Placebo effect: a psychosomatic component, or only an aggregate of other biases?

Review on placebo injections on Knee Osteoarthritis -- not sure whether it warrants an own thread. Thought Edzards' Ernst blog article including others' comments could be interesting;

Previtali D, Merli G, Di Laura Frattura G, Candrian C, Zaffagnini S, Filardo G. The Long-Lasting Effects of "Placebo Injections" in Knee Osteoarthritis: A Meta-Analysis. Cartilage. 2021 Dec;13(1_suppl):185S-196S. doi: 10.1177/1947603520906597. Epub 2020 Mar 18. PMID: 32186401; PMCID: PMC8808779.

Free PMC full text:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8808779/

Abstract

Objectives

To quantify the placebo effect of intraarticular injections for knee osteoarthritis in terms of pain, function, and objective outcomes. Factors influencing placebo effect were investigated.

Design

Meta-analysis of randomized controlled trials; Level of evidence, 2. PubMed, Web of Science, Cochrane Library, and grey literature databases were searched on January 8, 2020, using the string: (knee) AND (osteoarthritis OR OA) AND (injections OR intra-articular) AND (saline OR placebo). The following inclusion criteria were used: double-blind, randomized controlled trials on knee osteoarthritis, including a placebo arm on saline injections. The primary outcome was pain variation. Risk of bias was assessed using the RoB 2.0 tool, and quality of evidence was graded following the GRADE (Grading of Recommendations Assessment, Development and Evaluation) guidelines.

Results

Out of 2,363 records, 50 articles on 4,076 patients were included. The meta-analysis showed significant improvements up to the 6-month follow-up: Visual Analogue Scale (VAS)-pain −13.4 mean difference (MD) (95% confidence interval [CI]: −21.7/−5.1; P < 0.001), Western Ontario and McMaster Osteoarthritis Index (WOMAC)-pain −3.3 MD (95% CI: −3.9/−2.7; P < 0.001). Other significant improvements were WOMAC-stiffness −1.1 MD (95% CI: −1.6/−0.6; P < 0.001), WOMAC-function −10.1 MD (95% CI: −12.2/−8.0; P < 0.001), and Evaluator Global Assessment −21.4 MD (95% CI: −29.2/−13.6; P < 0.001). The responder rate was 52% (95% CI: 40% to 63%). Improvements were greater than the “minimal clinically important difference” for all outcomes (except 6-month VAS-pain). The level of evidence was moderate for almost all outcomes.

Conclusions

The placebo effect of knee injections is significant, with functional improvements lasting even longer than those reported for pain perception. The high, long-lasting, and heterogeneous effects on the scales commonly used in clinical trials further highlight that the impact of placebo should not be overlooked in the research on and management of knee osteoarthritis.


Edzard Ernst's take on the authors' conclusion:

I would dispute that!

To explain why it might help to read our 1995 BMJ paper on the subject:

We often and wrongly equate the response seen in the placebo arm of a clinical trial with the placebo effect. In order to obtain the true placebo effect, other non-specific effects can be identified by including an untreated control group in clinical trials. A review of the literature shows that most authors confuse the perceived placebo effect with the true placebo effect. The true placebo effect is highly variable, depending on several factors that are not fully understood. A distinction between the perceived and the true placebo effects would be helpful in understanding the complex phenomena involved in a placebo response.

In other words, what the authors picked up in their analysis (i.e. the changes that occurred in the placebo groups between the start of a trial and after placebo application) is not just the placebo response; it is, in fact, a combination of a placebo effect, concomitant interventions/care, regression towards the mean, natural history of the condition and possibly other factors.

Does it matter?

Yes, it does!

Placebo effects are not nearly as powerful and long-lasting as the authors conclude. And this means virtually all their implications for clinical practice are incorrect.
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https://edzardernst.com/2022/08/effects-of-placebo-injections-in-knee-osteoarthritis/


Mind that one of the commenters on Ernst's blog who seems to make some reasonable points might have her own blind spots with regard to what seems to be her hobbyhorse -- developing a hypothesis and offering a treatment of "non-malignant chronic pain without sufficient explanatory pathology".

It's fair to stress though that I don't think she uses her comments to promote her treatment or even just her ideas about that.
 
