A clinical vignette by Jens Foell (JF), edited by Mike Cummings (MC)
Bian Que is a prominent figure in the history of medicine. Allegedly he possessed xray eyes and amazing healing properties. Legend says that he could cure people with one needle (eg getting an unconscious person back into action by needling Baihui – GV20). Performing the one-needle-wonder is every acupuncturist’s dream.
On an ordinary evening in a minor injury unit in rural North Wales I came close to living this dream. A ‘doctor advice’ callback appeared on the screen: a paramedic visited a 76 year old woman who had called emergency services because she experienced acute intense left sided shoulder/arm pain. Nothing had helped. She could not drive a car, because she could not move the steering wheel. The ambulance crew had checked her vital signs. They were all in normal range. They performed an ECG, which did not show any signs of cardiac disease. They did not know what to do next, because the shoulder was just as painful as before despite the regular pain medication she had taken plus the intravenous paracetamol she has been given. They were stuck, and so was the patient. The patient had COPD, high blood pressure, hypothyroidism and carpal tunnel syndrome as long-term conditions. I recommended that she should be seen face to face in the unit.
When she arrived with her daughter she was clearly not well. The daughter was doing the talking for her. The patient was holding her breath and grimaced in pain. She described the pain as dull and throbbing and unbearable. I re-examined chest and neck; the cervical foraminal closure maneuver did not reproduce her pain, she could move her shoulder blade and I could passively move her arm in all directions. In the next step I carefully palpated her shoulder muscles. The muscles of the posterior armpit were quite tender to touch and finally I found a taut band with an active trigger point in what must have been the teres major muscle. Pressing on the painful spot reproduced the patient’s pain and palpating across the fibres of the muscle with a pincer grip elicited a twitch response.
Is unscheduled care the right place to perform acupuncture? Is dry needling or injection of trigger points with local anaesthetic standard practice in out of hours care? Certainly not. But what would be the alternative? The alternative would consist of escalating the drug regime in a frail elderly person with COPD by introducing stronger opioids or gabapentinoids or giving more nonsteroidal drugs with the added risk of injuries to kidney and stomach.
I explained the working diagnosis and the possible management options to the patient. She insisted that none of her medication had worked so far and going on like this is not an option. So I decided to offer acupuncture/dry needling. I used my purple middle-of-the-road standard needle, kept my controlling pincer grip on site and moved the needle around in the muscle bulk I held between my fingers. After removing the needle I asked the patient to relax her armpit muscles. I moved her arm around in several directions and gently stretched the muscle, followed by asking her again to relax the arm.
With an expression of astonishment she said she could move her arm again and that the pain has diminished substantially. She said it is still there, but bearable. I arranged with her that she should obtain a chest x ray film to make sure this was not the secondary feature of a potential primary malignancy (years of smoking!) and that I would contact her later to see how she was getting on after this non-pharmacological intervention for severe acute pain.
A week later I phoned the contact number to evaluate the intervention. It turned out the contact number belonged to the paramedic. The paramedic said that he had seen her in the village and that “acupuncture worked very well”. Eventually I obtained her home number and phoned her personally. She told me that indeed the intense shoulder pain had gone, that the chest x ray film was unremarkable and that she was getting physiotherapy for her carpal tunnel syndrome.
In retrospect I would not claim that this one-needle-intervention could be classified as a ‘wonder’ cure, but it certainly saved her from escalating the drug ladder or a hospital referral.
Generalising from this case there are several points to consider: acute myofascial pain can frequently be encountered in urgent-care-settings, but dry needling/acupuncture is not routinely part of the therapeutic culture in these settings. There is in my view an unmet need. Rather than in chronic pain settings skillful treatment of myofascial trigger points, identified by reproducing the patient’s pain pattern, can make a meaningful and immediate difference and keep the drug burden at bay.
El-Wahsh S, Efendy J & Sheridan M. Migration of self-introduced acupuncture needle into the brainstem. J Neurosci Rural Pract 2018; 9(3): 434 – 436.
An elderly man presented to an emergency department after an acupuncture needle (which he had inserted himself) had broken off in the attempt to withdraw it. Exploration of the neck was unsuccessful, and the patient required a CT scan to locate the needle (ultrasound failed to locate it); four days after initial presentation, it had migrated cranially through the foramen magnum and pierced the dura mater with the tip resting in the brainstem. It had to be removed by open surgery, followed by a patch repair of the dura mater. The tip of the needle was angulated. The patient made a good recovery and was free of symptoms at follow-up after a month.
Accidental perforations of anatomical structures are well documented as complications of acupuncture. Indeed there are several cases of penetration of the brainstem with acupuncture needles.[3–7] This presentation highlights a few safety issues, and suggests an approach to dealing with such incidents in future..
The location of the needle suggests insertion in the midline at GV16 (Fengfu), which the patient must have performed by touch alone, at a slight upward angle. When patients are taught self-acupuncture, the danger of deep insertion should be discussed in detail, and perhaps self-needling without the ability to see what is being done should be discouraged in potentially dangerous areas such as this. At this point it is salient to remind readers of the BMAS needling policy in the neck.
Above C2 – angle the needle tip towards the palpable occipital bone.
Perpendicular insertion should be avoided.
Below C2 – angle the needle tip towards the cervical articular pillar
(the pars interarticularis and facet joints usually between C3 and C5).
On presentation, the needle (0.25x30mm) was 8mm below the surface of the skin, embedded in the muscles of the neck. The patient had been unsuccessful in his attempt to retrieve the needle. Ultrasound scanning failed to show the needle, and an initial surgical attempt to remove the needle in the emergency department was unsuccessful. The authors felt that manipulations by the patient and doctors had contributed to the needle migration. This suggests that, should a needle break and disappear into the patient’s soft tissue, that neither patient or practitioner should attempt to remove it, but that the patient should be referred, or self-refer, immediately to an emergency department. Again, this needs to be discussed when instructing a patient in self-acupuncture.
It seems that this location is particularly vulnerable to needle migration because of the thickness of muscle and the lack of resistance to needle progression when the tip reaches the spinal canal or brainstem. It seems sensible for the patient to relax the postural muscles of the neck by lying down with the head supported without any pressure on the needle site, while specialist investigation with x ray films and CT is awaited.
