|Year : 2016 | Volume
| Issue : 2 | Page : 83-90
Efficacy of electroacupuncture at the Hegu (LI4) and Taichong (LV3) acupoints in the treatment of migraine: study protocol for a randomized controlled trial
Jian Pei, Jun Wang, Qin-hui Fu, Wei-wei Dong, Xiao-xin You, Ming Dai, Yi Song
Longhua Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
|Date of Web Publication||29-Apr-2016|
Longhua Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai
Source of Support: This study was supported by grants from the Leading Academic Discipline Project of the State Administration of Traditional Chinese Medicine of China (No. GJZYJZJ2010); Key Project from Science and Technology Commission of Shanghai Municipality, China (No. 14401971300); Traditional Chinese Medicine Academic Inheritance Studio Construction Project of Shanghai Bureau of Public Health of China (No. ZYSNXD-CC-HPGC-JD-004); Three-year Development Plan Key Discipline Construction Project of Shanghai Enterprise of Traditional Chinese Medicine of China; Shanghai Doctorate Construction Scientific Research and Development Program of China; Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function (No. 14DZ2260500)., Conflict of Interest: None
Background: Acupuncture is a relatively safe treatment for pain, and its analgesic effects have been confirmed. Electroacupuncture (EA) has been widely used to treat migraine because of its continuous and highly controllable stimulation. However, few rigorously designed randomized controlled trials have evaluated the efficacy of EA at the Hegu (LI4) and Taichong (LV3) acupoints in the treatment of migraine.
Methods/Design: A prospective, single-center, single-blind randomized controlled trial will be performed at Longhua Hospital, Shanghai University of Traditional Chinese Medicine. Ninety-two patients with migraine will be randomly assigned to either undergo EA treatment (20 EA stimulations at the Hegu and Taichong acupoints; EA group, n = 46) or receive oral flunarizine (control group, n = 46). The primary outcome will be the Migraine Disability Assessment questionnaire score after 10 and 20 EA stimulations. The secondary outcomes will be the Medical Outcomes Study 36-item short form health survey score, Visual Analogue Scale score, and peripheral blood concentrations of plasma nitric oxide, calcitonin gene-related peptide, and nuclear factor-kappa B after 10 and 20 EA stimulations.
Discussion: This trial is powered to investigate the efficacy of EA at the Hegu and Taichong acupoints in alleviating headache symptoms in patients with migraine and the interventional effects of this therapy on quality of life and social functioning to search for a more effective method of treating migraine.
Trial registration: This trial protocol was registered at ClinicalTrial.gov (identifier: NCT02580968) on 30 July 2015. It was approved by the ethics committee of Longhua Hospital of Shanghai University of Traditional Chinese Medicine, China (approval No. 14401971300).
Keywords: clinical trial; migraine; electroacupuncture; Hegu (LI4); Taichong (LV3); acupoint; headache; randomized controlled trial
|How to cite this article:|
Pei J, Wang J, Fu Qh, Dong Ww, You Xx, Dai M, Song Y. Efficacy of electroacupuncture at the Hegu (LI4) and Taichong (LV3) acupoints in the treatment of migraine: study protocol for a randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2016;1:83-90
|How to cite this URL:|
Pei J, Wang J, Fu Qh, Dong Ww, You Xx, Dai M, Song Y. Efficacy of electroacupuncture at the Hegu (LI4) and Taichong (LV3) acupoints in the treatment of migraine: study protocol for a randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2016 [cited 2019 Apr 21];1:83-90. Available from: http://www.actnjournal.com/text.asp?2016/1/2/83/181239
| Background|| |
Migraine is a clinically common and frequently occurring chronic neurovascular disorder characterized by diffuse or unilateral repeated onsets of intense severity. The incidence of migraine has tended to increase with rapid economic development, accelerating pace of daily life and increased work and life pressure. Repeated onsets and delayed resolution of migraine greatly influence affected patients' quality of life. The pathological mechanism behind migraine has not been fully clarified. From the viewpoint of modern medicine, migraine is mostly attributable to abnormalities in vasomotion and neurotransmitter transmission (Gao et al., 2014; Pei et al., 2015). In Western medicine, treatment of migraine mainly focuses on the analgesic and sedative effects of therapy. Ergotamine/caffeine and diazepam are widely accepted conventional treatment regimens and show positive sedative effects. However, many contraindications and adverse reactions may be encountered in the treatment of migraine using Western medicine. Therefore, a more effective treatment of this disease is needed.
