Research Review By Dr. Brynne Stainsby©

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Date Posted:

February 2021

Study Title:

Manual acupuncture versus sham acupuncture and usual care for prophylaxis of episodic migraine without aura: Multicentre, randomised clinical trial

Authors:

Xu S, Yu L, Luo X, et al.

Author's Affiliations:

Department of Neurology, Huazhong University of Science and Technology, Wuhan, China; Department of Neurology, Wuhan No.1 Hospital/Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, China; Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Scientific Research Management, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Publication Information:

BMJ 2020; 368: m697 doi: 10.1136/bmj.m697 (Published 26 March 2020)

Background Information:

The Global Burden of Disease Study demonstrated that 1.25 billion people experienced migraine headache in 2017 (1). In patients aged 15-49, migraine was the top cause of life lived with disability (2, 3). Given the potential ineffectiveness and/or contraindications to migraine medications, there is a need to investigate non-drug, conservative interventions (4, 5).

The effectiveness for acupuncture to be used as a prophylactic treatment has been investigated. Manual acupuncture has been used for pain relief (6), however, there is a paucity of clinical evidence for migraine prophylaxis (prevention). Although several randomized clinical trials (RCTs) have found no difference between manual and sham acupuncture (7-11), it is important to consider that inappropriate or inadequate placebo controls may be impacting the results of these trials. In order to be an appropriate placebo, sham acupuncture must be both physiologically inert and indistinguishable from true acupuncture. Some authors have suggested that sham acupuncture interventions are not completely inert and may be associated with moderate, non-specific effects (12, 13).

The aim of this RCT was determine the efficacy of manual acupuncture and quantify the true placebo response in the prophylaxis of episodic migraine without aura.

Pertinent Results:

  • A total of 210 potential subjects were screened, of whom, 150 were randomized. Baseline characteristics were similar between groups. Six (4%) subjects were lost to follow up (three in manual acupuncture, one in the sham and two in the usual care group); 147 were included in the full analysis and 144 in the per protocol set.
  • The reduction of migraine days and migraine attacks per four weeks from baseline was significantly greater in the manual acupuncture than the usual care group during weeks 1-20.
  • Compared to sham acupuncture, manual acupuncture resulted in a significantly greater reduction of migraine days during weeks 13-20, and a significant reduction in migraine attacks from weeks 17-20.
  • Sham acupuncture resulted in a significantly greater reduction in migraine attacks from weeks 5-20 compared to usual care.
  • With respect to secondary outcomes, all subscales of the Migraine-Specific Quality of Life questionnaire were improved significantly more in the manual acupuncture group than the two control groups at week 20. The visual analog scale (VAS) also showed a greater reduction for the manual acupuncture group than the control groups at week 20. No other significant differences were found between manual acupuncture and control.
  • No significant difference was found between the manual and sham acupuncture groups for subjects’ ability to correctly identify their allocation status (indicating blinding was maintained).
  • With respect to adverse events, five subjects reported at least one acupuncture-related adverse event, compared with no subjects in the sham group. One subject withdrew from the study due to an adverse event. No severe adverse events were reported.

Clinical Application & Conclusions:

Compared to usual care and sham (non-penetrating) acupuncture, this RCT demonstrated a reduction in migraine days and migraine attacks in acupuncture-naïve subjects with migraines without aura from manual acupuncture. The therapeutic effects in the manual acupuncture group tended to occur earlier, were larger and lasted longer than those in the sham acupuncture group.

While there is a relatively small (and conflicting) body of evidence regarding the effect of acupuncture on migraine headaches, it is important to note that only a small percentage of subjects experienced adverse events with manual acupuncture and there were no severe adverse events reported in this RCT. Given the results of this study, clinicians may wish to recommend a trial of manual acupuncture as a relatively safe and effective intervention for patients with migraine headache without aura.

