de nada

Stimulated by Vase 2020,[1] and Krause et al 2020.[2]

Image from Deniah’s initial visit to the BA first class lounge at Heathrow T5… de nada sweetie!

This week I had a couple of quite different papers that caught my interest, and I have been able to link them by chance with the help of my daily language training. De nada is a phrase that means ‘you’re welcome’ in both Spanish and Portuguese – currently I spend a few minutes each morning studying Portuguese and Mandarin. But ‘nada’ on its own means ‘nothing’, so with that word I can combine the main paper on placebo with a study on ear acupuncture using the NADA protocol.

I heard the author of the first study speak at the third NMAC meeting – Nordic Medical Acupuncture Congress, Copenhagen September 2019. She is a professor in the department of psychology at Aarhus University. I enjoyed her presentation, and picked up several new insights into placebo research, but there were a couple of aspects that were somewhat unsatisfactory, and I was reminded of these when I looked at this paper.

…the influence of an unblinded care provider

Before I get to those, perhaps the most crucial new aspect for me was that she mentioned evidence to support the influence of an unblinded care provider on outcome of an RCT without unblinding the subject. This is of course very pertinent to acupuncture research. Protagonists like Hróbjartsson have continued to assert that the very small difference between real and sham acupuncture can probably be attributed to the bias from an unblinded practitioner – see Trust Me I’m an Acupuncture Expert. I knew of no evidence to support this assertion until Lene Vase mentioned it, but frustratingly she gave no reference in her presentation, so I wrote to her, and she responded with a rather old but interesting letter from the Lancet.[3]

I’ve been sitting on that paper for a while now, so it is good to get it aired.

So the main paper is a condensed version of a doctoral thesis that analyses and tries to address the problem of an apparent increase in the placebo response in RCTs.

It is a considerable piece of work summarising results from meta-analyses of the placebo and nocebo effects in both clinical trials of interventions and in placebo/nocebo research. I had never thought to compare these, so it was news to me that meta-analyses clearly demonstrate a larger placebo effect in placebo mechanism studies than in clinical trials where placebo is used as a control for another intervention.[4–6] The clinical studies here are all often three armed: real, sham and no treatment. This design first came to my attention in the ART studies of the Modellvorhaben Akupunktur,[7] and was then thoroughly misused in meta-analysis by Hróbjartsson’s crowd.[8] We tried to protest![9]

It was also a surprise to learn that whilst nocebo can be clearly demonstrated in healthy subjects,[10] its effects do not appear significant in patient populations that have been tested to date.[11,12] Lene hypothesises that this could be because the context of the nocebo is not sufficiently alarming.

“the grumpy anaesthetist trial”

Lene notes the great variability of the effect size in both placebo and nocebo effects within reviews of the mechanistic studies of these phenomena but suggests that they are of similar magnitude. When reading through this paper the first time I was uncomfortable with this, and I think it was because I have developed a world view in which nocebo is more powerful than placebo. It took me a while before I could place from where that idea had been derived. Of course, it was one of my favourite papers! The one I like to refer to as “the grumpy anaesthetist trial”.[13] In short, by manipulating context, Ulrike Bingel and her colleagues demonstrated a doubling of the effect of IV remifentanil, and then a complete reversal of the effects of both drug and expectation of drug through negative suggestion – “I’ve turned it off [the drug] and we are going to burn you again” (hence grumpy anaesthetist). So, this paper gave me the impression that the negative expectation (nocebo) trumped both the drug and the positive expectation concerning the drug (placebo), which had roughly equally contributed to the maximum analgesia measured. Thus I had the impression of nocebo being roughly twice as powerful in this setting.

Lene does not mention this trial in her paper, but she did mention it in her presentation at NMAC.

That brings me on to the only remaining aspect that I struggled with, both in this paper, and also at the presentation at NMAC. It was the reference to the BMJ paper of sham acupuncture in IBS patients with either augmented or limited interaction.[14] Vase uses it correctly to support the notion that positive expectation can be enhanced by context. What upset me was the failure to mention the fact that, in this trial, but published later,[15] the difference between practitioners turned out to be twice as large as the difference between augmented and limited interactions. Indeed, two of the four practitioners were better even in their limited interactions when compared with the augmented interaction of one of the others.

Large differences have also been seen between practitioners in other trials,[16,17] and this leads me to think that the non-verbal practitioner-patient interactions may be more important than artificial attempts to manipulate the verbal interaction. It is possible that this is more important for interventions that involve touch, where the perceived competence of the practitioner by the patient might have a bigger influence on expectation and positive affect – two aspects that Lene emphasises in her paper.