Acupuncture is a relatively safe treatment for pain, and widespread interest in its analgesic effects has arisen. Acupuncture can alleviate cerebral angiospasm and slow intracranial arterial blood flow, thus improving blood circulation in the brain (Cai, 2006; Dai et al., 2007). Acupuncture has also been shown to accelerate the synthesis of endorphins and enkephalins, increase the activity of endogenous opioid peptides, and inactivate endogenous opioid peptidergic neurons to release opioid peptides, thereby increasing the level of opioid peptides in the brain (Wu et al., 2005).
Electroacupuncture (EA) has been widely used to treat migraine because of its effective and highly controllable stimulations. EA at the Taiyang acupoint for treatment of migraine with symptoms of liver yang hyperactivity shows positive instant analgesic effects that are superior to those of Western medicine (Zhou et al., 2007). EA at the Qiuxu (GB40) acupoint can improve symptoms in patients with migraine and increase the serotonin level (Jia et al., 2007). EA can also regulate glucose levels in the brain in patients with migraine (Yang et al., 2014) and induces analgesia by regulating the synthesis and release of endogenous opioid peptides (Shi et al., 2010).
Migraine attack is linked to abnormal ion channels in the nervous system, in which abnormal calcium channel function plays an important role in this process (Diener et al., 2002; Welch, 2003). In this prospective randomized controlled trial, flunarizine, a selective calcium channel blocker, will be used as a positive control drug to investigate the efficacy of EA at the Hegu (LI4) and Taichong (LV3) acupoints in the treatment of migraine.
| Methods/Design|| |
A prospective, single-center, single-blind randomized controlled trial.
Longhua Hospital, Shanghai University of Traditional Chinese Medicine, China.
The Migraine Disability Assessment questionnaire (MIDAS) score, Visual Analogue Scale (VAS) score, and Medical Outcomes Study 36-item short form health survey (MOS SF-36) score will be collected from all included patients to evaluate the degree of migraine, migraine-induced social functioning, and migraine-associated quality of life. Ninety-two eligible patients will be randomly assigned to either undergo EA treatment (EA group, n = 46) or receive oral flunarizine hydrochloride (control group, n = 46). Each course of treatment will constitute 10 days, and two courses of treatment will be performed ([Figure 1]). MIDAS, MOS SF-36, and VAS evaluations will be performed after one or two courses of treatment (10 and 20 days of treatment, respectively). Outcome evaluation and statistical analysis will be performed by a professional staff member blinded to grouping.
|Figure 1: Trial protocol regarding use of EA at the Hegu (LI4) and Taichong (LV3) acupoints for treatment of migraine. |
Note: EA: electroacupuncture; MIDAS: Migraine Disability Assessment; MOS SF-36: Medical Outcomes Study 36-item short form health survey; VAS: Visual Analogue Scale; NO: nitric oxide; CGRP: calcitonin gene-related peptide; NF-êB: nuclear factor-kappa B.
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Ninety-two eligible patients with migraine will be recruited from Longhua Hospital, Shanghai University of Traditional Chinese Medicine, China.