El-Wahsh S, Efendy J, Sheridan M. Migration of Self-Introduced Acupuncture Needle into the Brainstem. J Neurosci Rural Pract 2018;9:434–6. doi:10.4103/jnrp.jnrp_480_17
White A. A cumulative review of the range and incidence of significant adverse events associated with acupuncture. Acupunct Med 2004;22:122–33. doi:10.1136/aim.22.3.122
Anderson DW, Datta M. The self-pith. AJNR Am J Neuroradiol 2007;28:714–5.
Choo DC, Yue G. Acute intracranial hemorrhage caused by acupuncture. Headache 2000;40:397–8.
Zhu Y, Xue Z, Xie D, et al. Medulla oblongata hemorrhage after acupuncture: A case report and review of literature. Interdiscip Neurosurg 2018;11:1–3. doi:10.1016/j.inat.2017.09.013
He W, Zhao X, Li Y, et al. Adverse events following acupuncture: a systematic review of the Chinese literature for the years 1956-2010. J Altern Complement Med 2012;18:892–901. doi:10.1089/acm.2011.0825
Miyamoto S, Ide T, Takemura N. Risks and causes of cervical cord and medulla oblongata injuries due to acupuncture. World Neurosurg 2010;73:735–41.pm:20934166
Effect of Acupuncture on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage Breast Cancer – Hershman et al JAMA 2018
A large rigorous and statistically positive trial published in a prestigious general medical journal, and an increasingly familiar conclusion rings out – acupuncture is significantly better than sham, but the difference may not be of clinical significance. This was not the exact conclusion of Hershman et al, but the latter is similar to this common EBM (Evidence-Based Medicine) mantra, perhaps insisted upon by the JAMA editors.
Hershman et al is the biggest trial of acupuncture for joint pain related to the use of aromatase inhibitors in women with breast cancer, and it randomised 226 women in a 2:1:1 split to verum (110), sham (59) or waitlist (57). The acupuncture protocols involved 18 sessions over 12 weeks, with 2 per week for the first 6 weeks. The primary outcome was the worst pain score on the Brief Pain Inventory (BPI-WP) at 6 weeks. The authors chose a clinically meaningful difference on this scale to be 2 points based on the analysis of 11 point Numerical Rating Scales (NRS) performed by Farrar et al.
But is it a 2-point change from baseline that is clinically relevant, or a 2-point difference between groups. Well the individual patient only knows the change from their own baseline, and the proportion of that change attributed to natural history or expectation in the group mean differences of a trial is irrelevant to the individual.
In the analysis by Farrar et al, the change of 2 points considered to be clinically relevant was measured from baseline. In the present study by Hershman et al, at the primary end point (6 weeks) the mean BPI-WP score in the acupuncture group had dropped 2.05 from baseline, and the percentage of patients with a drop of 2 points or more was 58%. This seems to be clinically relevant to me, but the conclusion reads:
“…the observed improvement was of uncertain clinical importance.”
At all time points the difference between acupuncture and sham control was statistically significant, but the difference did not reach 2 points, and this probably explains their conclusion. At first I assumed it was the JAMA editors that insisted on this conclusion, having seen this done before in a high profile general medical journal. But having checked the protocol of Hershman et al, I see that the authors have made the error of taking Farrar et al’s 2-points’ difference from baseline as a between group difference instead:
Reduction in worst joint pain at 6 weeks between the true acupuncture compared to sham acupuncture and waitlist control groups: A difference of two points in the modified Brief Pain Inventory worst pain score (item #2) has been identified as a clinically meaningful difference.
[From 10.1 of the protocol in supplement 1 of Hershman et al]
So I think this must be an error on the part of the authors rather than the insistence of the JAMA editors, but I expect it made it easier to publish the paper in this particular journal, based on its history of accepting negative acupuncture papers.
Whether this particular paper is considered positive or not, the data from it will inform future reviews, and currently these appear to be positive.[4,5]
Before I sign off on this blog, I should comment on the sham control group. It was a superficial penetrating off-point sham, and it did not seem to perform better than waiting list at 6 weeks, with the difference between acupuncture and sham at 0.92 and the difference between acupuncture and waiting list at 0.96. The effect of sham seemed to grow though, since at the 24-week point the difference between acupuncture and sham was only 0.59, and the difference between acupuncture and waiting list was 1.23.
Another pattern to note is that the difference between acupuncture and sham appeared smallest and not statistically significant for the outcome of pain interference, which is probably the closest of the outcomes used to health-related quality of life (HRQoL). Readers of this blog will be familiar with the finding from previous ‘big data’, and my blog on the same.
Hershman DL, Unger JM, Greenlee H, et al. Effect of Acupuncture vs Sham Acupuncture or Waitlist Control on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage Breast Cancer: A Randomized Clinical Trial. JAMA 2018;320:167–76. doi:10.1001/jama.2018.8907
Farrar JT, Young JP, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94:149–58. doi:10.1016/S0304-3959(01)00349-9
Brinkhaus B, Ortiz M, Witt CM, et al. Acupuncture in Patients With Seasonal Allergic Rhinitis. Ann Intern Med 2013;158:225. doi:10.7326/0003-4819-158-4-201302190-00002
Chen L, Lin C-C, Huang T-W, et al. Effect of acupuncture on aromatase inhibitor-induced arthralgia in patients with breast cancer: A meta-analysis of randomized controlled trials. Breast 2017;33:132–8. doi:10.1016/j.breast.2017.03.015
Halsey EJ, Xing M, Stockley RC. Acupuncture for joint symptoms related to aromatase inhibitor therapy in postmenopausal women with early-stage breast cancer: a narrative review. Acupunct Med 2015;33:188–95. doi:10.1136/acupmed-2014-010735
Saramago P, Woods B, Weatherly H, et al. Methods for network meta-analysis of continuous outcomes using individual patient data: a case study in acupuncture for chronic pain. BMC Med Res Methodol 2016;16:131. doi:10.1186/s12874-016-0224-1
Acupuncture has become very popular within the field of assisted reproduction, and particularly as an intervention within IVF (In-Vitro Fertilisation). In an editorial from 2015 in Acupuncture in Medicine, David Carr lists 12 meta-analyses on the subject in just 6 years, including a total of 34 RCTs. There was no clear conclusion from the reviews – most outcomes showed no benefit for acupuncture, but some did. In general we see quite large benefits over control in open studies, and no effects in blinded sham control studies.
