The design and protocol of acupuncture for migraine prophylaxis: A multicenter randomized controlled trial

Migraine leads to recurrent attacks of mostly unilateral, pulsating headache with associated symptoms such as photophobia, phonophobia, nausea, and vomiting. The diagnosis of migraine is based on criteria developed by the International Headache Society in 1988 and revised in 2004 – the International Classification of Headache Disorders II (ICHD II) [1]. Migraine prevalence are roughly 12% of the adults in western countries [2] and 4.2%–14.6% in China [3]. Epidemiological studies from several countries showed that the prevalence of migraine was 16–18% in women and 6–8% in men [4, 5]. Approximately 90% of the migraine patients have moderate or severe pain, three quarters have a reduced ability to function during the headache attacks, and one-third require bed rest during their attacks [6].

Some patients with migraine are able to identify headache triggers. Triggers may be inconsistent or additive and are not specific to migraine. For example, menses is a trigger for 60% of female migraine patients. Stress or "let-down" after a stressful event, change in meal schedules or insomnia, and such environmental factors as loud noise, odors, or flickering lights may also precipitate migraine headache [7].

Migraine headache has a complex pathophysiology. Both vascular and neuronal mechanisms have been proposed. Although the mechanisms haven't been exactly known yet, several medications have been given to alleviate pain of patients. Pharmacotherapy can be abortive or prophylactic, and patients who experience frequent, severe headaches often require both approaches. Abortive medications used more than 2 days a week on a regular basis may lead to chronic daily or rebound headaches, so patients with headaches symptoms more than a few days a week should be on headache prophylactic therapy [7]. The goals of migraine prophylactic therapy are to (1) reduce attack frequency, severity, and duration, (2) improve responsiveness to treatment of acute attacks, and (3) improve function and reduce disability. Additional goals are to reduce costs and possibly prevent progression of episodic to chronic migraine. Prophylactic medication groups include β-adrenergic blockers, antidepressants, calcium-channel antagonists, serotonin antagonists, anticonvulsants, nonsteroidal anti-inflammatory drugs, and others (vitamins, minerals, natural products) [8]. Calcium-channel antagonists such as flunarizine have been used commonly in China. Choice is based on efficacy, adverse events, and coexistent conditions. However, most of medications have side effects and contraindication that may limit their use.

Acupuncture, which is one of the main treatment modalities of Traditional Chinese Medicine (TCM), has been used for both the prevention and treatment of diseases for over three thousand years [9]. Although how acupuncture works is still unknown [10], the range of indications of acupuncture (especially for pain management), the variety of different acupuncture methods and the probability that the effects are made up of a specific and a nonspecific component have been acknowledged by more and more western countries [11].

Many studies have already reported encouraging results in the therapy of migraine by acupuncture. In 2001 a systematic review on acupuncture for idiopathic headache had underlined the existing evidence that acupuncture had an effective role in the treatment of patients with migraine [12], but methodological or reporting shortcomings were found in the majority of the studies, so the evidence was insufficient to determine the efficacy of acupuncture compared to medication, or to wait list control or sham acupuncture, in the management of patients with migraine. Since that systematic review, several large, randomized trials on the effectiveness of acupuncture as treatment for migraine prophylaxis have been published in western countries, but there seems to be a lack of high quality randomized controlled trials from China. China is the origin of acupuncture and the country where acupuncture has been used most commonly in clinical practice. Therefore, we are performing a randomized controlled trial to investigate the efficacy of acupuncture compared with flunarizine in patients who have frequent migraine attacks in China.

This trial is a multicenter prospective, randomized, controlled clinical trial. The central randomization is performed by Research Center of Clinical Epidemiology Affiliated to Peking University in China, which uses block randomization to generate the random allocation sequence and prepares a predetermined computer-made randomization opaque sealed envelopes. The opaque sealed envelopes are numbered consecutively and were connected into a strain. It is requested that each envelope should be separated from the strain and then be opened in sequence only after baseline period when the patient has been registered in the trial. Patient and assessors are blinded (blinded telephone interviewers) with regard to the acupuncture treatment administered. The trial is executed in the following five hospitals from June 2007 to June 2009: Beijing Traditional Chinese Medicine Hospital Affiliated to Capital Medical University, Peking University Third Hospital, Beijing Tiantan Hospital Affiliated to Capital Medical University, Huguosi Hospital Affiliated to the Beijing University of Chinese Medicine and Dongzhimen Hospital Affiliated to the Beijing University of Chinese Medicine. Physicians who enroll participants and assessors who collect data in these five hospitals must have a 3-day training seminar concerning treatment modalities and trial's documentation prior to the trial to make sure all practices at each of the five hospitals were the same. Periodic check-up contained the coincidence of the practices taken in every hospital.

