Oct 19 2010

What’s In Placebos?

Perhaps I was naive, but even though I have written about placebos numerous times here and elsewhere I have always assumed that placebo pills were literally sugar pills. It had not occurred to me that placebo content needs to be specifically disclosed, and that their composition might not be as standard as I had assumed.

A new study in the Annals of Internal Medicine reviews clinical trials over the last two years. They found that only 8.2% of clinical trials with a placebo pill as a control specifically disclosed the placebo content. Meanwhile 26.7% of trials involving injections and procedures disclosed the precise nature of the treatment. This difference makes sense, in that there is much more interest in the nature of a placebo treatment when it is more complex than just taking a pill.

The concept of a placebo is that it is completely physiologically inert, therefore any response to the placebo is due to other factors (other than a physiological response to an active intervention). Typically, in pharmaceutical trials, the company that makes the drug being studied will also manufacture look-alike placebos. These can contain the sugar base and any other fillers, the same coating, etc. – but not the active drug. But according to the study authors perhaps we cannot assume that these placebo pills are completely inert.

It is possible that some of the other ingredients (fillers) in the pill may have biological activity. They may produce effects or side effects that can obscure the effect of the drug they are being compared to. Or, negative side effects in the placebo may produce the illusion of a beneficial effect in the drug being studied, even if it does not work.

All of this seems like common sense to me, and therefore nothing that could have a significant physiological effect should be an undisclosed component of a placebo. The authors do not imply that there is deliberate manipulation of the placebo, but if the contents are not disclosed this cannot be ruled out. More likely there is unintentional use of a placebo that is not entirely inert. Either way, requiring full disclosure of placebo content will go a long way to addressing this issue.

I should mention that there is also the concept of an active placebo – a placebo treatment that is deliberately not inert but meant to mimic the side effects of the active treatment. The purpose of this is to prevent subjects in a clinical trial from being unblinded. Getting side effects can clue someone in to the fact that they are on the active treatment, while the absence of side effects may be a hint that someone is getting the placebo. So a placebo that does nothing but produce a mild side effect  can trick subjects in the placebo arm into thinking they are getting the active treatment. But of course, this introduces the problem of obscuring the results if the active placebo may accidentally provide a beneficial effect.

This problem is more of a factor with non-drug trials. In acupuncture trials, for example, sham acupuncture (at non-acupuncture points) or placebo acupuncture (without skin penetration) is often given as an active placebo. Of course, when these trials are negative proponents can claim that the placebo form of acupuncture was not inert and accidentally provided a clinical effect.

Conclusion

The take home message from this new study is that designing the placebo arm of a clinical trial is not always as straightforward as might be assumed. In some types of trials great attention is paid to designing the placebo treatment, but in drug trials it is often assumed that the sugar pills provided by the company performing the study are simply “placebos” without further thought being given.

I agree with the authors that it should become standard for clinical trials to disclose the exact content of the placebo treatment. This should be a trivial matter for those making the placebos. When it comes to clinical trials (as with science in general) transparency is vital.

13 responses so far

13 Responses to “What’s In Placebos?”

  1. Todd W.on 19 Oct 2010 at 10:35 am

    Placebos are quite interesting. The design of a proper placebo can be extremely difficult, particularly when you get into medical devices. And even beyond the design, there are ethical considerations (e.g., placebo surgery isn’t allowed anymore because the increased risk to the patient outweighs any potential benefit they may receive from the placebo effect).

    Nice article highlighting some of the considerations that must be taken into account.

  2. superdaveon 19 Oct 2010 at 12:42 pm

    This too might be a naive thought, but I would think that if you are looking for control for substance x, and the active group receives x+fillers and coating, that i makes sense for the placebo group to just get the fillers and coating. This of course assumes that the relationship between any effects due to the coating and fillers and the drug are totally linear, but any other functional relationship could work if the knowledge of the drug interactions are well known.

  3. sonicon 19 Oct 2010 at 3:38 pm

    Having ‘inactive’ placebos can effectively unmask the blinding of an experiment.
    In 1986 it was found that patients could determine if they were on the ‘real’ treatment or placebo due to the side effects. Of course this would be true of the doctors (knowing if the person they are seeing is getting the treatment or not)

    http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TBV-46041RC-D9&_user=10&_coverDate=09%2F30%2F1986&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=acc67de62e8e38893d4b66c8bd7391a8&searchtype=a

    This has been studied most extensively with regards to anti-depressants–

    http://www.srmhp.org/0201/media-watch.html

    (a good article with links to many relevant studies).

  4. tmac57on 19 Oct 2010 at 5:41 pm

    I was in a support group for caregivers of cancer patients,and the husband of a patient that was in a clinical trial told us repeatedly that he and his wife were sure that she was getting Avastin (I think that was the drug ) because she was breaking out in skin sores. It made me wonder about the blinding of the trial.

  5. Paul N.on 20 Oct 2010 at 4:46 am

    I wonder, if a placebos mimic side effects, what conclusions con be drawn from assertions like: “All side effects have been at placebo level.” given in some monographs. So we would need an other arm in each placebo controlled studies placebo with side effects vs. placebo without side effects. Furthermore who is going to control the placebo content and manufacturing? I propose the inauguration of a Junk Food and Placebo Administration. 😉

  6. ccbowerson 20 Oct 2010 at 10:56 am

    “Active” placebos seem like they would introduce more noise into the picture. Anything that produce a “side effect” has an “effect,” therefore not a placebo.