It is worth noting that in one high quality double blind study (n=370), the sham acupuncture group had a significantly better outcome than the real acupuncture group (live birth rate 38.4% versus 29.7% respectively). The research team from Hong Kong went on to test the same protocol (treatment before and after embryo transfer – ET) in frozen-thawed cycles (FET; n=226). The results were very similar (live birth rate 35.4% with sham versus 29.2% with real), significantly favouring sham in all outcomes. Following directly on from this the team decided, logically but rather surprisingly, to test sham versus sham: a single session of sham acupuncture after ET with sham before and after ET, as in the original protocol. This trial was presented in a meeting at The Hague in 2011, where it won a research prize (I was part of the awarding committee), and I remember discussing the topic with the first author of the paper – Emily So. There was no significant difference in pregnancy outcomes, but the two-session protocol conferred a significant benefit in terms of anxiolysis (details from the abstract submitted to the meeting, 2011).
So where am I going with this? Well it seems likely that acupuncture or sham acupuncture confer a context-related benefit in terms of supportive care mediating anxiolysis. But beyond this, it seems possible that real acupuncture has some potential disadvantages when performed around embryo transfer. In brief, strong somatic stimulation in the segments related to the uterus, or indeed outside those segments, may influence contractile behaviour of the uterus. This is mostly harmless of course, but increasing contractions after ET in an otherwise quiescent uterus may expel the embryo. Equally, contractions initiated by the instrumentation during ET may be suppressed by acupuncture, which might prevent expulsion of the embryo. It was on the latter basis that Paulus first used the technique around ET (personal communication, Irina Szmelskyj). A panel of experts presenting at the BMAS Spring meeting in Newcastle (2015) concluded that acupuncture should be avoided around ET and implantation unless the woman had symptoms that might be ameliorated with acupuncture – abdominal cramps for example.
…it seems possible that real acupuncture has some potential disadvantages when performed around embryo transfer.
The paper that stimulated this blog was published in JAMA in May 2018. I heard the results presented in a meeting in Berlin a year before, and discussed them with the lead author Caroline Smith. Essentially it is the largest sham controlled trial of acupuncture within IVF to date (n=824), and it failed to demonstrate any benefit of acupuncture over sham. The live birth rate was 18.3% in the acupuncture group versus 17.8% in the sham group. The clinical pregnancy rate was marginally higher in the acupuncture group at 25.7% versus 21.7%, but this was negatively offset by an increased rate of pregnancy loss.
Given what I said above about Emily So’s research, the results are not particularly surprising. The rates of live birth appear much lower, but that is likely related to the fact that nearly half of the women in Caroline Smith’s study had already failed 2 or more cycles of IVF, whereas the majority in Emily So’s research were on their first cycle.
I was particularly interested to see in the supplementary data of Caroline Smith’s huge multicentre trial that in two of the 15 sites there was a significant benefit of sham over real acupuncture, and at no site was there a significant benefit for real over sham. Data was pooled from 4 sites, leaving 12 comparisons in the forest plot (see figure below). Using 95% confidence intervals we would only expect a type I statistical error (a significant difference in the sample data when there is no real difference between the populations sampled) to occur 5% of the time ie 1:20. So 2 occurrences in 12 comparisons does not seem likely by chance alone. This adds some weight to my comments above regarding potential risks associated with the somatovisceral reflex effects of real acupuncture.
Does acupuncture have a role in fertility or not? The majority of the clinical trial data comes from within IVF cycles, and more specifically either side of ET. I have always thought this was a long shot from a physiological point of view, since acupuncture generally requires a course of regular treatments to mediate measurable effects in clinically relevant outcomes. So I am pleased that this trial will probably place the last nail in the coffin for this very limited technique. But is there any role for acupuncture in fertility? Well we have also seen a very large negative trial from China on segmental electroacupuncture (EA) versus clomiphene for ovulation induction in PCOS: the subject of a previous blog. I still hold out some hope that we will find a useful place for the technique since Elisabet Stener-Victorin first opened the whole chapter in 1996 with her trial on the influence of segmental EA on uterine artery impedance.
In terms of acupuncture research and practice I think the focus should be outside IVF.
Either for couples with unexplained infertility and no male factor (unless treatment is aimed at the man of course – that’s another topic entirely), or in the weeks and months prior to an IVF cycle. This phase, theoretically at least, has always held the greatest promise, but because of the trial by Paulus in 2002, the research, in my opinion, went on a very loud and frantic wild goose chase.
After posting this blog I decided to email the team to ask about the live birth rate in the third of Emily So’s studies – the one comparing sham with sham. I emailed the senior author Ernest Hung Yu Ng, and to my surprise he answered with a further abstract describing more unpublished research from his team. They had gone on to test sham acupuncture either side of ET in an open pragmatic trial against no additional acupuncture in 800 women undergoing IVF! Live birth rate was not included in the abstract, but the on-going pregnancy rate was 32.3% in the sham acupuncture group and 33.3% in the no acupuncture group.
This is very useful addition data that clearly now points to the fact that sham acupuncture around ET is not beneficial, and therefore implies that real acupuncture may sometimes confer risks when applied at ET. This does not apply to acupuncture performed at other times, and further encourages me to promote the testing of acupuncture performed in the lead up to IVF rather than during the process.
Carr D. Somatosensory stimulation and assisted reproduction. Acupunct Med 2015;33:2–6. doi:10.1136/acupmed-2014-010739
So EWS, Ng EHY, Wong YY, et al. A randomized double blind comparison of real and placebo acupuncture in IVF treatment. Hum Reprod 2009;24:341–8. doi:10.1093/humrep/den380
So EWS, Ng EHY, Wong YY, et al. Acupuncture for frozen-thawed embryo transfer cycles: a double-blind randomized controlled trial. Reprod Biomed Online 2010;20:814–21. doi:10.1016/j.rbmo.2010.02.024
Paulus WE, Zhang M, Strehler E, et al. Influence of acupuncture on the pregnancy rate in patients who undergo assisted reproduction therapy. Fertil Steril 2002;77:721–4.