Study Methods:

Study Design & Subjects:
  • This was a randomized, single blind, three arm clinical trial conducted at seven centres in China from June 2016 to November 2018.
  • Eligible participants were diagnosed by a neurologist with episodic migraine without aura on the basis of the International Classification of Headache Disorders (ICHD). Subjects were between 15-65 years of age with a history of migraine without aura for more than 12 months, an initial onset of migraine before the age of 50, able to provide informed consent and naïve to acupuncture.
  • Following baseline assessment, an independent investigator randomized eligible subjects in a 2:2:1 ratio to receive manual acupuncture, sham acupuncture, or usual care. Treatments were allocated in a centralized manner via an interactive web response system with stratification by centre and a block size of 5.
  • To maintain blinding of subjects, outcome assessors and statisticians, the allocation sequence was concealed until the end of the study.
Interventions:
 
Fourteen licensed acupuncturists, each with over five years of experience and centralized training, delivered treatments. All subjects received 20 sessions of 30-minute acupuncture treatment or usual care over eight weeks, as follows:
  • Manual acupuncture was applied at 10 acupoints (bilateral LI4 [between thumb and index finger], LR3 [between first and second toe], EX-HN5 [taiyang – temple], GB20 [sub-occipital] and GB8 [on the head, directly above the apex of the auricle]). Additional acupoints were selected on the basis of the meridian diagnosis and symptoms. Acupuncturists then tried to elicit acupuncture ‘de-qi’ sensation by manual manipulation of the needles, lasting 10 seconds and repeated four times over a 30-minute period.
  • Sham acupuncture was non-penetrating and performed at four bilateral non-acupuncture points on the back. Placebo needles with blunt tips were used, simulating a puncture, but retracting when pressed against the skin (so, a non-penetrating sham).
  • Usual care was provided to all three groups in accordance with the migraine guidelines developed by the Canadian Headache Society Prophylactic Guidelines Development Group (14). Subjects were taught about lifestyle factors that may contribute to the frequency of migraine, such as sleep hygiene and regular exercise, and encouraged to maintain a headache diary. In the case of severe migraine pain (VAS > 8), diclofenac sodium enteric coated tablets (25 mg/tablet, maximal dose 200 mg/day) were allowed as a rescue medication.
Outcome Measures:
  • The primary outcomes in this RCT were change in the average number of migraine days and migraine attacks per four week cycle (during weeks one to 20).
  • Secondary outcomes included the proportion of subjects achieving at least a 50% reduction in the average number of migraine days or migraine attacks during weeks 17-20, and changes in the severity of migraine as measured by VAS, the Migraine-Specific Quality of Life Questionnaire (15), the Pittsburgh Sleep Quality Index (16), the Migraine Disability Assessment Score (17), the Beck Anxiety Inventory (18), the Beck Depression Inventory II (19) and the average dose of rescue medication.
  • The Acupuncture Expectancy Scale (20) was used to measure subjects’ expectations of positive outcomes with acupuncture.
  • At the end of the study, subjects were asked if they thought the needles had penetrated the skin to assess blinding.
  • Subjects were also asked to record adverse events following each treatment (including bleeding, subcutaneous haemorrhage, serious pain, palpitations, fainting and local infection) throughout the study.
Statistics:

Sample size was calculated based on a pilot study and anticipated a mean difference of 1.8 (SD 2.8) days and 1.2 (1.8) attacks for manual versus sham acupuncture and a difference of 2.2 (2.8) days and 1.5 (1.8) attacks for manual acupuncture versus usual care. A sample of 135 subjects (54 manual, 54 sham, 27 usual care) would be needed to provide 90% power at a two-sided level of significance level of 5%, thus 10 subjects were recruited to account for an anticipated 10% dropout rate. For all subjects who completed at least one session, any missing data was imputed by carrying forward the last observation.

