MD, PhD, MAE, FMedSci, FRSB, FRCP, FRCPEd.

Placebo effects are a fascinating subject. In so-called alternative medicine (SCAM), they are particularly important because much of SCAM seems to rely on little more than placebo effects. Therefore, I think this new paper is of some relevance to us.

The aim of this systematic review was 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.

The authors concluded that 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.

The authors furthermore confirmed that “the main finding of this meta-analysis is that placebo is an important component of the effect of injective treatments for patients with KOA, with saline injections being able to provide relevant and long-lasting results not only in terms of pain relief but also with respect to stiffness resolution and function improvement. These results are both statistically and clinically significant and can be perceived by patients up to 6 months.”

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.

20 Responses to Effects of “Placebo Injections” in Knee Osteoarthritis

  • Crislip’s view is that no biological effects have been noted for placebo, and that placebo “effect” is fully explained by regression to the mean, false attribution (eg other non-specific factors), error of judgement, or delusion.

    By getting a measure for placebo effect and detracting that from the apparent effect of an intervention, I assume it’s possible to get a more accurate measure for efficacy of the intervention.

    This is really the only real use for placebo, arriving at more accurate analysis of the efficacy of the intervention being tested.

    • I don’t know who Crislip is, but his opinion is not evidence-based. I can suggest tons of papers on placebo effects, showing they are real biopsychological phenomenons. There’s even a paper by Ernst that can give a short overview in this sense: doi:10.1016/j.drudis.2007.03.007
      I don’t understand why people against CAMs need to minimize the placebo effect.

      • “I don’t understand why people against CAMs need to minimize the placebo effect.”
        THEY DON’T!
        They might, however, be tired of the argument HOMEOPATHY MIGHT BE A PLACEBO, YET IT HELPS PATIENTS AND THUS IS FINE.

      • Fabio wrote “I don’t know who Crislip is, but his opinion is not evidence-based.”

        QUOTE
        Mark Alden Crislip (born April 25, 1957) is an infectious disease doctor in Portland, Oregon and chief of infectious diseases at Legacy Health hospital system.

        He attended the University of Oregon from 1979 to 1983, where he earned a Bachelor of Science degree in physics. He then earned a Doctor of Medicine (MD) degree at the Oregon Health & Science University School of Medicine in 1983. He completed an internship and residency at Hennepin County Medical Center in Minneapolis in 1986, followed by a fellowship at Harbor–UCLA Medical Center. He is currently a board-certified infectious disease specialist at several medical centers in the Portland area.

        Crislip is listed as editor (emeritus) for the Science-Based Medicine blog where he regularly wrote posts on investigating the claims of alternative medicine until 2017. He is the co-editor, along with Steven Novella and David Gorski, of a 12-volume series of Science-Based Medicine Guides, based on posts from the Science-Based Medicine blog.

        https://en.m.wikipedia.org/wiki/Mark_Crislip
        END OF QUOTE

        • Frankly, I didn’t know him, I was just being humble. But writing his career , as you did, won’t change my conclusion. If he said that the placebo effect is just spontaneous remission, regression to the mean and response bias, I have to say that his opinion is not evidence-based. And I’ve mentioned evidence for the opposite conclusion (see previous comments).
          I don’t doubt that he’s a great scholar, but that doesn’t mean he is right. If you think that he is right just because he is an expert, you’re falling into the “appeal to authority fallacy”.

  • I totally agree that the mentioned study confuses the perceived placebo effect with a true placebo effect.
    Anyway i don’t agree with you when you say “Placebo effects are not nearly as powerful and long-lasting as the authors conclude. “. Your conclusion is not evidence-based too:
    1) placebo effect has been shown really powerful for some conditions like pain, and we know that the effect size is variable, since placebo depends on context information. Maybe to investigate the magnitude of the placebo effect we should compare it with the drug effect size: that’s been done (10.1371/journal.pone.0062599) and the results are interesting
    2) I don’t think there’s evidence for long lasting placebo effects, even though in some trials placebo has been shown to be consistent (https://doi.org/10.1016/j.jpsychores.2007.11.007). But at the same time I don’t see any evidence showing that the placebo is short-lasting. I just think that long term, three arm trials are needed. Until then, any conclusion is just speculative.

    I want to point out that my arguments DO NOT support the use of alternative medicine. Even if the placebo was incredible powerful and long-lasting, that’s not a justification for CAMs. If homeopathy is just placebo, call it placebo, not homeopathy
    Also since every treatment has a placebo component in it, there’s no reason of commercializing placebo pills, unless drug-placebo difference are small and the placebo is shown to be consistent.

    • Fabio I read the study, thank you for offering it. Unfortunately this study didn’t identify any biological effect and merely reported probable error or judgement or delusion.

      I’m not sure I agree that the findings were significant or even useful because they apply only to a very limited context and don’t provide predictability.

      Neither do I agree that excluding placebo responders from trials is beneficial. Better to use placebo responders in a control group to simply deduct their outcomes from the intervention group outcomes, provided of course that the trial is well-designed and doesn’t include variables in one group that are not present in the other, particularly when those variables are non-specific effects.

      One of the biggest problems with have with psychology research is the uninformative mismatching of control and intervention groups, and subsequently the provision of conclusions that are unfounded.