Smith CA, de Lacey S, Chapman M, et al. Effect of Acupuncture vs Sham Acupuncture on Live Births Among Women Undergoing In Vitro Fertilization: A Randomized Clinical Trial. JAMA 2018;319:1990–8. doi:10.1001/jama.2018.5336
Stener-Victorin E, Waldenström U, Andersson SA, et al. Reduction of blood flow impedance in the uterine arteries of infertile women with electro-acupuncture. Hum Reprod 1996;11:1314–7.
For some time, a group on the US east coast have been quietly scanning brains with functional magnetic resonance imaging (fMRI) and related techniques to examine the effects of acupuncture. They hit the headlines in rather a dramatic manner in 2017.[1,2]
At the beginning of the fMRI story we saw some extraordinary claims concerning point specificity in acupuncture from a famous name in the development of fMRI, but these were later retracted. I was relieved to see the retraction, as the claims did not seem mechanistically credible from a neurophysiological point of view. The authors retracted their paper because the results were not in line with the body of developing evidence that acupuncture with typical deep tissue sensation (I prefer this term, but it equates to de qi) seems to cause a general deactivation of limbic structures,[4,5] rather than very specific and targeted functional activations.
So why am I a year behind the headlines? Well I was asked to discuss the research for a television programme, so I read the paper thoroughly in preparation and discovered an interesting observation that had previously escaped my notice. Then there was a mix-up with storyboards and we discussed other research instead. So I thought I had better put all those hours of preparation to good use by describing my thoughts on this rather complex area of research.
The team concerned here first came to my attention when they demonstrated a change in cortical mapping of the second and third fingers (D2/D3) in patients with carpal tunnel syndrome (CTS) treated with acupuncture. This was a departure from the fMRI studies prior, which had tended to simply watch what happened in the brain after acupuncture or control procedures in healthy subjects. Whilst it was an interesting finding, the study was observational rather than a strict RCT, and I felt that the change in cortical mapping was likely to be downstream of the main effects of acupuncture rather than a direct effect, ie a consequence of the acupuncture mechanism rather than part of the mechanism. This is always the problem with observational data – is the observed association causal or consequential?
The team continued to study CTS, and the research published in 2017 was a three-armed study of 80 patients with CTS  – a relatively large study in fMRI terms, but small and underpowered in terms of standard clinical trials of acupuncture in pain. The 3 different interventions principally involved electroacupuncture (EA): local EA (PC7–TE5), distant contralateral EA (SP6–LR4) and ipsilateral regional sham EA (non-points on the flexor aspect of the mid forearm). Manual points were included in the same regions as the EA in each group.
The symptom scores in all groups declined over the course of treatment with no significant differences, although noticeably bigger change scores in the local and sham groups, where the focus of treatment was in the correct limb. Despite this, the median nerve conduction latency improved in both EA groups and deteriorated in the sham EA group. D2/D3 cortical separation distance improved marginally more (not significant) with local EA than distant EA, and not at all in the sham.
…median nerve conduction latency and D2/D3 cortical separation distance improved in both EA groups
So despite there being no difference between groups in terms of symptoms, there was a clear difference in objective measures of nerve function and brain function. And there is more! The degree of improvement in D2/D3 cortical separation distance immediately after the 8-week 16-session treatment course predicted (correlated with) the symptom score at 3 months follow-up. That is very interesting, and somewhat counters my assumption that the cortical remapping is downstream (ie a consequence rather than a cause) of the effect of EA.
The degree of improvement in D2/D3 cortical separation distance correlated with the symptom score at 3 months follow-up
Another interesting aspect is the rate of deterioration in symptom score of the sham group after they were unmasked, and the continued improvement of the distal group after they learned that they had a genuine treatment. This makes me ponder over the influence of other brain centres – those related to cognition analysis and expectation – and how these can add unwanted noise in group means for subjective outcomes.
And there is still more! The bit I originally missed because it was just too much effort to read and understand. The team studied the microstructure of the white matter adjacent to the relevant areas of the primary somatosensory cortex (S1). I didn’t even know this was possible, but it has been around for about 15 years. Fractional anisotropy is a measure of order in the structure of white matter based on diffusion of water. A perfect isotropic material would have an even pattern of diffusion in all directions, but uniform tracts of myelinated neurones will disturb this, and cause a degree of anisotropy. Got it? Anyway, the team discovered that the changes after real EA (local & distant) in fractional anisotropy near the S1 cortex related to the contralesional hand correlated with latency changes in the median nerve. This was not true of sham. Even more interesting is that this correlation between changes in fractional anisotropy and median nerve latency occurred in different areas of the ipsilesional SI cortex depending on whether the EA was local or distant.
This has to be considered speculative, since it was a bit of a fishing trip, but it is very exciting to speculate that in the future we may be able to develop ways of tracking the course of plastic changes in the central nervous system and design optimal treatment approaches as a result; moving us from ancient philosophy, through neuroscience from the last century (segmental neuromodulation) perhaps to real-time neural remodelling.
Maeda Y, Kim H, Kettner N, et al. Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture. Brain 2017;140:914–27. doi:10.1093/brain/awx015
Cho ZH, Chung SC, Lee HJ, et al. Retraction. New findings of the correlation between acupoints and corresponding brain cortices using functional MRI. Proc Natl Acad Sci U S A 2006;103:10527. doi:10.1073/pnas.0602520103
Wu MT, Hsieh JC, Xiong J, et al. Central nervous pathway for acupuncture stimulation: localization of processing with functional MR imaging of the brain–preliminary experience. Radiology 1999;212:133–41.http://www.ncbi.nlm.nih.gov/pubmed/10405732 (accessed 28 Aug2011).
Hui KK, Liu J, Makris N, et al. Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects. Hum Brain Mapp 2000;9:13–25.
