• Where Truth Lies: Placebos

    By Reed Loring Levine, MD

    Albert: “My hands are shaking…Agador, l need some Pirin tablets. Quickly!”

    Armand: “What are you giving him drugs for? What the hell are Pirin tablets?”

    Agador: “It’s aspirin with the ‘A’ and the ‘S’ scraped off.”

    Armand: “My God, what a brilliant idea!”

        -The Birdcage, 1996

    I can give you a treatment that significantly reduces the searing pain of shingles in about one-third of patients.  I can give you a pill that has been shown to significantly reduce depression in more than 50% of its users.  An erection pill that helps 24% of men produce erections of subjectively-better quality.  A migraine treatment that significantly reduces headache pain in 30-40% of patients…

    The thing is, none of these remedies should work.

    Because they are all placebos.

    Each is the “control group” in a major study of an FDA-approved medication, and these placebos appear to produce significant benefit for many users.

    Placebos (traditionally defined as a medically-ineffective treatment) and the placebo effect (a perceived or actual outcome from a placebo) are well known, but most people know very little about how and why placebos work, how they can be tweaked or manipulated to alter our perceptions and behaviors.

    In casual conversation, an oncologist colleague told me that in the world of cancer treatment, patients commonly utilize “holistic” and “natural” treatments to complement science-based care.  She listed a half-dozen such things she commonly encountered, from prayer and ritualized meditation to many variant forms of “juicing”.  Many of the treatments her patients used were pseudo-scientific nutrition regimens focused on what they eat or drink.  She expressed that her approach is that if a patient buys into a “holistic” diet and supplement or other such program in addition to standard proven treatment that she will not only “let it slide” but encourage it.  Her patients are involved in a process in which they are in many ways powerless, having given over control to both their disease and their physicians.  She believes that the placebo effect of letting the patient feel some degree of control through these self-guided regimens is beneficial, although “the specifics of their regimen doesn’t seem to matter at all.” Perhaps there is such a frequent focus on rituals that involve food or supplements because cancer patients are often faced with long stretches where nausea and vomiting limits their intake, so any act where they can take control of what goes in their body takes on extra meaning for them, and when coupled with the idea that the food is itself a treatment, you have a set up for a potent placebo effect.

    There is good evidence that the placebo effect has a profound impact on clinical outcomes and can be manipulated.  How can we leverage the existing data to ethically improve the medical care of patients?  We know a few things, including:

    1. It appears that being honest about placebos may not, in some cases, decrease their efficacy: you can sometimes tell people you are giving them placebos and they still work

    2. Brand-name placebos are more effective than generics.

    3. Multiple-tablet placebo doses appear more effective than single-tablet doses

    4. Tablet color and shape matters. (ie: blue pills treat insomnia better than red pills; anxiety is best treated with green pills)

    5. Route of administration matters. (ie: tablets are less effective than capsules which are less effective than shots or medical devices)

    6. Costly treatments are more effective than inexpensive ones.

    7. The physician’s description of what to expect has a great impact on the actual effect of the treatment.

    Keeping all of this in mind, a physician might ethically prescribe a treatment they believe has a good probability of working for patient’s condition while utilizing this knowledge to enhance the probability of a positive effect and decrease the probability of adverse effects. Although it’s not always advisable to prescribe non-generic drugs, in cases where a physician does so for a good reason they might spend time explaining to the patient the thought process for their decision and explain what benefits this brand-name, more costly treatment choice offers.  If I am choosing a more expensive option for a patient, I should be able to justify my decision medically, and taking the time to explain that decision to my patient may actually enhance the effect of the treatment (Facts #2, #6 & #7, above).

    In clinical practice we often will have patients gradually taper up medications to a desired goal-dose.  This is is typically done to reduce the incidence of side-effects.  Explaining the taper using key phrases may theoretically enhance the benefits and reduce the side-effects, for instance, one might say, “this gentle tapering up on the medication will reduce the probability of side-effects, and may make any ones you have less severe, as you gradually work your way up to the full, effective dosage”.

    Placebos and the placebo effect have a profound, often under-appreciated impact on both the practice of clinical medicine and, taken in a more broad sense, on a wide variety of our daily experiences.  Over a series of short pieces, I will examine with you the literally-unreal landscape of placebos, from pharmaceutical testing, to quack-medicine, and beyond.  I look forward to exploring these curious corners of human experience with you in the coming months.