Study Strengths / Weaknesses:

Strengths:
  • A high-quality, randomized controlled design
  • Successful assessor and subject blinding
  • Appropriate concealment and subject allocation
  • Use of a reasonable (non-penetrating) sham comparator (at non-acupuncture points)
  • Reporting and monitoring of adverse events
  • Intention to treat analysis
Weaknesses:
  • It could be argued that the authors included too many (and some likely unrelated) secondary outcome measures.
  • While the frequency of visits may replicate clinical practice, a plan of management lasting 20 weeks may not be feasible for all patients, potentially limiting the external validity of this trial.

Additional References:

  1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392: 1789-858..
  2. GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018; 17: 954-76.
  3. Steiner TJ, Stovner LJ, Vos T et al. Migraine is first cause of disability in under 50s: will health politicians now take notice? J Headache Pain 2018;19:17.
  4. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007; 68: 343-9.
  5. Schulte LH, May A. Headache research in 2014: Advancing migraine therapy. Lancet Neurol 2015;14:6-7.
  6. Zhao ZQ. Neural mechanism underlying acupuncture analgesia. Prog Neurobiol 2008; 85: 355-75.
  7. Li Y, Zheng H, Witt CM, et al. Acupuncture for migraine prophylaxis: a randomized controlled trial. CMAJ 2012; 184: 401-10.
  8. Linde K, Streng A, Jürgens S, et al. Acupuncture for patients with migraine: a randomized controlled trial. JAMA 2005; 293: 2118-25.
  9. Diener HC, Kronfeld K, Boewing G, et al. GERAC Migraine Study Group. Efficacy of acupuncture for the prophylaxis of migraine: a multicentre randomised controlled clinical trial. Lancet Neurol 2006; 5: 310-6.
  10. Wang Y, Xue CC, Helme R, et al. Acupuncture for frequent migraine: a randomized, patient/assessor blinded, controlled trial with one-year follow-up. Evid Based Complement Alternat Med 2015; 2015: 920353.
  11. Wallasch TM, Weinschuetz T, Mueller B, et al. Cerebrovascular response in migraineurs during prophylactic treatment with acupuncture: a randomized controlled trial. J Altern Complement Med 2012; 18: 777-83.
  12. Linde K, Niemann K, Schneider A, Meissner K. How large are the nonspecific effects of acupuncture? A meta-analysis of randomized controlled trials. BMC Med 2010; 8: 75.
  13. Lund I, Lundeberg T. Are minimal, superficial or sham acupuncture procedures acceptable as inert placebo controls? Acupunct Med 2006; 24: 13-5.
  14. Pringsheim T, Davenport W, Mackie G, etal. Canadian Headache Society Prophylactic Guidelines Development Group. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci 2012; 39(Suppl 2): S1-59.22683887.
  15. Cole JC, Lin P, Rupnow MF. Validation of the Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v. 2.1) for patients undergoing prophylactic migraine treatment. Qual Life Res 2007; 16: 1231-7.
  16. Buysse DJ, Reynolds CF, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989; 28: 193-213.
  17. Santoro A, Fontana A, Miscio AM, et al. Quarterly repeat cycles of onabotulinumtoxin A in chronic migraine patients: the benefits of the prolonged treatment on the continuous responders and quality-of-life conversion rate in a real-life setting. Neurol Sci 2017; 38: 1779-89.
  18. Leyfer OT, Ruberg JL, Woodruff-Borden J. Examination of the utility of the Beck Anxiety Inventory and its factors as a screener for anxiety disorders. J Anxiety Disord 2006; 20: 444-58.
  19. Geisser ME, Roth RS, Robinson ME. Assessing depression among persons with chronic pain using the Center for Epidemiological Studies-Depression Scale and the Beck Depression Inventory: a comparative analysis. Clin J Pain 1997; 13: 163-70.
  20. Mao JJ, Armstrong K, Farrar JT, Bowman MA. Acupuncture expectancy scale: development and preliminary validation in China. Explore (NY) 2007; 3: 372-7.

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