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Date: November 20, 2023

Reference: Jones et al. Time to reflect on open-label placebos and their value for clinical practice. PAIN October 2023

Caitlin Jones PhD

Guest Skeptic: Dr. Caitlin Jones is a Postdoctoral Research Associate at Sydney University’s institute for Musculoskeletal Health. Her research evaluates the benefits and harms of treatments for musculoskeletal conditions with a particular interest in high-risk treatment options such as opioid medicines and spinal cord stimulators for pain. She has a goal to improve patient outcomes and reduce harm from inappropriate treatments.

We have an interesting back story on how we met. Dr. Sergey Motov and I did a structured critical appraisal of the OPAL trial (SGEM#419). You were the lead author on that study. You pointed out we missed some details in our review and provided some additional information. We were happy to hear from you and updated the SGEM episode based upon your comments. Not everyone has been so receptive to your study and your feedback.

  • Thanks for appraising OPAL and for engaging with me about it. There were lots of varied responses to OPAL. Most were positive and interested. Some had opinions that the trial doesn’t reflect their practice or their patients, so it’s not relevant to them (reasonable position). Some are furious that we would even suggest that opioids don’t work and they are certain this is part of a corrupt evil agenda (I don’t engage with this stance because nothing I can say will change their minds). I do engage when it’s just a genuine misunderstanding, or someone has missed some details.Everyone is free to make up their own mind about how they will or won’t apply these findings into their clinical practice, but I do feel an obligation to correct misunderstandings when I see them.

After our exchange I looked up some of your other publications. One of them caught my eye as being very thought-provoking. It looked at open label placebo being used in clinical trials. The title of the paper was Time to reflect on open-label placebos and their value for clinical practice [1]. What got you interested in that topic?

  • A lot of my research compares treatments for MSK pain to placebo to establish efficacy (how well it works). In my field we often find, sadly, that some of the treatments used for decades in clinical practice don’t show effects above that of the placebo when someone finally tests them properly. There’s been increasing chatter about OLPs with a few editorials written in big journals, and an increase in publications on the topic, so it is clearly gaining traction in the clinical and research community. A lot of my work so far has been about testing treatments that have been used for decades without proper testing, and then when we finally test them, we discover we were doing more harm than good all this time. Open label placebos as a clinical treatment are new enough that there is time to intervene and advocate for some thorough testing before they become common place in clinical care. I don’t want this to be another thing where we realize in 50 years’ time that we were harming not helping.

SGEM listeners are probably familiar with the placebo effect, but can you give us a brief definition or description?

  • The placebo effect is the positive effect on outcomes stemming from positive expectations around receiving a treatment, but not the treatment itself. Placebo in a research context is the gold standard comparison in efficacy trials that can provide an estimate of the treatment effect, filtering out all the biases and contextual effects that aren’t directly caused by the treatment of interest, so we are left with an estimate of the direct effects of the treatment itself.

Then along came some research which caused some excitement. They reported that you could elicit a placebo effect without deceiving the patients (ie telling them it is a placebo) [2].

  • Yes, some very interesting research came out that even when you tell people they are getting a placebo, they still seemed to cause some positive effects. That was really appealing to a lot of people who believed in the power of placebo, but felt the main barrier to usage was with unethical element of deception – suddenly no deception seemed necessary.

Open Label

I love talking nerdy and the methods section is my favourite section of a publication. So, what were the fundamental misunderstandings of the open label placebo (OLP) and research methodology?

  • Mismeasuring / over inflating the placebo effect by confusing response for effect
  • Lack of blinding in trials, plus positive preamble, overinflates OLP group and deflates control group effects.
  • Sampling bias, advertising for mind-body treatments and having participants self-select(only examining people with a pre-existing belief or interest). Not including co-design or input from the people who we think would be most likely to receive this (conditions hard to diagnose and treatg. chronic pain, chronic fatigue)

I understand there were some experts opining that open label placebos should be part of clinical care [3.4]?

  • Yes, some are calling for OLPs in clinical care. Some are overlooking the limitations of the current research, taking these effect sizes at face value, and assuming there are no harms, so why not? That sounds better than a lot of the genuine treatments we regularly use.

There are even some clinicians who report on surveys as to prescribing placebos.

  • Surveys from 2008, 2010, and 2019 conducted in primary care settings in Australia and the United States found that many doctors have prescribed a placebo at least once (from 55% to 80%). Yes, a lot of doctors are willing to admit in surveys they’ve used something they knew wouldn’t likely beeffective but did it anyway to illicit the placebo effect. One of the problems here is that the American Medical Association’s code of ethics warns against using placebos to “mollify” a “difficult” patient. It says that they can be considered if the patient is aware that it is a placebo and can therefore provide informed consent. This has given rise to the potential use of OLPs.

Do you think open-label placebos are the answer?

  • Definitely not yet, and possible not ever unless we find a way to ascertain that the benefits outweigh the risk of causing harm. I believe this is true even for patients with conditions where there is no effective treatment. This is a tough ask, because there is enormous pressure on clinicians to “do something”, and they want to reach for a treatment where the risks are low. This is perceived to be the case with OLPs although we don’t actually know that yet and I suspect there I substantial risk of stigmatizing and alienated patients.