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I see we have reached the No true placebo stage. Neat.
In other words, what the authors picked up in their analysis (i.e. the changes that occurred in the placebo groups between the start of a trial and after placebo application) is not just the placebo response; it is, in fact, a combination of a placebo effect, concomitant interventions/care, regression towards the mean, natural history of the condition and possibly other factors.
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In other words, button soup consists of meat, vegetables, broth, herbs and spices. Also a button.

Having such ridiculously large effect sizes really should clue in people that this is obviously invalid data. May as well believe in the actual healing power of kisses from mama on a booboo. But nope, magical thinking is that powerful. Not powerful enough to have the effect people attribute to "placebo", but definitely enough for people to believe that such a magical thing must exist, because otherwise the world out there is bleak and scary and beyond our control and so so stressful. Pfft.
 
The following inclusion criteria were used: double-blind, randomized controlled trials on knee osteoarthritis, including a placebo arm on saline injections.
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Good.

But how many of those trials also had a no treatment, no placebo arm?

–––––

Placebo effects are not nearly as powerful and long-lasting as the authors conclude.

The placebo/nocebo effect has yet to be demonstrated to have sustained clinical significance.
 
There is a new German podcast episode about placebo/nocebo effects. (German public broadcasting) The power of expectation - placebo and nocebo effects.
The main author has become well known for a very good and the most listened Corona podcast in Germany.

This podcast is unfortunately very uncritical about claims how powerful placebo/nocebo effects are: You can get very ill from Google and medication leaflets.

We must try to use placebo effects to make therapies more effective. Open placebos also help. etc.. It is presented as a scientific consensus. Placebo scientists and a neurologist who wrote a book about the powerful nocebo effect are interviewed.

https://www.ardaudiothek.de/episode...tung-placebo-und-nocebo-effekte/ndr/12478073/

Whether it's symptoms of illness or side effects of medications: Placebo responses can do great things. The flip side is the nocebo effect, which can make people sick simply by negative expectations.

Psychology and neurology are getting better at demonstrating these complex mechanisms neurobiologically. Science journalist K. H. spoke with placebo researchers and searched for case reports. In an interview with host L. K., she explains the path that pain expectation takes through the spinal cord and brain, and the role that neurotransmitters play in this process. We talk about the amazing effects of green-colored strawberry milk, the cross with package inserts, a baffling study with Parkinson's patients - and dubious vaccine reactions in the pandemic.

BACKGROUND INFORMATION

- Homepage of the Collaborative Research Center "Treatment Expectation" | https://treatment-expectation.de/

- Review of Nocebo Effects in the Placebo Arm of Registration Trials of Covid Vaccines | Haas JW, Bender FL, Ballou S et al. Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials. A Systematic Review and Mega-analysis. JAMA Network Open. 2022;5(1). https://doi.org/10.1001/jamanetworkopen.2021.43955

- Review on nocebo effects in the placebo arm of influenza vaccine clinical trials | Bender FL, Rief W, Wilhelm M. Really just a little prick? A meta-analysis on adverse events in placebo control groups of seasonal influenza vaccination RCTs. Vaccine. 2023;41: 294-303. https://doi.org/10.1016/j.vaccine.2022.11.033


- Study on the Significance of the Expectation Effect on the Opioid Remifentanyl | Bingel U, Wanigasekera V et al. The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil. Science Translational Medicine. 2011;3(70). https://doi.org/10.1126/scitranslmed.3001244


- Study on expectancy and independent control of pain therapies | Strube A, Horing B, Rose M, Büchel C. Agency affects pain interference through prior shift as opposed to likelihood precision modulation in a Bayesian pain model. Neuron. 2023;01(002): 1-16. https://doi.org/10.1016/j.neuron.2023.01.002

- Neurobiological mechanism in placebo responses in pain therapy | Levine JD, Newton C et al. The Mechanism of Placebo Analgesia. The Lancet. 1978;312(8091): 654-657. https://doi.org/10.1016/S0140-6736(78)92762-9


- Study of placebo responses in Parkinson's disease patients | Benedetti F, Frisaldi E et al. Teaching neurons to respond to placebos. The Journal of Physiology. 2016;594 (19): 5647-5660. https://doi.org/10.1016/S0140-6736(78)92762-9

automatic translation with deepl
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