    Special thanks to Greg Stikeleather, Jamy Ian Swiss and Max Maven, whose engaging dinner conversation helped inspire this series of articles.


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    2. de Craen, AJM, et al.  Effect of colour of drugs: systematic review of perceived effect of drugs and of their effectiveness.  BMJ 1996;313:1624. http://www.bmj.com/content/313/7072/1624
    3. Howick J..  Saying things the “right” way: avoiding “nocebo” effects and providing full informed consent. Am J Bioeth. 2012;12(3):33-4.  http://www.ncbi.nlm.nih.gov/pubmed/22416748
    4. Hussain, MZ.  Effect of Shape of Medication in Treatment of Anxiety States. The British Journal of Psychiatry (1972) 120: 507-509.  http://bjp.rcpsych.org/content/120/558/507.short
    5. Jacobs, KW & Nordan, FM.  Classification of Placebo Drugs: Effect of Color. Perceptual and Motor Skills: Volume 49, Issue , pp. 367-372.  http://journals.lww.com/psychopharmacology/Abstract/1982/08000/…
    6. Kam-Hansen, S. Altered Placebo and Drug Labeling Changes the Outcome of Episodic Migraine Attacks.  Sci Transl Med 8 January 2014: Vol. 6 no. 218 pp. 218ra5.  http://stm.sciencemag.org/content/6/218/218ra5.full.html)
    7. Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, et al. Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome. PLoS ONE 5(12): e15591. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015591
    8. Kaptchuk TJ, et al.  Sham device v inert pill: randomised controlled trial of two placebo treatments.  BMJ. 2006 Feb 18;332(7538):391-7.  http://www.ncbi.nlm.nih.gov/pubmed/16452103
    9. Kelley, JM, et al.  Patient and practitioner influences on the placebo effect in irritable bowel syndrome.  Psychosom Med. 2009 Sep;71(7):789-97. http://www.ncbi.nlm.nih.gov/pubmed/19661195
    10. Lang, EV, et al.  Can words hurt? Patient-provider interactions during invasive procedures.  Pain. 2005 Mar;114(1-2):303-9. http://www.ncbi.nlm.nih.gov/pubmed/15733657
    11. Meyers, SS, et al.  Patient expectations as predictors of outcome in patients with acute low back pain.  J Gen Intern Med. 2008 Feb;23(2):148-53. http://www.ncbi.nlm.nih.gov/pubmed/18066631
    12. Srivastava, RK & More, AT. Some Aesthetic Considerations for Over the Counter (OTC) pharmaceutical Products.  International Journal of Biotechnology, 2010.  http://www.sciencedaily.com/releases/2010/11/101115110959.htm
    13. Waber, RL, et al.  Commercial Features of Placebo and Therapeutic Efficacy.  JAMA. 2008;299(9):1016-1017. http://jama.jamanetwork.com/article.aspx?articleid=181562
    14. Wells, RE & Kaptchuk, TJ.  To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect for informed consent. Am J Bioeth. 2012;12(3):22-9.  http://www.ncbi.nlm.nih.gov/pubmed/22416745
    15. Winslow, R.  Placebos Might Work Even Better With a Brand Name. Health Blog. Wall Street Journal, March 4, 2008.  http://blogs.wsj.com/health/2008/03/04/placebos-might-work-even-better-with-a-brand-name/
    16. Zimmermann-Viehoff, F. Expensive placebos–what is free, what is without value.  Forsch Komplementmed. 2008 Oct;15(5):288-9.  http://www.ncbi.nlm.nih.gov/pubmed/19009728
    17. Several pharmaceutical package inserts were also utilized in preparing this piece.  These include but are not limited to those available online for: rizatriptan, high-potency capsaicin, fluoxetine HCl and sildenafil citrate.


    Reed Levine MD
    Reed Levine MD

    Reed Loring Levine, MD, ABPN is a Board-Certified Neurologist and Pain Management Specialist who serves as the Director of Medical Education of a large subspecialty private practice medical group.  Actively engaged in clinical research, he formerly served as an elected council member of the Pain and Palliative Care Section of the American Academy of Neurology and has published over a dozen peer-reviewed scientific articles and textbook chapters and been interviewed by national publications including TIME Magazine and The Huffington Post.  He has a dog, who is an untraditional beauty.

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  • Article by: Reed Levine