      • “mismatching of control and intervention groups”
        randomization should do the trick.

        • Edzard I meant for example comparing a group which received the intervention plus let’s say some non-specific effects such as meeting regularly with a human being, and a group that doesn’t get the regular meetings but is given a placebo pill, or just supplied with information. Of course the intervention is going to look pretty good, even if it’s useless.

          Another example is when a control group is given a treatment that we know isn’t very efficacious, and the treatment group is provided with an intervention that is hardly clinically-significantly superior, and yet the intervention is claimed to be successful even though it’s not very efficacious either.

          To assess an intervention meaningfully, the human effects must be the same for both control and intervention group, and the control has to be informative (not a waiting list for example).

          Also we’ve got to get more discerning about what counts as significant, that it’s not just statistical noise, but represents real clinical significance for clients.

      • Thanks for replying Christine. My original comment was reffered to the post, and not to your reply. I’m not sure to which of the 2 studies I mentioned you refer.
        Anyway, in regard to biological mechanisms of placebo there are a lot of studies. And some findings are well replicated. Here I suggest some articles that can give an overview, even though the literature is very big:
        – Wager, T., Atlas, L. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci 16, 403–418 (2015). https://doi.org/10.1038/nrn3976
        – Frisaldi, E., Shaibani, A., & Benedetti, F. (2020). Understanding the mechanisms of placebo and nocebo effects. Swiss Medical Weekly, (35).

        Again, I want to remark that I’m not for the use of placebos in practice, the evidence is weak for that. But I think that the placebo is a biological phenomenon, and we should try to maximize the placebo component of non-placebo treatments.

        • Thanks Edzard, I read “Flies in the Ointment” (Crislip) some time ago and recalled a claim that no biological effect had been measured so I will read these and hopefully fill in some gaps.

          • “Take a look at the Wikipedia entry for ‘placebo’. It covers the essential ground very reasonably.

            I’m not sure exactly what it is about ‘placebo’ that confuses you. Maybe it’s the need to appreciate that a placebo (an ‘inert substance or treatment which is designed to have no therapeutic value’) is a thing, whereas the ‘placebo effect’ is the consequence of (wrongly) attributing an apparent change in a medical condition to treatment with a placebo.”
            — Professor Frank Odds

            https://edzardernst.com/2019/09/does-placebo-research-boost-pseudoscience/#comment-116776

          • Pete I’m right with you on this, placebo meaning no therapeutic value, and placebo effect meaning regression to the mean, false attribution, error of judgement/delusion.

            I’m being challenged that a placebo can have measurable biological effect and am ready to read and concede that studies may show my understanding is incorrect, but haven’t found these yet.

          • Christine, I thoroughly recommend reading the following, which includes the term “true placebo effect” proposed by Edzard Ernst (1995) [1]:
            Placebo, Are You There?, by Jean Brissonnet, translation by Harriet Hall, MD.
            https://sciencebasedmedicine.org/placebo-are-you-there/

            [1] Ernst E., Resch KL.(1995). Concept of true and perceived placebo effects. BMJ 311: 551‑553 .

        • Fabio the paper is behind a paywall, but even the abstract notes an absence of verifiable mechanisms, and fails to even hint at anything other than a temporary distraction, with outcomes most likely due to regression to the mean, false attribution, error of judgement or delusion.

          The evidence for placebo is weak in practice precisely because it’s not a real effect.

          There are aspects of therapy that are separate to any intervention and these are the very basis of humane treatment of clients. These can provide comfort, a sense of dignity, enhance the therapeutic liaison, and increase the probability that the client will stay the course, amongst other benefits.

          Calling those aspects placebo components is misleading.

          Crislip is renowned for his evidence-based scientific analysis of studies. He has certainly examined a very wide range of studies, not just a couple of outliers which don’t even look promising at first glance. His book “Flies in the Ointment” makes excellent reading and is heavily referenced.

          • Christine, as I already said Crislip can be an expert, that doesn’t mean he is always right (appeal to authority fallacy).
            That being said, the article I sent you talks about real biological mechanisms of placebo. Placebo can activate the release of dopamine in Parkinson disease, can activate the release of endogenous opioids in Pain, they can modulate COX products, they can modulate immune and endocrine parameters.
            Please read this review: https://doi.org/10.4414/smw.2020.20340

          • Fabio without being able to read the paper itself, I can’t assess it.

          • Christine the paper is open access. Anyway, if you write me you email address, I’ll send you the paper and we can further discuss the topic, if you want

  • Fabio I read the paper, and found that it makes a very large number of unsupported claims and assumptions, right from the opening sentence, claiming that placebo effect is regarded as a nuisance in scientific studies.

    I’m sorry, I simply do not have enough hours in the day to pick apart this frankly awful paper.

  • Christine, I find your opinion full of prejudice. I do study placebo effect and the literature on it is just huge. You can find reviews in a lot of high quality journals, like Nature, Lancet and NEMJ. I can suggest a lot of papers if you want. There’s scientific agreement on the fact that genuine placebo effects exist. I think Ernst can tell you that.
    And yes, placebo effect is a nuisance in clinical trials, I don’t see what’s wrong here. What RCT do is excluding pacebo effects and other confounding factors, in order to detect the specific drug effect, if present.

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