events.

Funnel plot analysis

Based on guidelines delineated in the Cochrane Handbookof Systematic Reviews of Interventions,35 funnel plotanalysis was not conducted due to the small number ofincluded RCTs and the diversity of comparisons andoutcomes.

Discussion

This review could not obtain conclusive evidence about thetherapeutic effect of electroacupuncture for DPN becauseof the poor methodological quality of the included trials.There was no strong evidence to recommend electro-acupuncture for DPN, and the positive findings should beinterpreted conservatively.

The review showed that limitations existed in both studydesign and the implementation process of included RCTs.The methodological quality of the included trials wasgenerally poor, which increased risk of bias of the evalua-tion for interventions. All included trials mentioned randomallocation, however, only 5 trials37e39,44e46 provided infor-mation regarding the method of randomization, and thiswas insufficient to judge whether the randomization wasperformed adequately. None of the trials adopted alloca-tion concealment, which might have led to the in-vestigators having prior knowledge of the allocationsequence, and caused selection bias. Blinding method wasnot reported in any included trials. Both the investigatorand the participants clearly knew which treatment wasbeing given, which may have introduced bias due to theconfounding factor of the placebo effect. We concede thatfor trials of different forms of intervention and controlgroups, the application of blinding to researchers andsubjects would have been difficult, however, blinding couldstill have been used on outcome assessors. Blinding of theoutcome assessors would have been especially importantfor assessing the subjective outcome of the patients’ self-reported index. No trial provided specific informationregarding drop-outs and follow-up, and ITT analysis was notperformed to ensure authenticity of the results. The pre-registered protocols of the included trials could not beaccessed, which prohibited us from judging whether therewas publication bias. No included trial reported that samplecalculation had been performed, such that this and theabsence of pre-registered protocols may have led to otherbias. One trial42 did not report whether the baseline char-acteristics of the treatment and control group were com-parable, so we deemed the risk of other bias in this RCT tobe high.

Table 4 Effect estimations of electroacupuncture for diabetic peripheral neuropathy in included trials.