Patients who meet all of the following criteria will be recruited:
- Age 18 to 65 years
- Migraine corresponding to the International Classification of Headache Disorders, 3 rd edition (beta version) (Headache Classification Committee of the International Headache Society, 2013)
- Migraine corresponding to the diagnosis, treatment, and curative effect assessment criteria of wind syndrome of the head (National Encephalopathy Emergency Cooperation Group of State Administration of Traditional Chinese Medicine, 1993)
- Currently in the onset period of migraine
- Migraine attacks occurring ≥ 5 days per month for > 3 consecutive months, have a > 1-year history of migraine
- Provide informed consent
Patients with any of the following conditions will be excluded:
- Cardiovascular, hepatic, or renal dysfunction or severe primary hematopoietic system disorders
- Organic brain diseases, such as intracranial tumors or cerebrovascular accidents
- Cluster headache, trauma, cervical spondylosis, systemic disease, or intracranial organic diseases causing headache
- Drug or alcohol abuse
- Pregnant or lactating
- Blood coagulation disorders
- Contraindications to use of routine drugs (e.g., presence of hepatic or renal insufficiency)
- History of drug treatment or acupuncture for prevention of migraine in the most recent 6 months
- History of epilepsy or psychosis
- Unable to cooperate during acupuncture treatment because of fear of acupuncture
- Predisposing factors including infection, bleeding, or allergies
- Currently participating in other clinical trials
- Unable to manage himself/herself or have poor self-control ability
Patients will be withdrawn from the rtial if any of the following conditions occur:
- Withdrawal of informed consent or refusal to continue treatment
- Development of severe adverse events that necessitate discontinuation of trial based on physician's experience
- Development of complications that influence therapeutic effects or safety
- Poor compliance
- Ineligible therapeutic effects induced by nondesignated treatment or other drugs to prevent or treat migraine
Prior to treatment, each patient will be randomly assigned one serial number using Stata 7 software (StataCorp, College Station, TX). A staff member who will not participate in the treatment will perform grouping by informing each patient of his or her number via a telephone call. The serial numbers will be preserved in an opaque sealed envelope by a researcher not participating in the acupuncture or data analysis. After collection of baseline data and acquisition of written informed consent, the grouping information will be disclosed to the statisticians.
Sample size calculation
The sample size was calculated according to the following formula:
where α = 0.05 and β = 0.1. According to the current literature, the mean total effective rate of EA on migraine is 60% (i.e., p1 = 0.6), and the effective rate in the EA group is expected to be 90% (i.e., p2 = 0.9, then n = 38). Lost patients will account for 20%; thus, 92 patients will be required. Due to expense and limitations in manpower and time, 92 patients will be practically included (46 patients in each group). The sample size was calculated according to the principles of intention-to-treat analysis.
Recruitment of participants
Participants will be recruited via advertisements in newspapers, hospital bulletin boards, and the hospital website home page. Patients interested in participation will contact staff responsible for this trial via telephone or e-mail. After providing written informed consent, all potential participants will be screened according to the above-mentioned inclusion and exclusion criteria.
Interventions EA group
- Qualification for acupuncturists: All acupuncturists must have > 5 years of clinical experience.
- EA procedure: Patients will be asked to sit in a chair or lie on their back in a bed. After skin disinfection using alcohol, disposable acupuncture needles (0.25 × 40 mm) will be quickly inserted perpendicularly with one hand at the Hegu (LI4) and Taichong (LV3) acupoints both at a depth of 0.5 to 0.8 cun (1 cun = 3.33 cm) based on the methods described in the book titled Shuxue Xue, 6 th edition (Luo, 1994).
- Location of Hegu and Taichong acupoints: According to the acupoint locations described in Shuxue Xue, 6 th edition (Luo, 1994), the Hegu acupoint is located on the dorsal side of the hand between the first and second metacarpal bones of the middle dorsal interosseous muscle, opening the thumb and forefinger in the middle of the junction line between the first and second metacarpal bones ([Figure 2]A). The Taichong acupoint is located on the dorsum of the foot, in a depression distal to the junctions of the first and second metatarsal bones ([Figure 2]B). After acquiring the maximal needling sensation of numbness or distension (i.e., de qi; in acupuncture, activation of de qi is one indication that acupuncture is exerting its beneficial effects, and acupuncturists are trained to inquire about specific needle sensations when providing true acupuncture), the G6805-II EA device will be equipped.
- Stimulation parameters: EA stimulation (frequency, 50-100 Hz; voltage, 2-4 V; sparse-dense wave; stimulus intensity from low to high based on patient's tolerance) will be performed for 20 minutes once daily. Ten stimulations will constitute one course of treatment, and two courses of treatment will be performed.
Flunarizine, a selective calcium channel blocker, will be used at 5 mg twice per day (once in the morning and once in the evening) for 20 successive days.
