Acupuncture vs Standard Pharmacological Therapy for Migraine Prevention Report Writing
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Background—Standard pharmacological treatment of migraine has many shortcomings. Acupuncture is becoming a more widely used therapy for the prevention and treatment of migraine, but its effectiveness is still in question when compared to the pharmacological treatments even though very few of these have Class A and B evidence for migraine prevention. This is a systematic review of data from existing randomized trials that compare the effectiveness of acupuncture treatment with conventional migraine preventative medications.
Methods—Custom-designed strategy was used for searching Pubmed (includes MEDLINE), Scopus (includes EMBASE). The inclusion criteria were English language and randomized trials. No date restriction was utilized. We included randomized trials and randomized controlled trials in adult patients that compared the clinical effects of acupuncture with a standard migraine preventive medication in patients with a diagnosis of chronic or episodic migraine with or without aura. We excluded letters and studies on acupuncture for headaches other than migraine. Two reviewers checked eligibility; extracted information on patients, interventions, methods, and results; and assessed the quality of the acupuncture intervention based on the American Academy of Neurology Classification of evidence matrix for therapeutic trials. The present review was not registered.
Results—Out of the 706 search results, 7 clinical trials, with a total of 1430 participants, met inclusion criteria for trials comparing the effectiveness of acupuncture to standard pharmacologic treatment. Several of the studies showed acupuncture to be more effective than standard pharmacological treatments for migraine prevention; however, methodological heterogeneity precluded aggregation of these data.
Conclusions—There is growing evidence that acupuncture is just as effective and has fewer side effects than many of the standard pharmaceutical agents that are currently used. However, the heterogeneity of the existing studies limits the effective comparison and analysis.
Key words: migraine, acupuncture, preventive medications, review
Acupuncture is becoming a more widely accepted form of integrative medicine for the prevention and treat ment of migraine in the West. Its mechanism of action does not have a definite explanation, but some studies suggest that acupuncture may have anti-inflammatory action via release of neuropeptides from nerve endings, including calcitonin gene-related peptide (CGRP).1,2 Other theories suggest that acupuncture may exert anal gesic effects by the hypothalamic-pituitary-adrenal axis and the endogenous opioid system which are important mediators of the stress response to pain.3
In acupuncture research, true acupuncture is often compared with sham acupuncture. There are many dif ferent types of sham acupuncture intervention; these include lack of skin penetration by the needle, shallow penetration of the needle, insertion at points that are not traditional acupuncture points, or not achieving “deqi” which is an expected needling response (subjective sen sation of local warmth, paresthesia tenderness) that is considered an integral element of the healing process. The 2016 Cochrane review by Linde is one of the most recent and comprehensive investigations that concluded that acupuncture is more effective than no prophylactic treatment, more effective than sham acupuncture, and as effective as pharmaceutical intervention in reducing the frequency of headaches in patients with episodic migraine.4 The authors found that acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment, and has fewer adverse effects. Since 2016, several new studies appear to support the effectiveness of acupuncture in migraine prevention. This article is a focused, systematic review of high quality, randomized controlled trials that study the effective ness of acupuncture for the treatment of episodic, or chronic migraine compared to the effectiveness of stan dard pharmacological therapies for the treatment of migraine. In addition, we examined and summarized point selection, treatment period, total number of treat ment sessions, and the frequency of treatments.
Inclusion Criteria.—We included randomized con trolled trials in adults that were published in English. The last search was conducted on May 15, 2019. Subjects had a diagnosis of chronic or episodic migraine with or without aura. Studies focusing on migraine but includ ed patients with other types of headache were included. Treatments involved needle insertion at acupuncture points, pain points, or trigger points. Studies involving laser stimulation and transcutaneous electrical stimula tion (electroacupuncture) at acupuncture points were not excluded. In electroacupuncture, a small electric current is passed between pairs of acupuncture needles and cre ates a stronger stimulation than using the needle alone. In clinical practice, licensed acupuncturists typically offer both the standard acupuncture and electroacupuncture to patients. Some trial control interventions included no treatment or routine care, sham intervention (either no skin penetration or insertion at points that are not traditional acupuncture points), and other treatments (drugs). The primary outcomes differed across studies; the main outcome for the majority of studies was reduction of migraine days per month. Custom search strategies (see Appendix) were written by 2 Stanford University Information Services Librarians for Pubmed (includes MED LINE) and Scopus (includes EMBASE). The present review was not registered.