Outcomes Effect estimates [95% CI] Study ID

1. Electroacupuncture vs. methylcobalamin

1.1Global symptom improvement RR 1.29 [1.14, 1.46] Li,36 Wang,40 Xue,41 Ye43

1.2 Change in NCV in each nerve MD 1.70 [0.92, 2.47]

1.2.1 Change in MNCV in common peroneal nerve MD 1.11 [0.18, 2.05] Wang,40 Ye43

1.2.2 Change in MNCV in median nerve MD 3.16 [1.00, 5.33] Xue,41 Ye43

1.2.3 Change in SNCV in median nerve MD 1.72 [�0.11, 3.55] Xue,41 Ye43

1.2.4 Change in MNCV in left median nerve MD �1.60 [�5.81, 2.61] Li37,38

1.2.5 Change in MNCV in right median nerve MD 2.80 [�1.28, 6.88] Li37,38

1.2.6 Change in SNCV in left median nerve MD 7.50 [1.88, 13.12] Li37,38

1.2.7 Change in SNCV in right median nerve MD �1.20 [�6.84, 4.44] Li37,38

1.2.8 Change in SNCV in left superficial peroneal nerve MD 5.40 [1.14, 9.66] Li37,38

1.2.9 Change in SNCV in right superficial peroneal nerve MD 2.70 [-0.88, 6.28] Li37,38

1.2.10 Change in SNCV in sural nerve MD 2.89 [1.05, 4.73] Ye43

1.2.11 Change in MNCV in tibial nerve MD 3.10 [0.69, 5.51] Xue41

1.2.12 Change in SNCV in tibial nerve MD 1.58 [0.70, 2.47] Wang,40 Xue41

1.2.13 Change in left MNCV in tibial nerve MD �3.70 [�6.85, �0.55] Li37,38

1.2.14 Change in right MNCV in tibial nerve MD �1.40 [�4.94, 2.14] Li37,38

1.2.15 Change in MNCV in left ulnar nerve MD 3.20 [�1.08, 7.48] Li37,38

1.2.16 Change in MNCV in right ulnar nerve MD �1.20 [�4.99, 2.59] Li37,38

2. Electroacupuncture vs. vitamin B

2.1 Global symptom improvement RR 1.60 [1.33, 1.94] Yang,42 Zhang47

2.2 Change in NCV in each nerve MD 3.21 [1.66, 4.77]

2.2.1 Change in MNCV in common peroneal nerve MD 3.30 [0.85, 5.75] Zhang47

2.2.2 Change in SNCV in common peroneal nerve MD 5.20 [2.79, 7.61] Zhang47

2.2.3 Change in MNCV in median nerve MD 1.30 [�1.38, 3.98] Zhang47

2.2.4 Change in SNCV in median nerve MD 2.80 [0.37, 5.23] Zhang47

3. Electroacupuncture D methylcobalamin vs. methylcobalamin

3.1 Global symptom improvement RR 1.20 [1.03, 1.40] Liu,39 Zhao45

3.2 Change in NCV in each nerve MD 6.41 [4.96, 7.86]

3.2.1 Change in MNCV in common peroneal nerve MD 7.70 [6.66, 8.74] Liu39

3.2.2 Change in SNCV in common peroneal nerve MD 4.20 [3.37, 5.03] Liu39

3.2.3 Change in MNCV in median nerve MD 8.50 [7.01, 9.99] Liu39

3.2.4 Change in SNCV in median nerve MD 8.90 [7.71, 10.09] Liu39

3.2.5 Change in MNCV in left median nerve MD 5.93 [4.10, 7.76] Zhao45

3.2.6 Change in SNCV in left median nerve MD 6.42 [4.68, 8.16] Zhao45

3.2.7 Change in MNCV in right tibial nerve MD 3.12 [1.52, 4.72] Zhao45

3.2.8 Change in SNCV in right tibial nerve MD 4.63 [2.90, 6.36] Zhao45

3.2.9 Change in MNCV in left ulnar nerve MD 4.17 [2.33, 6.01] Zhao45

3.2.10 Change in SNCV in left ulnar nerve MD 8.18 [6.60, 9.76] Zhao45

4. Electroacupuncture vs. inositol

4.1 Global symptom improvement RR 1.12 [0.93, 1.35] Li36

5. Electroacupuncture vs. thioctic acid injection

5.1 Global symptom improvement RR 0.94 [0.73, 1.21] Zhao44

5.2 Change in NCV in each nerve MD �1.16 [�2.14, �0.17]

5.2.1 Change in MNCV in left median nerve MD �0.99 [�2.44, 0.46] Zhao44

5.2.2 Change in SNCV in left median nerve MD �2.95 [�4.31, �1.59] Zhao44

5.2.3 Change in MNCV in right tibial nerve MD 0.95 [�0.82, 2.72] Zhao44

5.2.4 Change in SNCV in right sural nerve MD �0.40 [�1.63, 0.83] Zhao44

5.2.5 Change in MNCV in left ulnar nerve MD �1.94 [�3.28, �0.60] Zhao44

5.2.6 Change in SNCV in left ulnar nerve MD �1.25 [�2.61, 0.11] Zhao44

6. Electroacupuncture D thioctic acid injection vs. thioctic acid injection

6.1 Global symptom improvement RR 1.23 [1.02, 1.47] Zhao44

6.2 Change in NCV in each nerve MD 7.31 [5.50, 9.13]

6.2.1 Change in MNCV in left median nerve MD 9.79 [8.49, 11.09] Zhao44

6.2.2 Change in SNCV in left median nerve MD 8.29 [6.98, 9.60] Zhao44

6.2.3 Change in MNCV in right tibial nerve MD 4.15 [2.63, 5.67] Zhao44

(continued on next page)

Electroacupuncture for treatment of diabetic peripheral neuropathy 17

Table 4 (continued )

Outcomes Effect estimates [95% CI] Study ID

6.2.4 Change in SNCV in right sural nerve MD 5.76 [4.61, 6.91] Zhao44

6.2.5 Change in MNCV in left ulnar nerve MD 9.70 [8.32, 11.08] Zhao44

6.2.6 Change in SNCV in left ulnar nerve MD 6.09 [4.50, 7.68] Zhao44

Abbreviations: CI, confidence interval; MD, mean difference; MNCV, motor nerve conduction velocity (m/s); NA, not available; NCV,nerve conduction velocity (m/s); RR, risk ratio; SNCV, sensory nerve conduction velocity (m/s).

Fig. 4 Forest plot of electroacupuncture versus conventional medicine for diabetic peripheral neuropathy on global symptomimprovement.

