Stimulated by Krecké et al 2023.[1] HRV – heart rate variabilityCCK – cholecystokinin key to acronyms I have always been intrigued by placebo and nocebo effects as well as the more subtle differences between men and women that we...
Stimulated by Krecké et al 2023.[1]
Mike receiving a thermal pain stimulus to his ventral forearm under the watchful eye of colleagues in Greifswald (2023).
HRV – heart rate variability
CCK – cholecystokinin
I have always been intrigued by placebo and nocebo effects as well as the more subtle differences between men and women that we encounter in healthcare environments. This paper combines both and seems to have found a biomarker that predicts placebo responsiveness, but it only works for men.
The research comes from the University of Luxembourg, which I think is new to me and to this blog. I remember driving with colleagues to Luxembourg on a Sunday from Spangdahlem (USAF base in Germany) sometime in the late 80’s. It appeared to be closed so we headed to Belgium. I don’t believe I have returned since but have flown past many times on my way to Frankfurt airport, which is 160km (and 2 days walk) directly east of Spangdahlem. The latter is 70km northeast of Luxembourg.
This paper reports data from 2 studies that have been combined to analyse the baseline HRV component that was measured in both. The studies were performed on healthy men and women in their early 20’s and there was a small payment for participation, so presumably they were mostly students at the university. The first study (n=36) examined brain connectivity using fMRI and the results have already been published elsewhere.[2] It looks as though the second study was added to enhance statistical power (n=41), since fMRI studies are expensive and therefore tend to be smaller. So, the total number with baseline HRV and placebo hypoalgesia outcomes was 77.
I first recall hearing about HRV from a professor of gastroenterology at the BMAS Spring meeting in Warwick 2006. It seemed a little strange at the time and was associated with esoteric terms such as power spectral analysis. Jump back to the present and it is an established biomarker for parasympathetic tone, and I find that my own HRV is now measured regularly, amongst a plethora of other things, by my fancy wristwatch.
Both studies used thermal pain applied to the ventral forearm and manipulated expectation of pain using either a topical placebo analgesic cream application (study 1) or sham TENS applied either side of the test site on the forearm. Placebo responses were conditioned by a manipulation phase in each experiment where the intensity of the test stimulus was reduced during the supposedly therapeutic intervention and increased during the control.
The test subjects rated both intensity and unpleasantness of the thermal pain stimulus on a VAS scale. Both sets of results were similar, with a slightly greater reduction in unpleasantness than in intensity under the placebo condition compared with control. You may remember that we mentioned a similar difference in a previous blog, which may have influenced the key result in a network meta-analysis where bothersomeness was pooled with VAS pain (see Does sham point location matter).
The remarkable finding, however, was when male and female participants were analysed separately, and the size of the placebo response was correlated with each person’s baseline HRV. The male group show a consistent and highly significant correlation in reductions of both pain intensity and unpleasantness with measures of higher baseline HRV. By contrast there appeared to be absolutely no correlation in the female group.
The authors suggest that their results may reflect differences in pain modulating processes, with men recruiting more descending inhibition where there is overlap with vagal mediation of HRV. Another possible explanation relates to testosterone levels, which have been shown to correlate with HRV as well as mediating antinociceptive effects.
Systematic reviews on sex differences in placebo and nocebo effects conclude that men do respond more to placebo than women, and that women respond more to nocebo. Furthermore, men are more likely to respond to verbal suggestions to generate placebo effects, whereas women respond more to conditioning of nocebo effects.[3,4]
An umbrella review published at the end of September 2023 focussed on placebo and nocebo effects associated with pharmaceutical interventions.[5] One of the authors is Fabrizio Benedetti, who I generally refer to as Professor Placebo, having invited him to speak at the BMAS Spring meeting in Bristol 2007. I was fascinated by his description of an experiment in which a drug (the CCK antagonist proglumide) had no analgesic effect when given without the subject’s knowledge but enhanced the analgesic effect of a placebo injection. The same drug appeared to block the nocebo response.[6]
Anyway, this umbrella review estimates the effect sizes for placebo as 0.37 to 0.89 and for nocebo as 0.24 to 1.00 (these are 95% CIs). I’m going to have to stop saying that nocebo is generally bigger than placebo now!
Addendum
I have just remembered where my impression that nocebo is more powerful than placebo came from… it was the grumpy anaesthetist trial, as I like to call it.[7] This was a trial involving intravenous remifentanil with manipulation of the expectation of receiving it, plus fMRI imaging to give objective correlation with the subjective assessments of pain.
It was a landmark experimental trial with fascinating results… if you haven’t heard about it, log on the webinar on Wednesday evening.
References
1 Krecké J, Dierolf AM, Rischer KM, et al. Baseline heart rate variability predicts placebo hypoalgesia in men, but not women. Front Pain Res. 2023;4:1213848.
2 van der Meulen M, Kamping S, Anton F. The role of cognitive reappraisal in placebo analgesia: an fMRI study. Soc Cogn Affect Neurosci. 2017;12:1128–37.
3 Vambheim SM, Flaten MA. A systematic review of sex differences in the placebo and the nocebo effect. J Pain Res. 2017;10:1831–9.
4 Enck P, Klosterhalfen S. Does Sex/Gender Play a Role in Placebo and Nocebo Effects? Conflicting Evidence From Clinical Trials and Experimental Studies. Front Neurosci. 2019;13:160.
5 Frisaldi E, Shaibani A, Benedetti F, et al. Placebo and nocebo effects and mechanisms associated with pharmacological interventions: an umbrella review. BMJ Open. 2023;13:e077243.
6 Benedetti F, Amanzio M, Vighetti S, et al. The Biochemical and Neuroendocrine Bases of the Hyperalgesic Nocebo Effect. J Neurosci. 2006;26:12014–22.
7 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.