Stimulated by Xu et al.
I casually picked up my copy of the BMJ on Friday 27th March 2020. The date on the cover was 28th March, in case any of you go searching. The cover image is a road sign mandating “Keep your distance”. Obviously COVID-19 is the big story, so it was by complete chance that I flicked through far enough to see the double page spread on manual acupuncture for migraine.
A nice, moderately big (n=150), sham controlled, three-arm trial from Hubai University of Chinese Medicine, yes, in Wuhan. A short time ago, nobody in the West would have heard of the place, but now nobody will ever forget it! No, not because of this research, although this research is good, and it is the first of its kind.
It is the first positive sham-controlled trial of acupuncture in migraine prophylaxis.
We have known that acupuncture has efficacy over sham in migraine prophylaxis since Klaus Linde led an update of his Cochrane review, which was published in 2016. This review noted a small but statistically significant effect over sham as well as superiority to drug prophylaxis immediately at the end of treatment.
Xu et al have achieved a considerably larger effect size (ES) over sham in their trial. I estimate the ES for acupuncture over sham from their data is close to 0.45. That is almost three times the ES for chronic headache measured by Andrew Vickers in the Acupuncture Trialist Collaboration (ATC) update of their IPDM – individual patient data meta-analysis (ES for chronic headache 0.16).
In terms of RR50 – the responder rate determined by a 50% or greater reduction in days with headache over a 4 week period – the acupuncture group in Xu et al achieved 82.5%. That is considerably greater than in the ART and GERAC migraine trials,[4,5] part of the Modellvorhaben Akupunktur, which achieved 51% and 47% respectively. The RR50 in the sham groups of these three trials was 46%, 53% and 39% respectively. For comparison, the RR50 for a placebo drug was 26.6% in a large trial of a CGRP receptor monoclonal and 23.3% in a large SR.[7,8]
How did Xu et al do so well?
Well the results in the sham and no treatment groups seem to be in line with other trials. The only other large trial based in China did not report on RR50, but the average reduction in days with headache in the acupuncture groups was comparable with Xu et al (4.1, 3.5, 3.7 vs 3.9). The sham groups of these trials had a very similar drop in days with headache (2.2 vs 2.2) despite one trial (Li et al) using penetrating needling with mild EA and the other using Streitberger, non-penetrating needles (Xu et al).
Could it be the acupuncture, and the length of follow-up? This trial monitored outcomes for 20 weeks, but all the treatment was packed into the first 8. Acupuncture was performed every other day in two courses of 10 sessions separated by just over a week. So, 20 sessions were fitted into about 50 days. Interestingly the effect of sham seemed to peak by the end of the treatment, but then gradually reduced over the next 8 weeks, whereas the effect in the acupuncture group increased slightly.
I guess the total number of treatments may be an important factor. It is the one thing that was highlighted in the IPDM update. The ART and GERAC trials used 12 sessions in 8 weeks (ART) and 10 sessions in 6 week (GERAC), the later with the option of 5 additional sessions for responders.
Now I want to move on to comment on the BMJ editorial that accompanied this research. It was written by a neurologist from the Royal Free called Heather, who has an interest in epilepsy and migraine. Her surname is quite distinctive, so very easy to search on PubMed. I don’t want to be too critical as the overall tone of the piece is very positive, but there are a few aspects that need to be addressed.
At the outset Heather suggests that this is only the second trial of acupuncture in migraine to demonstrate successful masking of the sham procedure, and references a rather small (n=50) trial from Australia as the only other to do so. I went back to check the ART and GERAC trials,[4,5] which had both used superficial needling in the sham groups. Since the timing and nature of credibility testing and its reporting differs widely between trials, I think it is far from clear to say some trials were successfully masked and some were not.
The major error that jumped out from this editorial was the suggestion that the new CGRP receptor monoclonals appeared to be substantially better than the effect of acupuncture in this trial. I had a vague memory of reading that the monoclonals reduced the number of days with headache by about 1.5 days, so when Heather quoted a figure of 3.7 days, I was obliged to check her reference. It turns out she had compared the figure for acupuncture vs sham (-2.1 days) from Xu et al, with the change from baseline for the monoclonal erenumab in its highest dose (-3.7 days. The correct figure for comparison was either -1.4 or -1.9 (low and high dose erenumab vs placebo, respectively).
Heather went on to suggest that 10 hours of acupuncture treatment would not be cheap, failing to comment on the eye watering price of drugs such as erenumab, for which the lowest price I could find was $5k per patient per year. $5k will buy you between 50 and 100 sessions of acupuncture in the private sector, which is one session a week for the whole year!
1 Xu S, Yu L, Luo X, et al. Manual acupuncture versus sham acupuncture and usual care for prophylaxis of episodic migraine without aura: multicentre, randomised clinical trial. BMJ 2020;697:m697. doi:10.1136/bmj.m697. https://www.bmj.com/content/368/bmj.m697
2 Linde K, Allais G, Brinkhaus B, et al. Acupuncture for the prevention of episodic migraine. Cochrane Database Syst Rev 2016;:CD001218. doi:10.1002/14651858.CD001218.pub3
3 Vickers AJ, Vertosick EA, Lewith G, et al. Acupuncture for Chronic Pain: Update of an Individual Patient Data Meta-Analysis. J Pain 2018;19:455–74. doi:10.1016/j.jpain.2017.11.005
4 Linde K, Streng A, Jürgens S, et al. Acupuncture for patients with migraine: a randomized controlled trial. JAMA 2005;293:2118–25. doi:10.1001/jama.293.17.2118
5 Diener H-C, Kronfeld K, Boewing G, et al. Efficacy of acupuncture for the prophylaxis of migraine: a multicentre randomised controlled clinical trial. Lancet Neurol 2006;5:310–6. doi:10.1016/S1474-4422(06)70382-9
6 Cummings M. Modellvorhaben Akupunktur–a summary of the ART, ARC and GERAC trials. Acupunct Med 2009;27:26–30. doi:10.1136/aim.2008.000281
7 Goadsby PJ, Reuter U, Hallström Y, et al. A Controlled Trial of Erenumab for Episodic Migraine. N Engl J Med 2017;377:2123–32. doi:10.1056/NEJMoa1705848
8 van der Kuy P-H, Lohman J. A Quantification of the Placebo Response in Migraine Prophylaxis. Cephalalgia 2002;22:265–70. doi:10.1046/j.1468-2982.2002.00363.x
9 Li Y, Zheng H, Witt CM, et al. Acupuncture for migraine prophylaxis: a randomized controlled trial. Can Med Assoc J 2012;184:401–10. doi:10.1503/cmaj.110551
10 Streitberger K, Kleinhenz J. Introducing a placebo needle into acupuncture research. Lancet 1998;352:364–5. doi:10.1016/S0140-6736(97)10471-8
11 Angus-Leppan H. Manual acupuncture for migraine. BMJ 2020;1096:m1096. doi:10.1136/bmj.m1096. https://www.bmj.com/content/368/bmj.m1096
12 Wang Y, Xue CC, Helme R, et al. Acupuncture for frequent migraine: A randomized, patient/assessor blinded, controlled trial with one-year follow-up. Evidence-based Complement Altern Med 2015;2015. doi:10.1155/2015/920353
13 Cummings M. Re: Manual acupuncture for migraine. BMJ 2020;1096:m1096/rr. https://www.bmj.com/content/368/bmj.m1096/rr