The primary outcome will be MIDAS score after 20 EA stimulations.The secondary outcomes will be MIDAS score after 10 EA stimulations and MOS SF-36 score, VAS score, and peripheral blood concentrations of nitric oxide (NO), calcitonin gene-related peptide (CGRP), and nuclear factor-kappa B (NF-κB) after 10 and 20 EA stimulations.
All measures in the trial are summarized in [Table 1].
|Table 1: Timing of data collection, interventions, and outcome evaluations in the trial |
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MIDAS questionnaire score: The MIDAS questionnaire was first introduced in 1999 by Stewart et al. (1999). The reliability and validity of the Chinese version were tested by Hung et al. (2006). The MIDAS questionnaire score is calculated by the sum of the days in the last 3 months in which the patient missed work or school; did not perform household work; missed family, social, or leisure activities; and experienced a reduction in work or school productivity by half or more because of headache. According to the MIDAS questionnaire, the degree of the patient's disability in this study will be rated as follows: MIDAS grade I (score of 0-5), little or no disability; grade II (score of 6-10), mild disability; grade III (score of 11-20), moderate disability; and grade IV (score of > 21), severe disability.
- MOS SF-36 score (Ware and Sherbourne, 1992): The MOS SF-36 assesses 36 items in eight health categories: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health. In the present study, the score from each item will be transformed to a 0- to 100-point scale according to the following formula: transformed score = (raw score − minimum possible raw score ) / possible raw score range × 100%. The sum of the transformed score from the eight health categories will be considered the total score of the MOS SF-36. Higher scores represent better health-related quality of life.
- VAS score (Collins et al., 1997): Patients rate their pain on a simple scale marked from 0 to 10, where 0 indicates no pain and 10 points indicates very severe pain.
- NO, CGRP, and NF-κB concentrations in the peripheral blood: NO is an endothelium-derived relaxing factor and an important neurotransmitter that plays an important role in the pathological mechanism of migraine (Olesen et al., 1994). CGRP is a vasoactive substance generated in the tissue surrounding vessels in the brain, and it is involved in the onset of migraine (Tepper, 2016). The inflammatory reaction is also involved in the onset of migraine, and NF-κB participates in the pathological mechanism of migraine as a key rapid transcription factor in the inflammatory reaction (Yang et al., 2007). A 2-mL peripheral venous blood sample will be obtained from each patient to measure the NO, CGRP, and NF-κB concentrations. The sample will be mixed with 30 μL of 10% EDTA and 40 μL of aprotinin in a tube and then centrifuged at 3,000 r/min for 10 minutes at 4°C. The separated plasma will be preserved at −30°C in the refrigerator. The concentration of nitrous acid, an NO metabolite, will be measured by high-performance liquid chromatography to indirectly indicate the NO concentration. The CGRP concentration will be measured using a CGRP kit (Beijing Sino-UK Institute of Biological Technology, Beijing, China) by radioimmunotherapy. The total protein of peripheral blood mononuclear cells will be extracted and the NF-κB activity will be detected by enzyme-linked immunosorbent assay (Shenzhen Jingmei Bioengineering Co., Ltd., Shenzhen, China).
Any expected or unexpected adverse events will be recorded and described as frequency and percentage by the participants and practitioners at every visit until completion of the study. Adverse events known to be related to acupuncture treatment include local bleeding or pain at the acupuncture points, local redness or bruising, itching, and dizziness during treatment (Xu et al., 2013). If any serious adverse event occurs, details of the event including the date of occurrence, measures taken related to the treatment, causal relationship with the treatment, and treatment of the adverse event will be immediately announced to the principal investigator and the institutional review board, and direct actions will be supplied to those involved.
Collection, management, analysis, and open access of data
All data will be collected in case report forms and collated. The case report forms will contain complete information, including demographic data, disease diagnosis, accompanying disease, history of drug allergy, scale evaluation outcomes, and adverse reactions. Professional staff will input the collected data into the Epidata database using the double-data entry strategy. A statistical manager will be in charge of the initial organizing, identifying, coding, and converting of the data to ensure that the format is proper for data analysis. An independent data-monitoring committee will monitor and administer the data throughout the trial to ensure a robust scientific study process as well as the validity and completeness of the data. The results of these trial data will be published at www.figshare.com.