    For medication trials, it would be better to require more studies to include cheaper comparator medications in addition to placebo when possible. I understand that this is a pipe dream the way things currently are, and such a requirement is not without its problems

  7. ChrisHon 20 Oct 2010 at 1:01 pm

    There is a great video on placebos here:
    http://tokenskeptic.org/2010/09/23/the-placebo-effect/

    Unfortunately the video is not working for me, so I downloaded the file from her RSS page:
    http://traffic.libsyn.com/tokenskeptic/The_Placebo_Effect_-_Token_Skeptic.m4v

  8. gotteon 20 Oct 2010 at 4:13 pm

    I have been involved in an RCT trial where I had to provide the palcebo. I learned a lot about this and found out that there are parafarmaceutical compagnies ( often subcontracted by big pharma) who are specialised in this especially in the development active placebo’s. I learned that not only the most known side effects of the type of active medication (fi NSAI–> GI sideeffects) had to be mimiced but also the feel, touch, taste, smell and most of the the physical proporties of the active medication (solvable in water, howdoes it burn etc..) as patients tend to contact others involved in a study in order to find out what is what.

    Dr. G. Otte

  9. zorrobanditoon 21 Oct 2010 at 11:15 am

    OK, having watched the cool video cited by ChrisH (the original doesn’t work for me either, it’s probably defective), I want to re-ask the question I asked on another thread: how can we harness this belief-ability so that it could have medical effects, like pain relief and even more fancy stuff like cancer regression? Because remember, placebos don’t have negative side-effects (unless we deliberately engineer them in).

    There’s obviously something going on here in the placebo effect. People do sometimes get better on sheer belief alone: pain is relieved, disease processes are reversed and so forth. (If this were not true there would be no reason for double-blind studies.) There is obviously some mind/body connection which is not adequately accounted for in our medical understandings, and which could be of good effect if we could understand and harness it.

  10. Todd W.on 21 Oct 2010 at 1:10 pm

    @zorrobandito

    I recall reading somewhere (can’t remember where, though) that, for example, in a pain study, even though the subjective measure of perception of pain improved with placebo, an objective measure (e.g., range of motion) did not improve. So then the question becomes, is there really improvement, or is there merely the perception of improvement?

    And placebos can actually have negative effects. This is generally referred to as a nocebo response or nocebo effect. Just as with placebos, some patients report improvement, the nocebo effect encompasses the negative reactions (e.g., headache, nausea, etc.) that patients report when they receive the placebo.

    As to harnessing the placebo effect to result in meaningful, improved outcomes (e.g., improved quality of life), I don’t think there’s a reliable way to do it, since every person’s response to a placebo is going to be different. One person may respond very strongly to, say, acupuncture’s placebo effects, while another will have absolutely no change whatsoever. Maybe there could be some way of screening people to find out which placebo would work best for them, but then you have the ethical quandary of lying to your patient.

  11. ccbowerson 23 Oct 2010 at 12:28 pm

    zorrobandito-

    You have some misunderstandings about placebos. You appear to have an overestimation of what placebos can do. In the long run their effects tend to be short lived and work better for subjective symptoms. (please give an example of placebo affected disease progression). “Placebos” can have negative effects as Todd pointed out the “nocebo effect,” and there is no reason to think that this effect is any less powerful. Put an harmless odd smell in an airplane and you will get people with headaches, nausea, and even vomiting.

    Also double blind studies are not just done to counter the effects of “sheer belief alone.” Not blinding may also affect the way a participant is treated in a study and the way the participant behaves in a study (conscious or not). I’m not big on the idea of “harnessing placebos” because active drugs also carry this effect plus their added pharmacological effects.

  12. MarkMarijnissenon 26 Oct 2010 at 6:19 am

    a lot of people dismiss the placebo effect as “absolutely useless” and see they see the placebo effect as an annoying cognitive fallacy that has to be eliminated to do proper science.

    don’t get me wrong; placebo’s don’t cure diseases by definition – since there are no effective components in them.

    i am not going to claim that there is some undiscovered, spiritual mind-body connection that should be investigated. science does not lie.

    however, i would like to see a change in attitude. While the placebo effect might make science more difficult, it is not all evil.

    it does give us insight in how people experience their reality subjectively. people do feel really better because of placebo’s.

    When this results in delusion, and people stop solving the actual problem, this is harmful. (As is with alternitive medicine). However, when the placebo-effect is better understood, it could be used to increase happiness and the mental suffering that results from a disease (or from living in general).

    i think medicine or skeptics dismiss placebo’s as “useless and harmfull” with the assumption that the placebo-effect is unpredictable.

    I would like to see a fascination on how to harnass the placebo-effect in such way that it does not hinder real treatment, but instead provide with a set of psychological/cognitive tools that allow us to increase our happiness by altering our “subjective” reality, i.e. how we experience pain and discomfrt.

  13. MarkMarijnissenon 26 Oct 2010 at 6:22 am

    it would also further our understanding of how some CAM propenents manage to delude themselves — how they in spite of all the evidence keep believing that their woo-woo is true.

    since what they are doing is something similar to the placebo-effect; their minds also distort reality by assumptions. (pill will make me better -vs- CAM will make us better)

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