When Lee D. Park, M.D. and Uno Covi, M.D. from the Department of Psychiatry at Johns Hopkins University School of Medicine in Baltimore, MD, back in the 1960s, gave their depressed patients placebos, they did exactly this — told them that the pill did not contain an active pharmacological agent (at that time, likely a classical tricyclic antidepressant), but was a placebo. They were surprised to see that it did work (1): 14 of their 15 patients reported improved symptoms a week later, and no difference was found between those that had believed they were taking the placebo and those that had — upon questioning — believed they had received a real drug.
It lasted almost 50 years until two research groups dared to test the OLP paradigm again. In 2008, Sandler & Bodfish from Departments of Pediatrics & Psychiatry, UNC at Chapel Hill, reduced by 50% the actual medication (methylphenidate or amphetamine) in 26 children ages 7-15 with Attention Deficit Hyperactivity Disorder (ADHD) and substituted it with placebos for one week, with full information about the nature of the intervention (2). Such a “dose-extension” study design follows the principles of Pavlovian conditioning (3), one of the (few) basic mechanisms to provoke the placebo effect. Here, the important bottom line is: Reducing ADHD medication and substituting it with placebo was acceptable by children and parents and did not worsen the ADHD symptoms in the eyes of the patients, their parents, and their teachers.
Two years later, a placebo research group at Harvard Medical School, led by Ted Kaptchuk, presented an OLP study in another patient group with irritable bowel syndrome (IBS). This was the first well-designed and effectively-controlled OLP study (4), randomizing 80 patients to placebo treatment (twice daily for 3 weeks) or non-treatment control group to observe the spontaneous variation of symptoms. OLP patients received full disclosure that “… explained in an approximately fifteen minute a priori script the following ´four discussion points´: 1) the placebo effect is powerful, 2) the body can automatically respond to taking placebo pills like Pavlov’s dogs who salivated when they heard a bell, 3) a positive attitude helps but is not necessary, and 4) taking the pills faithfully is critical” (ibd, p 2). Needless to say: OLP produced higher global IBS symptom improvement, less severe IBS symptoms, better adequate relief scores, and trends towards a better quality of life than the control condition.
Since then, five more OLP studies have been published, with more clinical conditions: One in depression (5), one in low-back pain (6), two for seasonal sinusitis (7,8), and one for fatigue in cancer therapy (9). They resemble the range of applications, similarities in their strength, but also pitfalls of OLP, as visible in the table: e.g., treatment-as-usual is usually not specified or standardized in the trials, and all study samples are small considering the distribution of the patients on two study arms.
Two meta-analyses have summarized the results so far (15, 16) but missed some important issues that are critical for the validation and implementation of OLP in medical practice. For one, all these examples have shown that while openly-applied placebos affect symptoms (depression, motor activity, pain, fatigue, etc.), none have yet shown that it may also affect disease biomarkers. Secondly, patient (self-)selection has to be tested for biases, e.g., whether the recruited patients are prone to respond to placebo, while others not recruited are not. Last but not least, it would be important to know how OLP compares to effective drug treatment of the same condition and in the same patients. A study protocol of such a four-arm trial (18) has been proposed for the treatment of IBS, and we are eagerly awaiting the results.
This is part 3 of a series covering “placebo” provided by Paul Enck and Sibylle Klosterhalfen from the Tübingen University Hospital. Continuous updates on placebo research can be found at www.jips.online.
- Park LC, Covi L. Nonblind placebo trial: An exploration of neurotic patients´ responses to placebo when ist inert content is disclosed. Archives of general psychiatry. 1965;12:36-45.
- Sandler AD, Bodfish JW. Open-label use of placebos in the treatment of ADHD: a pilot study. Child: care, health and development. 2008;34:104-10.
- Colloca L, Enck P, DeGrazia D. Relieving pain using dose-extending placebos: a scoping review. Pain. 2016;157:1590-8.
- Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, Singer JP, et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PloS one. 2010;5:e15591.
- Kelley JM, Kaptchuk TJ, Cusin C, Lipkin S, Fava M. Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychotherapy and psychosomatics. 2012;81(5):312-4.
- Carvalho C, Caetano JM, Cunha L, Rebouta P, Kaptchuk TJ, Kirsch I. Open-label placebo treatment in chronic low back pain: a randomized controlled trial. Pain. 2016;157:2766-72
- Schaefer M, Harke R, Denke C. Open-Label Placebos Improve Symptoms in Allergic Rhinitis: A Randomized Controlled Trial. Psychotherapy and psychosomatics. 2016;85:373-4.
- 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:e0192758.
- Hoenemeyer TW, Kaptchuk TJ, Mehta TS, Fontaine KR. Open-Label Placebo Treatment for Cancer-Related Fatigue: A Randomized-Controlled Clinical Trial. Scientific reports. 2018;8:2784.
- El Brihi J, Horne R, Faasse K. Prescribing Placebos: An Experimental Examination of the Role of Dose, Expectancies, and Adherence in Open-Label Placebo Effects. Annals of behavioral medicine : a publication of the Society of Behavioral Medicine. 2018.
- Locher C, Nascimento AF, Kirsch I, Kossowsky J, Meyer A, Gaab J. Is the rationale more important than deception? A randomized controlled trial of openlabel placebo analgesia. Pain. 2017;158:2320-8
- Trogen B, Caplan A, Klass P. The Ethics of Open-Label Placebos in Pediatrics. Pediatrics. 2017;140, doi: 10.1542/peds.2016-4328.
- Blease C, Colloca L, Kaptchuk TJ. Are open-Label Placebos Ethical? Informed Consent and Ethical Equivocations. Bioethics. 2016;30:407-14
- Miller FG, Wendler D, Swartzman LC. Deception in research on the placebo effect. PLoS medicine. 2005;2:e262.
- Charlesworth JEG, Petkovic G, Kelley JM, Hunter M, Onakpoya I, Roberts N, et al. Effects of placebos without deception compared with no treatment: a systematic review and meta-analysis. J Evid Based Med. 2017;10:97-107.
- Petkovic G, Charlesworth JE, Kelley J, Miller F, Roberts N, Howick J. Effects of placebos without deception compared with no treatment: protocol for a systematic review and meta-analysis. BMJ open. 2015;5:e009428.
- Ballou S, Kaptchuk TJ, Hirsch W, Nee J, Iturrino J, Hall KT, et al. Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial. Trials. 2017;18:234.