Statistical analysis will be performed by a statistician blinded to grouping using Stata 7 software (StataCorp) and will follow the intention-to-treat principle. Repeated-measures analysis of variance will be used for comparisons between the EA and control groups at 0, 10, and 20 days after treatment. If the differences between groups are significant, Tukey's test will be further used for pairwise comparison. The paired t test will be used to compare baseline data and post-treatment data in the same group. If the data are not normally distributed, the Kruskal-Wallis test will be used. A P level of < 0.05 will be considered statistically significant.
The trial protocol was approved by the ethics committee of Longhua Hospital of Shanghai University of Traditional Chinese Medicine, China (approval No. 14401971300) and will be performed in accordance with the Declaration of Helsinki as formulated by the World Medical Association. Written informed consent will be obtained from each patient.
| Discussion|| |
Migraine is a common disorder, but its diagnostic accuracy and treatment remain unsatisfactory. Increasing attention has been paid to migraine treatment with traditional Chinese medicine, and acupuncture therapy has been widely used because of its good analgesic and functioning-regulating effects and positive curative effects (Diener et al., 2006). Growing numbers of clinical studies on migraine treatment with acupuncture therapy in recent years have led to the performance of increasingly more high-quality randomized controlled trials. Thirteen randomized controlled trials on migraine treatment with acupuncture were reported in the Web of Science from January 2006 to May 2013, including four from Germany, six from China, two from Italy, two from Brazil, and one from Spain. Wang et al. (2011) performed a multicenter, single-blinded, double-dummy randomized controlled trial to investigate the efficacy of acupuncture versus flunarizine in the treatment of migraine. They found that acupuncture was more effective than flunarizine in decreasing the number of days during which migraine attacks occurred, and there were no significant differences in the reduction of pain intensity or improvement in quality of life between acupuncture and flunarizine.
In this study, we will investigate the efficacy of normalized EA on patients with migraine and obtain an optimized combination of stimulation parameters to provide evidence-based reference data regarding the treatment and prevention of migraine with EA. In this randomized controlled trial, flunarizine, a calcium channel blocker commonly used in the clinical setting (Welch, 2003) will be used as the positive control drug. Flunarizine prevents and treats migraine through regulation of certain neurotransmitters and receptors; e.g., the L-type calcium channel in neurons of the trigeminal vascular system participates in the release of CGRP, and the P/Q-type calcium channel can alter the activity of neurons in the trigeminal nucleus caudalis (Lauritzen, 2001; Akerman et al., 2003). There is evidence that long-term use of flunarizine can alleviate the degree of headache, reduce the number of attacks, and induce few adverse reactions; it can thus be used to prevent and treat migraine (Yu et al., 2007).
Acupuncture therapy exhibits longer-lasting effects, costs less, and has fewer adverse events compared with medication. The Hegu and Taichong acupoints have been confirmed to be effective in the treatment of migraine (Yang, 2006). Acupuncture therapy at these points increases the plasma NO concentration in patients with migraine (Zou et al., 2003) and can increase blood flow in the frontal and temporal lobes (Xu et al., 2004), regulate the cerebral vessel diameter, expand the cerebral vessels, and improve intracranial blood circulation (Duan et al., 1996). In this study, we will evaluate the efficacy of EA at the Hegu and Taichong acupoints versus the clinically common drug flunarizine on alleviating pain in patients with migraine, and thereby improving these patients' quality of life and social functioning. Results from this trial will help to clarify the clinical role and application value of EA at the Hegu and Taichong acupoints for treatment of migraine.
Recruitment of patients at the time of submission.
Conflicts of interest
JP conceived and designed this trial protocol. JW, QHF, WWD, XXY, MD and YS contributed to writing of the paper. All authors read and agreed the final version of this paper for publication.
This paper was screened twice using CrossCheck to verify originality before publication.
This paper was double-blinded and stringently reviewed by international expert reviewers.
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[Figure 1], [Figure 2]