Napadow V, Liu J, Li M, et al. Somatosensory cortical plasticity in carpal tunnel syndrome treated by acupuncture. Hum Brain Mapp 2007;28:159–71. doi:10.1002/hbm.20261
Earlier in 2017 this paper popped up in JAMA. It was from the same group that had published a huge multicentre trial of electroacupuncture (EA) for chronic severe functional constipation, which was featured in a previous blog. This was a large sham controlled trial (n=504) although not as big as the previous one on constipation (n=1075).
EA can influence symptoms in overactive bladder
We have known for some time that EA can influence symptoms in overactive bladder, albeit under another name. These are mainly urge symptoms, and a similar mechanism that reduces pain perception might be postulated to explain the results. Urinary stress incontinence (SUI) seems entirely different, and so the results of this trial were rather unexpected (by me at least).
I revisited the paper to examine the intervention in more detail and consider the anatomy involved. The active EA intervention involved just two points on each side (I love the simplicity!) – BL33 and BL35. 75mm needles were employed, and inserted 50 to 60mm. At BL33 the angulation (oblique inferiomedial) aimed to have the needle tip entering the S3 foramina. At BL35 (just lateral to the coccyx) the needle was angled superiolateral. In terms of safety, the structure to be avoided in this area is the rectum, and a paper in Acupuncture in Medicine studied the position of needle tips relative to the rectum when inserted into sacral foramina, but not BL35. Needles inserted into S4 got close to the rectum (4-8mm), but there was a bigger margin in S2 and S3 (19-29.5mm). At BL35, a sufficient lateral angulation would avoid getting close to the rectum, but this angulation would be critical.
In terms of physiological effects the needle placement at the S3 foramina would certainly stimulate the dorsal ramus of S3, and possibly the ventral ramus, depending on depth. A superiolateral angulation at BL35 might approach the pudendal nerve as it passes over the sacrospinous ligament, lateral to the sacrum at about the level of S4 (sacral hiatus). Direct stimulation of the pudendal nerve has been described in a small case series of patients with spinal stenosis refractory to less invasive EA, and nerve stimulation was confirmed by perineal sensation. The study in JAMA on SUI does not mention perineal sensation but just mentions mild shivering of the skin around the points, presumably secondary to muscle contraction. EA at 50Hz was applied at a current of 1-5mA. If either needle tip was close to motor fibres, the relevant muscle would have contracted quite strongly for the entire period of stimulation (30 minutes). The authors do not report such effects, but they do discuss the possibility of S3 and pudendal nerve stimulation. If direct electrical nerve stimulation occurred, the effect may have been in some part attributed to pelvic floor muscle contraction induced by motor nerve stimulation. With this in mind it is interesting to note that the effect observed after 18 sessions of acupuncture over 6 weeks was similar to 12 weeks of a pelvic floor exercise programme.
18 sessions of acupuncture over 6 weeks was similar to 12 weeks of a pelvic floor exercise programme
I should note that the sham technique involved no skin penetration and no electrical output, so if there was direct motor nerve stimulation in the active group, there would have been quite a considerable difference in terms of the physiological stimulation applied between the groups.
Liu Z, Liu Y, Xu H, et al. Effect of Electroacupuncture on Urinary Leakage Among Women With Stress Urinary Incontinence: A Randomized Clinical Trial. JAMA 2017;317:2493–501. doi:10.1001/jama.2017.7220
Liu Z, Yan S, Wu J, et al. Acupuncture for Chronic Severe Functional Constipation: A Randomized Trial. Ann Intern Med 2016;165:761–9. doi:10.7326/M15-3118
Peters KM, Carrico DJ, Perez-Marrero R a, et al. Randomized Trial of Percutaneous Tibial Nerve Stimulation Versus Sham Efficacy in the Treatment of Overactive Bladder Syndrome: Results From the SUmiT Trial. J Urol 2010;183:1438–43. doi:10.1016/j.juro.2009.12.036
Katayama Y, Kamibeppu T, Nishii R, et al. CT evaluation of acupuncture needles inserted into sacral foramina. Acupunct Med 2016;34:20–6. doi:10.1136/acupmed-2015-010775
Inoue M, Hojo T, Nakajima M, et al. Pudendal nerve electroacupuncture for lumbar spinal canal stenosis – a case series. Acupunct Med 2008;26:140–4.pm:18818559
In 2012, the first individual patient data meta-analysis (IPDM) in the field of acupuncture was published. It was also one of the first in the field of pain research. It was a struggle to publish, principally (I guess) because the IPDM method was relatively new to journal editors, and because the general medical journals tend towards conservatism and orthodoxy, so positive research on unorthodox interventions probably have higher hurdles to clear prior to publication.
The 2012 IPDM included data from 29 trials and 17 922 patients. The update has just been published, and it includes data from 39 trials and 20 827 patients.
It should be noted that trials were only included where allocation concealment was unambiguously determined to be adequate, so this is a data set built on what used to be called the highest quality trials.
Trials were grouped into 3 clinical categories for analyses: osteoarthritis, chronic headache, non-specific musculoskeletal pain (back and neck pain), and shoulder pain. Acupuncture was shown to be superior to sham controls with effect sizes of 0.24 (previously 0.26), 0.16 (0.15), 0.30 (0.37) and 0.57 (0.64) respectively. Acupuncture was also shown to be superior to no acupuncture controls with effect sizes of 0.63 (0.57), 0.44 (0.42) and 0.54 (0.55) respectively for osteoarthritis, chronic headache, and non-specific musculoskeletal pain. [Effect sizes here are standardised mean difference – SMD – using fixed effects; those in brackets are from the 2012 IPDM].
Acupuncture is superior to sham with an effect size of about 0.2 and superior to no acupuncture with an effect size of about 0.5
Overall we see an effect over sham of about 0.2 and an effect over no acupuncture of about 0.5 SMD. The question remains over whether decisions to use acupuncture should be made with the former or the latter comparison. The effect over sham excludes the context effects that naturally occur in practice, and is small – NICE guideline development groups tend to use this. The effect over no acupuncture is the pragmatic comparison, and closest to real life practice, but naturally includes different context effects for different interventions, and this is favourable to interventions such as acupuncture that might be seen as more dramatic to the patient than say a pill. It is currently impossible to separate out the different context related factors, and the compassionate touch of an acupuncture practitioner should be included in the therapeutic effect, whereas the expectation of the patient being needled perhaps should not. Sham acupuncture includes both of these and is much more effective than most other shams including placebo pills.