DATA COLLECTION AND ANALYSIS Selection of Studies.—One reviewer screened all abstracts identified by the search strategy. Custom search strategies yielded a total of 706 articles. A total of 158 duplicates removed. Based on abstract/ title, an additional 318 irrelevant items were removed. A total of 230 articles were available for full text screening. One reviewer extracted seven articles for review (Fig. 1). Clearly irrelevant articles and dupli cates were excluded. Full texts of relevant articles were reviewed by 2 reviewers for eligibility. Orig inal authors did not need to be contacted. Data extraction included review of headache classifications used, number of randomized patients, reporting of acupuncture protocol in accordance with STRICTA (Standards for Reporting Interventions in Clinical Trials of Acupuncture),5 duration of treatment, and follow-up periods, number of drop outs, treatment characteristics (total number of sessions, frequency, duration of each session, point selection). Extract ed data were summarized in narrative form by each reviewer and then compared. Disagreements were resolved by discussion.
Custom search strategies yielded a total of 706 articles. A total of 158 duplicates removed. Based on abstract/title, an additional 318 irrelevant items were removed. A total of 230 articles were available for full text screening. Seven articles were extracted for review (Fig. 1).
We set out to aggregate these data, but methodological heterogeneity precluded us from doing so. Specifically, the comparison groups differed drasti cally among the studies. Several studies used an acu puncture sham, whereas most of the studies used an active comparator; therefore, we could not estimate a meaningful relative improvement of the treatment vs the comparator. In addition, the primary outcomes dif fered substantially among studies (disability, headache days, and percent responders). Other design elements differed substantially as well. For example, the follow up periods differed, the use of double dummy designs. Because of the aforementioned differences, a systematic review without meta-analysis is warranted. The following is a summary of the evidence for the efficacy of acupuncture for migraine prevention and treatment. General information regarding safety and tolerability is included. Main outcome measures include reduction of headache days, disability, percent responders (Table 1).
Facco et al6.—A total of 82 out of 100 patients com pleted this randomized controlled trial that studied the effects after a total of 20 sessions of acupuncture vs valproic acid 600 mg/day, over 10 weeks. The primary end point was the Midas Index (MI). The study fol lowed STRICTA. At 3 months, MI improved in both groups but pain intensity was better in the valproic acid group. At 6 months, pain intensity, Pain Relief score (PRS), and rizatriptan intake were better in the acu puncture group. The rate of adverse events was 47.8% in the valproic acid group and 0% in the acupunc ture group.
Wang et al7.—In this multicenter trial, treatment with true acupuncture (12 total sessions over 4 weeks) plus placebo was compared to treatment with sham acupuncture plus flunarizine. Sham acupuncture protocol involved using 5 acupoints near the elbow and knee that were defined as unrelated to headache (Table 2). A total of 140 patients with more than 2 migraine attacks within 4 weeks were recruited for the study; 120 patients completed the study. The primary end point was the proportion of responders with at least a 50% reduction in migraine days. At 3 months, the patients in the acupuncture group had better responder rates (a reduction of migraine days by at least 50%) and fewer migraine days compared with the control group (P < .05).
Streng et al8.—There was failure to meet recruitment target because of high drop out in the metoprolol group. Only exploratory analyses could be performed, no con firmatory interpretation, and the results of the trial must be interpreted with caution. Acupuncture (8-15 sessions over 12 weeks) was similarly effective and bet ter tolerated than metoprolol. The improvements per sisted during follow-up in both groups, with a tendency to favor acupuncture. The population was somewhat biased given that 50% of participants had received acu puncture treatment for migraine before and 95% of the patients in the acupuncture group expected a definite improvement. Only a minority of patients received a daily dose of metoprolol exceeding 100 mg.