We have mentioned intervention bias many times on the SGEM. My mentor and Legend of EM, Dr. Jerry Hoffman, would frequently say…don’t just do something, stand there. In fact, that is the title of one of my favourite articles (Don’t just do something, stand there! The value and art of deliberate clinical inertia [6].

  • That is true in so many clinical settings, but I would imagine especially so in the ED? People didn’t wait 14 hours to be seen and then receive no treatment. The pressure must be huge.

Let’s look at the research on OLP. What is the quality in this area?

  • Like much of the evidence from open-label trials, research into OLPs lack unbiased, convincing evidence of their efficacy. Studies of OLPs do not properly control for the positive preamble delivered alongside the placebo pill.Perhaps an even more pressing issue with OLP research is that patients have not been involved in co-designing this program of research. Increasingly, medical funding calls for patients’ contributions to shift from merely passive recipients to active co-designers of research programs.

Dr. Steven Novella from the Skeptics Guide to the Universe (SGU) who has been on an SGEM Xtra and writes for Science Based Medicine has argued that it is unethical to knowing prescribe a placebo. Do you think it is ethical to offer patients placebos?

  • I am not sure I would say it is unethical in all circumstances. In the context of conditions where there is no known effective treatment, proposing OLPs as an option in the shared decision-making process is a gamble with unfavourable odds, when we do not know yet whether patients would likely find this stigmatising and offensive. If it is for a patient where the clinician feels they have a good relationship, and the person has shown interest in this sort of thing before then maybe the odds are more favourable. But you are risking destroying that trusting relationship if the suggestion offends them. Also, to offer it honestly, a clinician would have to be honest about the limitations of the research – it isn’t ethical to present it as a powerful and proven remedy, because it isn’t. It is, at best, still a question mark.

Do you think it is there any utility in conducting properly designed studies that have involved patient input?

  • I have seen a survey where research recruits said in the majority that if it “works” then they would be happy to take an OLP. But we don’t really know if it works yet, so how can we ask patients if they would be willing to take it, when whether it works or not is probably the lynchpin in that decision. I think the first step would be to ask the people who are most likely to receive an OLP – those with hard to diagnose and treat conditions, like chronic pain and chronic fatigue – whether this is an avenue they would like to see taxpayer dollars spent on. Only if the answer to that is yes is it worth investing time and money into the puzzle that is how you would design an unbiased trial.

What was the goal of publishing this article?

  • Our hope is that this article gives clinicians and researchers pause to critically reflect on whether OLPs can and should be used in clinical care. If I had a time machine, I would go back and kick and scream about quite a few treatments that we adopted into clinical care without proper scrutiny first. For OLPs, we still have time to do this right.

As an expert in this area, what are your conclusions?

  • We think it is ethically questionable at best, to encourage positive treatment expectations from a treatment that lacks solid evidence of efficacy such as OLP. The good news is that we can use the broader concepts of an OLP in practice without actually giving anyone a sham treatment. We can encourage positive expectations when appropriate (e.g. with most MSK pain, the prognosis is good). We can capitalise on the positive effects of a warm and trusting patient-provider relationship by being good listeners, showing our genuine concern and respect for the person and their story.

Any final thoughts before we end?

  • I would like the hear the ED clinician’s perspective in the comments – do you use placebos in practice, and do you think it is ethical or not?

The SGEM will be back next episode doing a structured critical appraisal of a recent publication. Trying to cut the knowledge translation (KT) window down from over ten years to less than one year using the power of social media. So, patients get the best care, based upon the best evidence.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Jones, Caitlin M.P.a,b,*; Lin, Chung-Wei Christinea,b; Blease, Charlottec,d; Lawson, Jene; Abdel Shaheed, Christinaa,b,f; Maher, Christopher G.a,b. Time to reflect on open-label placebos and their value for clinical practice. PAIN 164(10):p 2139-2142, October 2023. | DOI: 10.1097/j.pain.0000000000003017
  2. von Wernsdorff M, Loef M, Tuschen-Caffier B, Schmidt S. Effects of open-label placebos in clinical trials: a systematic review and meta- analysis. Sci Rep 2021;11:3855.
  3. Uchendu SN, Wang A. Less pain, more gain: should placebo be a clinical therapeutic? Arthritis Rheumatol 2020;72:511–4.
  4. Kaptchuk TJ, Miller FG. Open label placebo: can honestly prescribed placebos evoke meaningful therapeutic benefits? BMJ 2018;363:k3889
  5. Foy AJ, Filippone EJ. The case for intervention bias in the practice of medicine. Yale J Biol Med. 2013 Jun 13;86(2):271-80. PMID: 23766747; PMCID: PMC3670446.
  6. Keijzers G, Cullen L, Egerton-Warburton D, Fatovich DM. Don’t just do something, stand there! The value and art of deliberate clinical inertia. Emerg Med Australas. 2018 Apr;30(2):273-278. doi: 10.1111/1742-6723.12922. Epub 2018 Jan 12. PMID: 29327445.