On a final positive note, whilst patient expectations seem key to generating enhanced effects of our treatments, the sometimes unavoidable generation of nocebo (eg discussion of possible adverse effects of treatment for purposes of consent) may be mitigated by prior generation of positive affect.[18] Another thing I learnt from the paper trail Lene laid out in this tome. It is another thing of course to successfully put that into practice.

I was about to sign off without a single comment on the NADA paper – the paper that effectively gave me my title!

Well it is another study with three parallel arms and 24 in each arm. Ear acupuncture at the NADA points (Shenmen, Sympathetic, Liver, Kidney, Lung) was compared with 5 points on the helix of the ear and with no treatment in 72 patients with alcohol addiction undergoing a 3-month inpatient rehabilitation programme. Heart rate variability (HRV) was measured as one of the outcomes, and it was just one of the HRV parameters that changed in the NADA group. It is tempting to wonder if needles in the cavum concha had an influence here, but the HRV measure (high frequency HRV) related to parasympathetic tone did not alter. Nothing else differed between the groups, including the most clinically relevant outcome – abstinence.

I think I need a drink!

Right, I have been on this blog for most of the weekend… I think I need a drink!


1         Vase L. Can insights from placebo and nocebo mechanisms studies improve the randomized controlled trial? Scand J Pain Published Online First: 30 June 2020. doi:10.1515/sjpain-2019-0183

2         Krause F, Penzlin AI, Ritschel G, et al. Randomized controlled three-arm study of NADA acupuncture for alcohol addiction. Addict Behav 2020;110. doi:10.1016/j.addbeh.2020.106488

3         Gracely R, Dubner R, Deeter W, et al. Clinicians’ expectations influence placebo analgesia. Lancet 1985;325:43. doi:10.1016/S0140-6736(85)90984-5

4         Hróbjartsson A, Gøtzsche PC. Is the Placebo Powerless? N Engl J Med 2001;344:1594–602. doi:10.1056/NEJM200105243442106

5         Vase L, Riley JL, Price DD. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain 2002;99:443–52. doi:10.1016/S0304-3959(02)00205-1

6         Vase L, Petersen GL, Riley JL, et al. Factors contributing to large analgesic effects in placebo mechanism studies conducted between 2002 and 2007. Pain 2009;145:36–44. doi:10.1016/j.pain.2009.04.008

7         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

8         Madsen MV, Gøtzsche PC, Hróbjartsson A. Acupuncture treatment for pain: systematic review of randomised clinical trials with acupuncture, placebo acupuncture, and no acupuncture groups. BMJ 2009;338:a3115. doi:10.1136/bmj.a3115

9         White A, Cummings M. Does acupuncture relieve pain? BMJ 2009;338:a2760. doi:10.1136/bmj.a2760

10       Petersen GL, Finnerup NB, Colloca L, et al. The magnitude of nocebo effects in pain: a meta-analysis. Pain 2014;155:1426–34. doi:10.1016/j.pain.2014.04.016

11       Vase L, Robinson ME, Verne NG, et al. The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. Pain 2003;105:17–25. doi:10.1016/S0304-3959(03)00073-3

12       Petersen GL, Finnerup NB, Grosen K, et al. Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions. Pain 2014;155:2687–98. doi:10.1016/j.pain.2014.09.036

13       Bingel U, Wanigasekera V, Wiech K, et al. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med 2011;3:70ra14. doi:10.1126/scitranslmed.3001244

14       Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 2008;336:999–1003. doi:10.1136/bmj.39524.439618.25

15       Conboy LA, Macklin E, Kelley J, et al. Which patients improve: characteristics increasing sensitivity to a supportive patient-practitioner relationship. Soc Sci Med 2010;70:479–84. doi:10.1016/j.socscimed.2009.10.024

16       Borud EK, Alraek T, White A, et al. The effect of TCM acupuncture on hot flushes among menopausal women (ACUFLASH) study: A study protocol of an ongoing multi-centre randomised controlled clinical trial. BMC Complement Altern Med 2007;7:6. doi:10.1186/1472-6882-7-6

17       White P, Bishop FL, Prescott P, et al. Practice, practitioner, or placebo? A multifactorial, mixed-methods randomized controlled trial of acupuncture. Pain 2012;153:455–62. doi:10.1016/j.pain.2011.11.007

18       Geers AL, Close S, Caplandies FC, et al. Testing a positive-affect induction to reduce verbally induced nocebo hyperalgesia in an experimental pain paradigm. Pain 2019;160:2290–7. doi:10.1097/j.pain.0000000000001618

Declaration of interests MC