Schaefer M, Sahin T, Berstecher B. Why do open-label placebos work? A randomized controlled trial of an open-label placebo induction with and without extended information about the placebo effect in allergic rhinitis. PloS ONE. 2018;13(3):e0192758. https://doi.org/10.1371/journal.pone.0192758
To examine the role of expectations for the open-label placebo effect.
Randomized controlled trial (RCT) comparing open-label placebo to nontreatment controls. Two-factorial design: 1) open-label placebo relative to no pills; and 2) detailed information on placebos relative to no information.
Forty-seven men and women, ages 18 to 60; all participants had a diagnosis of allergic rhinitis and were not taking medication for rhinitis.
Participants completed questionnaires to assess allergic symptoms, ranking each of the following symptoms on a 7-point scale from never (1) to always (7): itching, prickling, or burning feelings in the nose; congested or running nose; impaired sense of smell or taste; sneezing; feeling like they had a cold; itching or irritated skin; eczema; itching, burning, or red eyes; billowed eyelids; itching, prickling, or scratching feeling in the throat; sore throat; burning or mucus in the mouth or throat; breathlessness; cough; headache; exhaustion; lack of concentration; tiredness; and gastrointestinal symptoms. The 36-item short form health survey (SF-36), German version, was used to assess quality of life. All participants noted their allergy symptoms daily in an allergy diary.
All participants were informed that the study was about psychosocial interactions during the treatment of allergies and that they would either get a placebo pill containing no medication, to be taken twice a day, or no pills. They were then randomized into 2 groups. Half (the positive expectation group) received information on the power of the placebo, indicating that the body may automatically respond to a placebo pill, that a positive attitude may be helpful for the placebo effect but it was not necessary, and they needed to take the placebo faithfully. The other half (the no positive expectation group) received no information on the power of the placebo. All participants within the positive expectation and the no positive expectation groups were given the SF-36, German version, to examine quality of life. All participants in the positive expectation and no expectations groups were then randomized to either the placebo group or the control group. The placebo pill group was given a white tube of 28 pills with the logo of the local university and the information “placebo pills: take 1 in the morning and 1 before bed for 14 days.” The control group received no pills. Ultimately there were 4 randomized groups: 1) open-label placebo pills with placebo briefing (positive expectations); 2) open-label placebo pills without placebo briefing; 3) control with placebo briefing (positive expectations); and 4) control (no placebo pills) without placebo briefing. The study was conducted when pollen counts were high.
The placebo pills were white, round, 4 mm in diameter, and contained sugar, wheat, cornstarch, and glucose syrup. Subjects were asked to swallow rather than chew or suck on the pills.
There were no significant differences among symptom severities before the study began. There were no interactions between participants’ expectations, time (pre/post “intervention”), and placebo (P=0.24).
There was improvement in symptoms over time, irrespective of treatment (P=0.006) in all 4 groups. This could be explained in part by a decrease in pollen counts at the second visit.
Regardless, post-hoc t-tests revealed improvement from first to second treatment only when participants received open-label placebos (P=0.02, Cohen’s d=0.74). The open-label placebo pills improved symptoms independent of the information about placebos. Data from the allergy diaries revealed the improvement in symptoms took place only a few days after taking the open-label placebo pills.
Symptom categories were created for nose, eye, breathing, mouth, skin, and general allergy symptoms. For each symptom category, significant improvements were found in the open-label placebo pill group (P<0.05) but not in the control group (P=0.06).
There was no interaction between expectancy, time, and placebo (P=0.89) or expectancy and placebo (P=0.19). The open-label placebo improved symptoms of allergic rhinitis independent of the detailed information about placebos. There were no significant effects of ANOVA (time, placebo, expectancy) on physical or mental sum scores of the SF-36 (P=0.76). Mental sum scores were significantly different prior to the intervention (P=0.001) but physical sum scores were not. There was a significant effect of expectancy on mental sum score (P=0.006), but no significant interaction of expectancy with placebos on mental sum scores (P=0.23). Positive expectancy on the way placebos may work influenced mental sum scores on the SF-36 independent of taking open-label placebos.
Participants in the control groups were asked if they were disappointed about not being in the placebo group, but none stated they were. No adverse effects were reported due to the placebo pills.
The use of open-label placebo significantly improved symptoms of allergic rhinitis independent of detailed information about placebos. There was an across-the-board improvement in allergic rhinitis symptoms, but this may be partially due to an improvement in pollen counts by the second visit, 14 days later. However, symptom improvements in the nose, eyes, breath, mouth, skin, and general categories were significant in the open-label placebo group but not the control group. The significant effect of expectancy on mental sum scores (P=0.006) suggests that detailed information on the positive effects of placebo influenced the mental sum scores of SF-36 independent of taking an open-label placebo.
Several trials have demonstrated that placebo without concealment can reduce symptoms in attention-deficit/hyperactivity disorder (ADHD), major depression, and neurosis.1-3 Results of this study suggest that allergic rhinitis can be added to these conditions. In this trial positive expectancy by prior detailed information improved allergic rhinitis symptoms in the placebo compared to the control group. Expectations did improve the mental sum scores on the SF-36 independent of the open-label placebo effect. The results of expectations improving outcome were also demonstrated by a study of episodic migraines that compared open-label placebo without expectations that produced a 30% reduction in pain compared to no-treatment controls and pain reduction when rizatriptan and placebo were deliberately mislabeled.4
The use of open-label placebo significantly improved symptoms of allergic rhinitis independent of detailed information about placebos.