On the whole I am a pragmatist in the complex environment of clinical practice, but I like to be a reductionist when it comes to mechanistic analysis and planning interventions. So does this huge data set allow us any further insights through purely statistical analysis? Well I am afraid that with conventional levels of statistical probability very little is revealed; however, if we are not so rigid and examine the trends with a mechanistic eye a few interesting things start to pop out.
In terms of the characteristics of acupuncture, the only factor that had a clear influence was the number of treatments, and this was only apparent in the comparison against no acupuncture. This perhaps does not come as a surprise, but it does suggest that we should be more focussed on providing enough treatment sessions and not worrying as much about other aspects of the acupuncture approach.
Many readers will know that I have a particular interest in electroacupuncture (EA), so I am keen to highlight the fact that in the more mechanistic comparison of acupuncture over sham the use of EA as a treatment characteristic had the largest effect size (0.32) and the lowest p value (p=0.14) of any characteristic studied. This does not reach the commonly adopted level of statistical probability, but equates to a 6:7 chance of being a real effect.
Going back to the more pragmatic comparison of acupuncture over no acupuncture, there are a couple of interesting trends apparent. The largest was for ‘de qi attempted’, and this reached 0.74 with p=0.063. This might also suggest a dose effect, but strangely the characteristic ‘manual stimulation allowed’ actually had a moderately negative effect.
Another characteristic that approached significance in the pragmatic comparison was ‘male practitioner’ at a p value of p=0.084. The effect size associated with this was very small and negative at -0.07, but it is tempting to view this against a backdrop of mechanistic research on nocebo in pain, and suggest that male practitioners might think about channelling their more feminine sides during consultations.
male practitioners might think about channelling their more feminine sides during consultations
There are a couple of insights that have relevance to future research. First, there was a significant difference in the effect size measured between penetrating and non-penetrating shams. There was a smaller difference between acupuncture and penetrating shams, or needling against needling, as I like to refer to this comparison. I should note that this result was not maintained when outlying trials with large effect sizes were excluded; however, I would still advise researchers to avoid testing needling against needling in clinical trials! Second was in the pragmatic comparison with no acupuncture controls. The effect size of acupuncture was significantly smaller when compared with controls that were classified as high intensity, for example a course of individualised supervised physical therapy.
The team (ATC – acupuncture trialists’ collaboration) also studied the time course of acupuncture effects by analysing the change in effect size at different time points. This seems most relevant for the pragmatic comparison against no acupuncture, but they analysed both. The effects of acupuncture held up well against no acupuncture controls with an estimated drop of only 15% of the effect after one year.
There was an estimated drop of 25% at one year in the effect of acupuncture over sham acupuncture, but heterogeneity was significant. When neck pain trials were excluded the heterogeneity disappeared, and the drop in effect size reduced to about 6%. It is difficult to imagine what this means clinically, so I investigated a little. The overall effect size for acupuncture over sham in neck pain was the most remarkable at 0.83, which sits in stark contrast to the tiny 0.17 for back pain. Neck and back pain are not the same of course, with a higher proportion of soft tissue pain being the likely reason that acupuncture has greater effects in the former. But those huge effects on neck pain seem to disappear quickly in the statistics and generate heterogeneity by contrast with small effects of a longer time course in back pain. When you look more closely you see that there are only 3 trials in neck pain, and one of them is a clear outlier. I checked the original paper. It is the largest sham controlled trial in neck pain, and the control group received mock TENS. The treatment period was for 3 weeks and involved 5 treatment sessions. The mean pain score (0-100mm scale) in the acupuncture group dropped from a baseline of 68.7 to 26.6 after treatment and 27.6 after 6 months. The pain score in the control group was 72.3 at baseline, 58.3 after treatment, and 45.5 after 6 months. So you can see from these figures that the effect of acupuncture was actually maintained fully for 6 months, but the control group improved over 6 months to reduce the difference by about 50%, either by natural history or perhaps patients seeking other treatments. Just looking at the summary statistics of differences between groups gives a very different impression from the within group changes. This is one of the dangers of drawing conclusions from between group change values, without checking the within group data. We are given a false impression that the effect of acupuncture in neck pain is short-lived, when in fact it is not. The false impression comes from an improvement in the comparator, rather than a degradation of the effect in the treatment group. This change is almost certainly responsible for the statistical heterogeneity observed, and the consequent uncertainty is inappropriately directed at the acupuncture effect.
Well I think I’ll leave it there… please go and pour over the numbers in this update, it is a truly fabulous endeavour, which is giving us ever-greater clarity as the data grows, as well as more questions to debate.
Vickers AJ, Cronin AM, Maschino AC, et al. Acupuncture for chronic pain: individual patient data meta-analysis. Arch Intern Med 2012;172:1444–53. doi:10.1001/archinternmed.2012.3654
Vickers AJ, Vertosick EA, Lewith G, et al. Acupuncture for Chronic Pain: Update of an Individual Patient Data Meta-Analysis. J Pain Published Online First: 30 November 2017. doi:10.1016/j.jpain.2017.11.005
Meissner K, Fässler M, Rücker G, et al. Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Intern Med 2013;173:1941–51. doi:10.1001/jamainternmed.2013.10391
Vas J, Perea-Milla E, Méndez C, et al. Efficacy and safety of acupuncture for chronic uncomplicated neck pain: a randomised controlled study. Pain 2006;126:245–55. doi:10.1016/j.pain.2006.07.002
About a year ago I was surprised to see a sham controlled RCT of electroacupuncture (EA) published in Annals of Internal Medicine. I was surprised for several reasons: I review for Annals, and I had not seen the paper for review; it was on chronic severe functional constipation – a subject with few previous RCTs of acupuncture; it was positive; it was the biggest 2 arm RCT in the acupuncture literature to date (n=1075).