Diener et al9.—This was a multicenter trial that compared treatment with true acupuncture vs sham acupuncture vs standard therapy (metoprolol, flu narizine, or valproic acid) in patients who had 2-6 migraine attacks per month. Patients underwent a total of 10 true acupuncture or sham acupuncture sessions over a period of 6 weeks. Sham acupuncture was performed using points that were not traditional acupuncture points. Primary outcome showed a mean reduction of 2.3 headache days (95% CI 1.9-2.7) in the true acupuncture group, 1.5 days (1.1-2.0) in the sham acupuncture group, and 2.1 days (1.5-2.7) in the standard therapy group. These differences were statistically significant compared with the baseline (P < .0001), but not across the treatment groups (P = .09). The authors concluded that the treatment outcomes for migraine do not differ between patients treated with sham acupuncture, true acupuncture, or standard therapy. All treatments were effective. After 26 weeks, acu puncture treatment over 6 weeks had a similar efficacy compared with 24 weeks of continuous treatment with standard drug therapy.
Allais et al10.—This single center trial showed that acupuncture in episodic migraine patients is more effective than flunarizine in reducing the frequency and intensity of attacks after 2 and 4 months of treatment (T1a 2.95 ± 0.39 vs T1f 4.10 ± 0.42, 95% CI, 0.02-2.28. T2a 2.30 ± 0.20 vs T2f 2.93 ± 0.24 95% CI, 0.02-1.24). But there was no difference in frequency of attacks at 6 months (T3a 2.05 ± 0.22 vs T3f 2.32 ± 0.27; 95% CI, ?0.41-0.95). A total of 8 sessions of acupuncture were performed over 8 weeks and then 4 sessions were per formed over 16 weeks. Acupuncture reduced progressively and significantly the amount of analgesics taken for migraine relief and it showed greater effectiveness than flunarizine after the first 2 months of treatment. A good clinical result was maintained by acupuncture in the last 4 months of therapy with a very low frequency of therapeutic sessions (1 session per month). There were significantly lower number of side effects in the acupuncture group (sedation after treatment 10%, local pain 8%) than the flunarizine group (drowsiness 35%, weight gain 22%, depression 7%).
Yang et al11.—Conformance to STRICTA was fol lowed. This was a single-center study showing that the mean number of headache days decreased by 10.7 days in 1 month for chronic migraine patients in the acu puncture group (24 sessions over 12 weeks) and by 7.9 days per month for patients in the topiramate group (mean dose was 84.0 mg/day). These significant differ ences were also true for patients who were overusing acute headache medication. Acupuncture is similarly effective or more effective than prophylactic drug treat ment with less side effects in migraine prophylaxis. Side effects were reported in 6% of the acupuncture group. The side effects identified in the study included local pain, ecchymosis, and local paresthesia during the ses sion (Of note, local paresthesia is typically not consid ered an adverse event in acupuncture treatment because is usually considered part of “deqi” which describes the expected, subjective sensations experienced by patients during acupuncture.) Adverse side effects were reported by 66% of the patients in the topiramate group (pares thesia 48.4%, difficulty with memory 36.3%, dyspep sia 36.3%, fatigue 24.2%, dizziness 21.2%, somnolence 18.1%, nausea 12.1%). Three patients (9%) withdrew because of intolerable adverse side effects.
Naderinabi et al12.—In this single-center, random ized controlled study, 162 patients with the diagno sis of chronic migraine, were randomly allocated to 3 groups: (1) acupuncture (30 sessions over 60 days), (2) botulinum toxin-A group receiving PREEMPT 155 units (3) control group on sodium valproate 500 mg/day. A total of 150 patients completed the study while 12 patients dropped out because of low compliance with the survey but not affected by severe adverse effects. Reduction of pain intensity by VAS was the primary outcome. During the 3-month study, the pain intensity significantly decreased in all 3 groups (P = .0001) with greatest reduction in the acupuncture group (P = .0001). The rate of side effects was significantly lower in the acupunc ture group.