This trial is performed according to the principles of the Declaration of Helsinki (Version Edinburgh 2000). The trial protocol has been approved by the Research Ethical Committee of Beijing Traditional Chinese Medicine Hospital Affiliated to Capital Medical University on May 2007.

The question we put forward in this clinical trial is: "Is acupuncture prophylaxis as effective as flunarizine for migraine?" Flunarizine is a drug classified as a calcium channel blocker, which is commonly used in China for migraine prophylaxis. A large sample size study considered that flunarizine is safe and effective for the prophylactic treatment of migraine in China [23]. Therefore, we compare the efficacy of acupuncture with flunarizine which is chosen as a standard drug therapy. The strength of our trial is strictly concealed randomization, the successful blinding of the patients, data collection in diaries. Moreover, in this trial all physicians applying acupuncture treatments have more than 20 years of clinical experience of acupuncture.

According to the theory of traditional Chinese medicine, migraine headaches can be considered as syndromes of meridians [24]. So the acupuncture intervention is given based on the concept of syndrome differentiation of meridians. As an important part of the theory of meridians, syndrome differentiation of meridians has been performed in clinical practice for thousands of years. The aim of syndrome differentiation of meridians is to analyze the involvement of the meridians according to the distribution and indication of meridians for the purpose of providing evidence for selecting the needling methods [25]. For example, most migraine patients with headache on the temporal side, where the distribution of meridians of foot-Shaoyang, should pertain to Shaoyang headache, while some migraine patients with headache on the forehead should pertain to Yangming headache, because forehead is the distribution of meridians of foot-Yangming. In the case of Shaoyang headache, SJ5 and GB34 can be added besides obligatory points that have to be needled in the trial.

The protocol of sham points is developed in our trial according to international considerations about the methodological problems of sham acupuncture [26]. To avoid any effects on headache, firstly we searched points without effect on headache from both ancient and modern literature. This method of selecting sham points can be seen in Alecrim (2008) [22], but our research must be more extensive, because we searched many Chinese articles, particularly ancient books, which have not yet been translated into English. Secondly, as Linde (2005) [27] did, distant non-meridian point is used as sham point by needling 3 mm apart from the points without effect on headache to further avoid the meridian affects in the control group. Last but not least, there are 30 points without effects on headache extracted, but only 5 points will be used to each patient in control group. Points, which are chosen and made up as a control subgroup, are determined by computer-made randomization. This process of confirming sham points could further eliminate potential effects on headache.

To mask the patients in our trial, sham acupuncture is adopted in the control group while placebo medicine is used in acupuncture group, which is considered to benefit the homogeneity of potential psychological effects and improve compliance of patients in China. Alecrim (2008) [22], Diener (2006) [13] and Linde (2005) [27] reported that sham acupuncture had similar effects to verum acupuncture in reducing migraine headaches and both interventions were effective. They thought that several nonspecific factors could explain the high improvement of the sham group, such as the patient's belief in positive results of the acupuncture treatment and the frequent patient's contact with the acupuncturist. Even though in our trial these factors have been standardized as strictly as possible and the selection of sham points is different from previously published trials, we cannot rule out that sham acupuncture intervention may have some physiological effects. The nonspecific physiological effects of needling may include local alteration in circulation and immune function as well as neurophysiological and neurochemical responses as reported [28, 29]. Moreover, the placebo effects may be higher in pain sufferers than in patients suffering from other complaints [30] and invasive technical proceedings may have higher analgesic effects than oral drugs [31, 32]. Our design therefore might prefer the flunarizine group.

Acupuncture has been used for alleviating acute/chronic pain for thousands of years. The efficacy of acupuncture as abortive therapy for patients with migraine headaches has been proved by many studies [12]. Some studies suggested that sumatriptan was more effective than acupuncture at relieving headache [33]. Therefore, the purpose of this trial is not to discuss the efficacy of acupuncture as painkiller but evaluate the efficacy on preventing migraine attack. The results of our trial will be helpful to supply the evidence on the efficacy of acupuncture for migraine prophylaxis in China.