The treatment was relatively straightforward – EA to the rectus abdominis muscle bilaterally (ST25—SP14) and manual stimulation of a point in tibialis anterior bilaterally (ST37). The sham control involved shallow needling of points close by, but not on the meridians, avoidance of typical needling sensation (de qi) and sham EA (ie no electrical stimulus, but the power indicator and sound as if it were real EA). The frequency used varied from 10 to 50Hz and the intensity was between 0.1 and 1mA. The frequency covers the best range for autonomic modulation (as judged by visceral blood flow), but the intensity was varied from sub-threshold (in terms of nerve stimulation you generally need 0.3 to 0.5mA for the lowest electrical threshold nerves to respond) to a rather gentle stimulus of 1mA. In my experience, many patients do not perceive sensation until around 1.5mA when needle tips are placed into muscle.
Twenty-eight EA sessions were provided over 8 weeks
Twenty-eight EA sessions were provided over 8 weeks – 5 sessions per week for the first 2 weeks, and 3 sessions per week for the next 5 weeks. So it was quite an intense course of treatment. There was no comment about rotation of needling sites – with such an intense treatment regime it is common to alternate similar protocols so that needle sites do not get sore.
The primary outcome was based on a stool diary and was the number of complete spontaneous bowel movements (CSBM) per week. EA performed significantly better than sham at 8 weeks and the effect was maintained at 12 weeks follow-up.
Blinding appears to have been maintained at 4 and 8 weeks from a random sample of 140 participants. At 8 weeks about 90% from each group guessed that they had received the real EA.
The size of the effect appears to be clinically relevant, with a change from baseline in CSBM of greater than 1 per week, although the group average does not exceed 3 per week so most participants in the active group would still be considered to have constipation.
Of interest is a follow-up paper published recently that examines factors associated with the response to acupuncture in this trial. It found that age was inversely related to response to acupuncture (ie younger patients did better), and comorbidities reduced the likelihood of response.
Liu Z, Yan S, Wu J, et al. Acupuncture for Chronic Severe Functional Constipation: A Randomized Trial. Ann Intern Med 2016;165:761–9. doi:10.7326/M15-3118
Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol 2004;2:796–805. doi:10.1016/S1542-3565(04)00356-8
Yang X, Liu Y, Liu B, et al. Factors related to acupuncture response in patients with chronic severe functional constipation: Secondary analysis of a randomized controlled trial. PLoS One 2017;12:e0187723. doi:10.1371/journal.pone.0187723
Finally I have come to address this topic, some months following publication of an eagerly awaited (at least by me) large clinical trial. I have been a colleague and friend of the second author (ES-V) since proofreading her PhD thesis over 20 years ago. In those days I focussed solely on muscle so any suggestion of acupuncture being used to influence visceral function or blood flow was a bit of a conceptual stretch for me. After all my needles were going directly into the target that I wanted to influence, and I was just about comfortable with the idea that the needle alone actually did something useful without the need for injecting a drug. So the idea that acupuncture or electroacupuncture could have any useful effect through indirect influences only really arose when I read Lisa’s thesis.
Her early work stimulated interest in the use of acupuncture in fertility and augmented reproduction,[2,3] although the subsequent plume of clinical research that occurred in this field seemed to go a little off course from a basic science perspective, with an unwarranted focus on embryo transfer as part of IVF. Lisa observed this, but continued with her research path, which was by then on PCOS. She clearly showed that segmental electroacupuncture (EA) could have positive influences on the condition, both in terms of hormonal and metabolic markers, and apparently in terms of ovulation rates.[5,6]
Lisa regularly runs research updates for the BMAS, and we were all excited to hear of her involvement in this huge clinical trial in China on women with PCOS. With 1000 women to be randomised and treated the trial was a considerable undertaking, and several years passed with no news. Then on the 27th June 2017 the results were out… clomiphene was nearly twice as good as segmental EA, and segmental EA was no better than a very minimal non-segmental sham.
It did not seem to make sense from the basic science perspective! The numbers were big enough to power the comparison with sham (assuming similar size effects to those we see in clinical trials of chronic pain). The intervention appeared sufficient in neurophysiological terms, to generate the effects that had been demonstrated in the basic science experiments that had led up to this trial. Yes it was a penetrating sham, but the physiological stimulus of the sham intervention would not have generated any effect in the laboratory in terms of somatovisceral reflexes. In the clinical realm, with conscious humans, sham always seems to have a substantial context effect, but still I would have expected some physiological effect from the segmental EA.
Well there was a difference between real and sham EA in terms of adverse events. In the segmental EA group the rate of diarrhoea was 3 times that in the sham EA group, perhaps indicating an excess effect in somatovisceral reflexes in a small proportion of women. It should be noted that the absolute rate of diarrhoea was low at 1.6 and 5%, in sham and real segmental EA respectively.
The primary outcome was live birth rate. This is the most valid outcome for trials of this nature, but it is not the same as ovulation induction of course, so it is not a direct measure of the putative physiological effect of segmental EA. This could add noise to the statistics, but even so, there was not even a trend in favour of segmental EA.
The slightly curious thing is that both acupuncture groups seemed to substantially outperform metformin, which, in a large comparative trial with clomiphene resulted in a live birth rate of just 7.2%. The populations are not easily comparable though as there were notable differences in BMI that would favour acupuncture. The Chinese women were normal weight compared with an average BMI of about 35 in the metformin group in the prior comparative trial, and BMI is inversely related to outcome. Could that explain the difference between 7.2 and 15.4%? Well frankly, I’m afraid it probably can!
So where does that leave the acupuncture in the fertility arena? There is little or no high quality clinical data to support its use, just a lot of experimental data that did seem encouraging, although the results of this trial should give pause to the assumptions of advocates that anything demonstrated at the bench should automatically imply useful effects at the bedside.
For now at least we must encourage women with PCOS to consider clomiphene before acupuncture for ovulation induction.
Wu X-K, Stener-Victorin E, Kuang H-Y, et al. Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome. JAMA 2017;317:2502. doi:10.1001/jama.2017.7217
Stener-Victorin E, Waldenström U, Andersson SA, et al. Reduction of blood flow impedance in the uterine arteries of infertile women with electro-acupuncture. Hum Reprod 1996;11:1314–7.