Summary of Trials.—We reviewed a total of 7 ran domized controlled trials, 2 of which studied patients with chronic migraine, whereas the other 5 studies recruited patients with episodic migraine. Rates of adverse events were consistently higher in groups using standard pharmacological interventions. Allais et al found that acupuncture is more effective in reducing number of attacks in first 4 months but no difference at 6 months. Wang et al. reported that the acupuncture plus placebo groups had more people who had at least a 50% reduction in headache days compared to the group who had sham acupuncture and flunarizine (P < .05). Yang et al found that the acupuncture group had a greater decrease in headache days per month than the topiramate group. Diener et al did not find a mean reduction of headache days that was statistically significant across study groups which included acu puncture, beta blocker, valproic acid, and flunarizine. Streng et al was only able to perform exploratory analysis because of the high dropout rate in the metoprolol group. Facco et al found that in both the valproic acid group and the acupuncture group, the MI improved at 3 and 6 months (P < .0001); pain intensity was better at 3 months for the valproic acid group (P < .0001), but pain intensity and PRS were better in the acupuncture group at 6 months (P = .02). Finally, Naderinabi et al showed that patients in the acupuncture group had the greatest reduction in pain severity when compared to patients receiving botulinum toxin A and patients on sodium valproate.
In terms of acupuncture treatment protocol, treat ment period ranged from 4 to 24 weeks. The total num ber of acupuncture treatment sessions ranged from 8 to 24 sessions. The average number of treatments per week ranged from 0.5 to 3.5 sessions per week. Duration of each session mostly ranged from 20 to 30 minutes.
An analysis from the American Migraine Prevalence and Prevention (AMPP) Study showed that the vast majority of episodic migraine patients were not able to obtain minimal pharmacologic management.13 There is growing evidence that acupuncture is just as effective and has fewer side effects than many of the standard pharmaceutical agents that are cur rently used. In clinical practice, patients frequently ask for guidance on whether or not to try acupuncture and about how frequent and how long they need to try it for. However, we still have very little understand ing of the mechanism by which acupuncture works and the data are still limited. Since the publication of the systematic review in 2016 by Linde et al, several new studies have shown that acupuncture is effective in the prevention of migraine when compared to the standard pharmacological treatment.4 We conducted a focused review of existing randomized controlled tri als to study the effectiveness of acupuncture treatment. We also examined the duration and frequency of treat ments. Our objective was to use the available data to formulate a practical summary of results for clinicians and their patients.
The heterogeneity and variability of the study pro tocols bring up the larger question of how the study of acupuncture can be standardized. According to tra ditional Chinese medicine, migraine is a complex dis ease and a variety of syndrome diagnoses are possible.8 Traditionally, treatment is individualized and is not a uniform intervention that can be standardized easily.4,8 Acupoint selection is extremely variable, as can be seen even in the small collection of studies that we exam ined. Of these 7 studies, 4 used “part standardization” which involves the use of a set of obligatory points and additional points. The additional points are chosen depending on different syndromes present in the indi vidual patient. Therefore, the absence of standardized approaches to treatment makes it difficult to reproduce studies. Future studies are needed to confirm whether there is a real difference between individualized and standardized acupuncture. The most recent revision of STRICTA (Standard for Reporting Interventions in Clinical Trials of Acupuncture) is intended as a guideline to improve reporting of acupuncture trials and facilitate their interpretation and replication. Of the studies we reviewed, only the studies by Yang et al and Facco et al explicitly mention conformance to STRICTA.
Both the studies from Wang et al and Diener et al employed the use of sham acupuncture. Numerous studies have shown that sham acupuncture is just as effective as true acupuncture for treatment of migraine. In the 2009 review by Linde et al, pooled analyses of 14 studies did not show a statistically significant superiority for true acupuncture compared with sham acupuncture in migraine prophylaxis. But any intervention involving skin penetration cannot be considered an inert placebo.8,14 Sham acupuncture may still induce a wide range of peripheral, segmental, and central physiological responses to an unpredictable degree.11 Also, acupuncture-specific non-needle and/or needle components may be retained in sham treatments.15 Given these reasons, it may be more practical, in future studies, to compare acupuncture with standard therapies rather than comparing it to sham acupuncture.
The tolerability and safety of a treatment are key factors in maximizing compliance. Several large sur veys have shown that acupuncture is well tolerated and that serious complications are rare events.8 In several of the studies that we reviewed, a greater number of patients in the standard therapy group had to withdraw because of adverse effects. Reported side effects of acu puncture included mild bleeding at site of needle inser tion, ecchymosis, local pain, sedation, and fatigue. In all of the studies, acupuncture consistently had a lower rate of side effects compared to beta blockers, valproic acid, topiramate, and flunarizine.