Inspired by Wang et al 2021.
IBS – irritable bowel syndromekey to acronyms
OLP – open label placebo
DBP – double blind placebo
NPC – no pill control
COMT – catechol-o-methyltransferase (an enzyme that degrades catecholamines)
rs4680 – Val153Met SNP in the gene for COMT
Val – valine (an amino acid used in DNA and RNA)
Met – methionine (ditto)
SNP – single nucleotide polymorphism
This paper popped up on my PubMed searches on Saturday 19th March 2022. I thought it must be fairly new, but it turns out that it was first published online on the 4th January, and the reference dates it to 2021.
Frontiers in Pain Research is a relatively new open access journal in the Frontiers stable, having published its first paper in August 2020, so I guess PubMed is just getting around to listing it now, and this paper is part of a collection on the placebo effect in pain and pain treatment.
Anyway, the title struck me as interesting despite the lack of acupuncture, since I know that acupuncture has been a part of the story of placebo effects in IBS.
Kaptchuk et al thought that they could manipulate context effects, but it turned out that practitioner effects trumped their attempts to augment the consultation. The difference between individual practitioners was twice as large as the difference between a limited and an augmented consultation style associated with sham acupuncture treatment.
The term placebo was originally coined in English following an erroneous translation from Hebrew to Latin of the biblical verse 9 from Psalm 116. Instead of I will walk before the Lord in the land of the living we got I shall please the Lord in the land of the living from Saint Jerome, probably because in the Latin it reads so well, Placebo Domino in regione vivorum.
Later the term was adopted as a name for the 13th century ‘Office for the Dead’, as they used the Psalm in their vespers. Then Chaucer uses it in The Parson’s Tale: Flatterers are the Devil’s chaplains, always singing Placebo. From there the story is less clearly mapped, so I’ll stop this etymological tangent.
This detail is from a short piece in the BMJ by Jeff Aronson. I used to love reading these back in the days of fillers. But he is still active, and earlier this month he wrote on open access journals.
Following on from the flurry of papers using sham acupuncture in IBS in the noughties, there was a discussion of the background of the placebo effect, followed by the introduction of open label placebo (OLP), along with a discussion of the ethics of using such an approach.
In 2010 the open label placebo was compared with a no treatment control, but in the most recent trial, an OLP is compared with a double blind placebo (DBP) as well as a no treatment control – otherwise known as a no pill control (NPC). In this latter trial, there was no appreciable difference between the OLP and DBP groups, which were both significantly better than the NPC group.
This finally brings us to the paper I am highlighting. It is effectively a subgroup analysis of the same 3 arm trial comparing OLP, DBP and NPC, where the subgroups were defined by their expression of COMT rs4680.
COMT rs4680 is either Val/Val (homozygous Val), Val/Met (heterozygous), or Met/Met (homozygous Met). The Val/Val is the normal wild type variety and is characterised as a warrior, whereas by contrast the Met/Met is the worrier. The former has higher pain thresholds and more stress resilience.
The IBS patients homozygous rs4680 Met improved the most, and the warriors improved the least overall. There was a significant difference between these subgroups in the DBP group.
This is just a taster for what is to come in this area of research and more broadly in the field of personalised medicine based on genomics.
1 Wang R-S, Lembo AJ, Kaptchuk TJ, et al. Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome. Front Pain Res 2021;2:775386. doi:10.3389/fpain.2021.775386
2 Kaptchuk TJ, Stason WB, Davis RB, et al. Sham device v inert pill: randomised controlled trial of two placebo treatments. BMJ 2006;332:391–7. doi:10.1136/bmj.38726.603310.55
3 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
4 Kelley JM, Lembo AJ, Ablon JS, et al. Patient and practitioner influences on the placebo effect in irritable bowel syndrome. Psychosom Med 2009;71:789–97. doi:10.1097/PSY.0b013e3181acee12
5 Aronson J. Please, please me. BMJ 1999;318:716. doi:10.1136/bmj.318.7185.716
6 Aronson JK. When I use a word . . . . Bioscience journals-an open and shut case? BMJ 2022;376:o536. doi:10.1136/bmj.o536
7 Kaptchuk TJ, Kerr CE, Zanger A. Placebo controls, exorcisms, and the devil. Lancet 2009;374:1234–5. doi:10.1016/s0140-6736(09)61775-x
8 Kaptchuk TJ, Friedlander E, Kelley JM, et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PloS One 2010;5:e15591. doi:10.1371/journal.pone.0015591
9 Finniss DG, Kaptchuk TJ, Miller F, et al. Biological, clinical, and ethical advances of placebo effects. Lancet 2010;375:686–95. doi:10.1016/S0140-6736(09)61706-2