Carr D. Somatosensory stimulation and assisted reproduction. Acupunct Med 2015;33:2–6. doi:10.1136/acupmed-2014-010739
Stener-Victorin E, Maliqueo M, Soligo M, et al. Changes in HbA1c and circulating and adipose tissue androgen levels in overweight-obese women with polycystic ovary syndrome in response to electroacupuncture. Obes Sci Pract 2016;2:426–35. doi:10.1002/osp4.78
Johansson J, Redman L, Veldhuis PP, et al. Acupuncture for ovulation induction in polycystic ovary syndrome: a randomized controlled trial. Am J Physiol Endocrinol Metab 2013;304:E934-43. doi:10.1152/ajpendo.00039.2013
Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66. doi:10.1056/NEJMoa063971
Legro RS, Zhang H, Eunice Kennedy Shriver NICHD Reproductive Medicine Network. Letrozole or clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:1463–4. doi:10.1056/NEJMc1409550
I subsequently attended the Spanish Pain Society conference (#SEDPalma2018) and there was a whole session devoted to this paper and why it did not apply to the way these specialists used the technique :-/.
This piece has also been stimulated by a publication in JAMA, this time evaluating the use of denervation of joints in spinal pain. It is a set of three large (n=251, n=228, n=202), probably definitive, pragmatic trials that evaluate the use of radiofrequency denervation (RFD) as an addition to a 3 month standardised exercise programme. The design is such that the intervention was given the greatest possible opportunity to demonstrate an effect, that is both the specific effect of the intervention plus the context in which it is provided. This is rather similar to the Acupuncture in Routine Care (ARC) trials performed as part of the German Modellvorhaben Akupunktur; all of which were markedly positive for acupuncture.
…at no time point did the addition of RFD reach clinical significance for the primary outcome
The results seem clear – at no time point did the difference been intervention and control reach clinical significance in terms of pain intensity (the primary outcome); and in only one of 18 time points across the three trials did the difference reach statistical significance (the 3 week outcome in the sacroiliac joint trial). The measure used for clinical significance here was 2 points on a 0-10 scale of pain, or 20mm on a 100mm visual analogue scale, but at no point did RFD achieve the lower level of 1 point set by NICE in NG59.
The data from NG59 comparing acupuncture with no acupuncture controls (the closest equivalent comparison to the current trials of RFD) gave a pooled result at less than 4 months of more than 60% greater than the best outcome recorded in these trials of RFD. A result that was both statistically significant and clinically relevant by the standards used in NG59, although it would not have reached the standard set in these trials.
So what is RFD, and why am I drawing attention to this? RFD is a method of burning nerves, and the idea is that by denervating a pain source in the spine you might achieve sustained pain relief in chronic back pain. The typical targets are facet joints, sacroiliac joints and intervertebral joints. The radiofrequency term is unnecessarily confusing since the method uses electrical pulses at about 5000Hz rather than electromagnetic radiation in the radiowave spectrum. The latter stretches roughly from 3×103Hz to 3×109Hz equating respectively to wavelengths from 100km to 1mm, but that’s enough physics for now. Basically the high frequency electrical pulses cause a heating effect at the tip of the RFD probe and it typically reaches 80 degrees C, which coagulates the tissues at the tip.
Isn’t burning nerves a bit of an archaic technique? Yes it is, and in principle modern pain medicine tends to try to avoid neurolytic treatments. Damaging nerves can cause neuropathic pain in some individuals, and the nerves can grow back anyway.
Why was it recommended in NG59? This decision was controversial because the guideline development group (GDG) for NG59 recommended RFD based on quite limited data from very small trials, and the current Cochrane review clearly concluded that the evidence was insufficient to recommend it. The decision to recommend RFD and recommend against acupuncture was also controversial because of potential conflicts of interests of interventionists on the GDG and how these were addressed.
In reviewing the data on RFD used by NG59, I discovered that there was quite disproportionate weighting given to one particular trial despite it only having 20 patients per group (Tekin 2007 ). The reason for this is the meta-analytic software favours trials with low standard errors.
Anyway, I thought I would take a closer look at this paper, and discovered that the control group dropped from 6.8 to 4.3 on a 0 to 10 pain score from pre- to post-procedure. The slightly funny thing about this was that the control procedure involved exactly the same intervention as was used to determine eligibility for the trial – a diagnostic medial branch block ie a local anaesthetic block to the nerve that would then be coagulated or burnt in the active (CRF) group. In order to get in the trial the patients had to have a reduction in pain score of 50% or more, yet the control group who went on to have the same procedure again only dropped by about 37% (see Table 2 from Tekin 2007 below).
Well it all just goes to show that small trials are unreliable, but what should we do now? We should ask the centre that conducted the guideline (the National Guideline Centre hosted by the RCP) to perform an urgent review on the grounds of safety. As it stands NG59 has all but stopped NHS acupuncture for back pain and is likely to result in a vast increase in the use of RFD, which now we see doesn’t actually do anything worthwhile for patients, but may boost the Maserati-purchasing power of certain interventionists.
Juch JNS, Maas ET, Ostelo RWJG, et al. Effect of Radiofrequency Denervation on Pain Intensity Among Patients With Chronic Low Back Pain: The Mint Randomized Clinical Trials. JAMA 2017;318:68–81. doi:10.1001/jama.2017.7918
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
Maas ET, Ostelo RWJG, Niemisto L, et al. Radiofrequency denervation for chronic low back pain. Cochrane database Syst Rev 2015: CD008572. doi:10.1002/14651858.CD008572.pub2
Cummings M. NG59 used different levels of evidence for conventional interventions compared with those for acupuncture and may not have adequately addressed personal financial COIs of the GDG chair. BMJ. 2017;356. http://www.bmj.com/content/356/bmj.i6748/rr-6
Tekin I, Mirzai H, Ok G, et al. A comparison of conventional and pulsed radiofrequency denervation in the treatment of chronic facet joint pain. Clin J Pain;23:524–9. doi:10.1097/AJP.0b013e318074c99c