18 W. Xiong et al.

Electroacupuncture for treatment of diabetic peripheral neuropathy 19

Several problems existed in the study design of includedRCTs. Reporting of the baseline characteristics of partici-pants was not standardized, the inclusion and exclusioncriteria were indeterminate, the age range of participantswas large, and the TCM syndrome pattern differentiationwas lacking. These factors may have resulted in an imbal-ance between intervention and control groups such as theimbalance of the types of syndrome patterns that wereincluded, reduced the validity of outcomes, and did notreflect the uniqueness of TCM treatment based on patterndifferentiation. Future investigators should standardizestudy design and the reporting of baseline characteristics,and fully integrate TCM theory with their studies.

With regard to electroacupuncture intervention, therewere considerable differences in needling instrumentsused, number of needling sessions, selection of acupoints,depth of insertion, method of needle manipulation, andneedle retention time. None of the included trialsmentioned the practitioners’ background in accordancewith the CONSORT Statement51 and STRICTA recommen-dation,52 such as their qualifications, professional affilia-tion, or how long they had been practicing acupuncture.Future studies should adopt more rigorous reporting ofinterventions.

For control treatments, we regrettably found that othercontrol treatments have not been found except vitamin B,inositol or alpha-lipoic acid in included trials. The phar-maceutical drugs which are mainly used for DPN, especiallyin the U.S would be an important comparison for future RCTstudies.

In terms of outcome measurement, the therapeutic ef-fect index of each included trial was quite different, andthese were not reported in accordance with the unifiedinternational standard such as CONSORT Statement51 andSTRICTA recommendation.52 The majority of RCTs reportedglobal symptom improvement and changes in nerve con-duction velocity. However, the former was reported as ahierarchical outcome using categories, such as “markedlyeffective”, “effective” and “ineffective” and the gradingstandards of included RCTs were varied and lacked unifiedinternational standardization such as CONSORT Statement51

and STRICTA recommendation.52 For the convenience ofanalysis, we summed these as binary outcomes, whichprobably enlarged the uncertainty of results. Moreover, forthe changes in nerve conduction velocity, the nervesmeasured in each trial were too varied to perform a meta-analysis and draw a pooled result. No trial reported QoL orhealth economic outcomes, and the reports of follow-upresults were insufficient for estimating long-term thera-peutic effects of the treatment. Furthermore, of all theincluded trials, only 2 studies42,46 reported adverse events.This is a universal phenomenon of TCM trials performed andpublished in China, where researchers often considertreatments to be safe and overlook the importance ofsafety reporting. Because of this, we cannot ascertain thesafety of electroacupuncture, and recommend compre-hensive monitoring and reporting of adverse events areneeded in all future studies.

Our search found 1 published systematic review onmanual acupuncture for DPN53 However, manual acupunc-ture and electroacupuncture are different types ofacupuncture therapy, and their therapeutic mechanisms

and curative effects likely differ. For this reason, we didnot include that study. Our review had some limitations. Weonly searched Chinese and English databases and relevantreferences because of the language barrier. RCTs of elec-troacupuncture for DPN published in other languages stillneed to be assessed to more completely evaluate theeffectiveness and safety of electroacupuncture.

Conclusion

We were unable to obtain conclusive evidence about thetherapeutic effect of electroacupuncture for DPN throughthis review because the poor methodological quality of theincluded trials reduced the reliability of our findings. Morerigorously designed, multicenter, double-blind RCTs withreliable quality and credible conclusions are needed tosubstantiate findings. Future RCTs should include informa-tion about needling instruments, number of needling ses-sions, selection of acupoints, depth of insertion, needlemanipulation, needle retention time, and the qualificationand experience of the practitioner. Long-term follow-up,monitoring and reporting of adverse events are alsorequired.

Author contributions

Wenjing Xiong, Wei Chen conceived and designed the study.Wenjing Xiong, Xue Feng and Wei Chen conducted theliterature searches, data extraction, and quality assess-ment. Wenjing Xiong and Wei Chen performed the dataanalysis. Wenjing Xiong wrote the manuscript. Wei Chenand Jianping Liu critically revised the manuscript.

Competing interests

The authors declare that they have no conflicts of interest.

Acknowledgment

This research was supported by the Beijing IndividualOutstanding Talent Training Projects to Support the YoungBackbone People (No. 20140000204400001).

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