Placebo is Latin for “I will please,” with one of the oldest references found in Psalm 114 of the Gallican translation (the translation accepted by the Catholic church) of the Vulgate, a Latin translation of the Bible by Jerome (342-420 CE).5 A review by Beecher published in JAMA in 1955 established that placebo was clinically important and resulted from the brain’s role in physical health. Beecher also reported that placebo had been officially used in medicine since 1811, being also referred to as “counterfeit,” “dummies,” and “dummy tablets.”6 Beecher observed that placebo had an average effectiveness of 35.2% (±2.2%) based on 15 studies (involving a variety of conditions and a total of 1,082 participants), and that placebo produced toxic reactions that disappeared when placebo administration stopped.
In 1997 Kienle and Kiene reexamined Beecher’s data and concluded that the placebo effect did not exist; rather, it was the result of spontaneous improvement, fluctuation of symptoms, regression to the mean, other treatments, bias, experimental subordination, misjudgment, neurotic or psychotic misjudgment, and sloppy methodical thinking.7 A Cochrane review of 60 clinical conditions in 202 trials from 1980 to 2009 determined that placebo did not have important clinical effects, but it could influence patient reports of pain and nausea, although there was a risk of bias.8 They found no effect of placebo in pain, nausea, smoking, and depression, all of which had at least 3 trials each included in the review, but confidence intervals were wide.8
Placebo effect in depression using 4 new-generation antidepressants was determined to be 82% based on Kirsch et al’s meta-analysis of US Food and Drug Administration (FDA) clinical trials data.9 A later review determined that Kirsch et al’s methods were flawed and that placebo response was due to expectancy.10 A follow-up meta-analysis by Kahn et al of 8 trials over 12 weeks determined that 79% of patients on placebo remained well for the trial period, compared to 93% of those receiving antidepressants.11 Kahn et al concluded that medicine’s belief that the placebo response in depression is short-lived may be wishful thinking.11
The ethics of placebo trials is debatable and thus informed consent is required, in accordance with the World Medical Association Declaration of Helsinki (first adopted in 1964).12 One evidence-based researcher published a series of arguments that favored the placebo-controlled trial over the active-controlled trial.13 A 2010 Medscape survey of 10,078 doctors found that 24% would prescribe a placebo simply because the patient wanted treatment, 58% would not prescribe placebo, and 18% said it would depend on the circumstances.14
From the above findings and this allergic rhinitis trial, it seems that patients will respond to placebo and their clinical symptoms can improve. In this allergic rhinitis trial, this was independent of participants’ expectations. If the patient has expectations that the intervention will have a negative effect, rather than a positive effect, it is known as the nocebo effect (Latin for “I will harm”). Medicine in the clinical setting seems uncomfortable with when, where, and how to use placebo, and yet placebo or patient response modifiers are present in such things as the white coat, stethoscope, concerns of the doctor, touch, professionalism, and so much more.15,16
Allergic response to environmental allergens is common. In this 4-group trial the use of open-labeled placebo pills significantly improved allergic rhinitis symptoms independent of the detailed information provided about placebos. Symptom improvement was significant in the open-label placebo group but not in the control group. Positive expectancy significantly improved mental sum scores on the SF-36 in the placebo group. No adverse effects were reported in the placebo group, and the control group did not express disappointment about being in the control group. Positive expectations had a beneficial effect on the subjective well-being of the research subjects.
- Sandler AD, Bodfish JW. Open-label use of placebos in the treatment of ADHD: a pilot study. Child Care Health Dev. 2008;34(1):104-110.
- Kelly JM, Kaptchuk TJ, Cusin C, Lipkin S, Fave M. Open-label placebo for major depression disorder: a pilot randomized controlled trial. Psychother Psychosom. 2012;81(5):312-314.
- Park LC, Covi L. Nonblind placebo trial: an exploration of neurotic patients’ responses to placebo when its inert content is disclosed. Arch Gen Psychiatry. 1965;12:36-45.
- Kam-Hansen S, Jakubowski M, Kelley JM, et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med. 2014;6(21):218ra5.
- Jacobs B. Biblical origins of placebo. J R Soc Med. 2000;93(4):213-214.
- Beecher HK. The powerful placebo. JAMA. 1955;1602-1606.
- Kienle GS, Kiene H. The powerful placebo effect: fact or fiction? J Clin Epidemiol. 1997;50(2):1311-1318.
- Hrobjartsson A, Gotzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2010;106(1):CD03974.
- Kirsch I, Decan BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5(2):e45.
- Fountoulakis KN, Moller HJ. Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data. Int J Neuropsychopharm. 2011;14(3):405-412.
- Kahn A, Redding N, Brown WA. The persistence of the placebo response in antidepressant clinical trials. J Psychiatric Res. 2008;42(10):791-796.
- World Medical Association. WMA Declaration of Helsinki – ethical principles for medical research involving human subjects. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed September 19, 2018.
- Howick J. Questioning the methodologic superiority of placebo over active controlled trials. Am J Bioethics. 2009;9(9):34-48.
- Kane L. Exclusive ethics survey results: doctors struggle with tougher-than-ever dilemmas. Medscape. https://www.medscape.com/viewarticle/731485_4. Published November 11, 2010. Accessed September 19, 2018.
- Brody H. The placebo response. J Fam Practice. 2000.49(7):649-654.
- Hafner RJ, White MP, Handley SJ. The Goldilocks placebo effect: placebo effects are stronger when people select a treatment from an optimal number of choices. Am J Psychol. 2018.131(2):175-184.