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Published in: Trials 1/2017

Open Access 01-12-2017 | Study protocol

Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial

Authors: Sarah Ballou, Ted J. Kaptchuk, William Hirsch, Judy Nee, Johanna Iturrino, Kathryn T. Hall, John M. Kelley, Vivian Cheng, Irving Kirsch, Eric Jacobson, Lisa Conboy, Anthony Lembo, Roger B. Davis

Published in: Trials | Issue 1/2017

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Abstract

Background

Placebo medications, by definition, are composed of inactive ingredients that have no physiological effect on symptoms. Nonetheless, administration of placebo in randomized controlled trials (RCTs) and in clinical settings has been demonstrated to have significant impact on many physical and psychological complaints. Until recently, conventional wisdom has suggested that patients must believe that placebo pills actually contain (or, at least, might possibly contain) active medication in order to elicit a response to placebo. However, several recent RCTs, including patients with irritable bowel syndrome (IBS), chronic low back pain, and episodic migraine, have demonstrated that individuals receiving open-label placebo (OLP) can still experience symptomatic improvement and benefit from honestly described placebo treatment.

Methods and design

This paper describes an innovative multidisciplinary trial design (n = 280) that attempts to replicate and expand upon an earlier IBS OLP study. The current study will compare OLP to double-blind placebo (DBP) administration which is made possible by including a nested, double-blind RCT comparing DBP and peppermint oil. The study also examines possible genetic and psychological predictors of OLP and seeks to better understand participants’ experiences with OLP and DBP through a series of extensive interviews with a randomly selected subgroup.

Discussion

OLP treatment is a novel strategy for ethically harnessing placebo effects. It has potential to re-frame theories of placebo and to influence how physicians can optimize watch-and-wait strategies for common, subjective symptoms. The current study aims to dramatically expand what we know about OLP by comparing, for the first time, OLP and DBP administration. Adopting a unique, multidisciplinary approach, the study also explores genetic, psychological and experiential dimensions of OLP. The paper ends with an extensive discussion of the “culture” of the trial as well as potential mechanisms of OLP and ethical implications.

Trial registration

ClinicalTrials.gov, identifier: NCT02802241. Registered on 14 June 2016.
Appendix
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Literature
1.
2.
Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet Lond Engl. 2010;375(9715):686–95.CrossRef
3.
Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci. 2015;16(7):403–18.CrossRefPubMed
4.
Tilburt JC, Emanuel EJ, Kaptchuk TJ, Curlin FA, Miller FG. Prescribing “placebo treatments”: results of national survey of US internists and rheumatologists. BMJ. 2008;337:a1938.CrossRefPubMedPubMedCentral
5.
Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med. 2000;133(6):455–63.CrossRefPubMed
6.
Blease CR, Bishop FL, Kaptchuk TJ. Informed consent and clinical trials: where is the placebo effect? BMJ. 2017;356:j463.CrossRefPubMed
7.
8.
Kaptchuk TJ. Placebo studies and ritual theory: a comparative analysis of Navajo, acupuncture and biomedical healing. Philos Trans R Soc Lond B Biol Sci. 2011;366(1572):1849–58.CrossRefPubMedPubMedCentral
9.
Kaptchuk TJ. Powerful placebo: the dark side of the randomised controlled trial. Lancet Lond Engl. 1998;351(9117):1722–5.CrossRef
10.
Kaptchuk TJ. Intentional ignorance: a history of blind assessment and placebo controls in medicine. Bull Hist Med. 1998;72(3):389–433.CrossRefPubMed
11.
12.
Meissner K, Höfner L, Fässler M, Linde K. Widespread use of pure and impure placebo interventions by GPs in Germany. Fam Pract. 2012;29(1):79–85.CrossRefPubMed
13.
Fässler M, Meissner K, Schneider A, Linde K. Frequency and circumstances of placebo use in clinical practice—a systematic review of empirical studies. BMC Med. 2010;8:15.CrossRefPubMedPubMedCentral
14.
Kermen R, Hickner J, Brody H, Hasham I. Family physicians believe the placebo effect is therapeutic but often use real drugs as placebos. Fam Med. 2010;42(9):636–42.PubMed
15.
16.
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(12):e15591.CrossRefPubMedPubMedCentral
17.
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(12):2766–72.
18.
Kam-Hansen S, Jakubowski M, Kelley JM, Kirsch I, Hoaglin DC, Kaptchuk TJ, et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med. 2014;6(218):218ra5.CrossRefPubMedPubMedCentral
19.
Schaefer M, Harke R, Denke C. Open-label placebos improve symptoms in allergic rhinitis: a randomized controlled trial. Psychother Psychosom. 2016;85(6):373–4.CrossRefPubMed
20.
Kelley JM, Kaptchuk TJ, Cusin C, Lipkin S, Fava M. Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychother Psychosom. 2012;81(5):312–4.CrossRefPubMed
21.
Sandler AD, Bodfish JW. Open-label use of placebos in the treatment of ADHD: a pilot study. Child Care Health Dev. 2008;34(1):104–10.CrossRefPubMed
22.
Perlis M, Grandner M, Zee J, Bremer E, Whinnery J, Barilla H, et al. Durability of treatment response to zolpidem with three different maintenance regimens: a preliminary study. Sleep Med. 2015;16(9):1160–8.CrossRefPubMedPubMedCentral
23.
Ader R, Mercurio MG, Walton J, James D, Davis M, Ojha V, et al. Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom Med. 2010;72(2):192–7.CrossRefPubMed
24.
Schafer SM, Colloca L, Wager TD. Conditioned placebo analgesia persists when subjects know they are receiving a placebo. J Pain Off J Am Pain Soc. 2015;16(5):412–20.CrossRef
25.
Hills JM, Aaronson PI. The mechanism of action of peppermint oil on gastrointestinal smooth muscle. An analysis using patch clamp electrophysiology and isolated tissue pharmacology in rabbit and guinea pig. Gastroenterology. 1991;101(1):55–65.CrossRefPubMed
26.
Hawthorn M, Ferrante J, Luchowski E, Rutledge A, Wei XY, Triggle DJ. The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations. Aliment Pharmacol Ther. 1988;2(2):101–18.CrossRefPubMed
27.
Wechsler ME, Kelley JM, Boyd IOE, Dutile S, Marigowda G, Kirsch I, et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med. 2011;365(2):119–26.CrossRefPubMedPubMedCentral
28.
Sorokin I, Schatz A, Welliver C. Placebo medication and sham surgery responses in benign prostatic hyperplasia treatments: implications for clinical trials. Curr Urol Rep. 2015;16(10):73.CrossRefPubMed
29.
Freeman EW, Ensrud KE, Larson JC, Guthrie KA, Carpenter JS, Joffe H, et al. Placebo improvement in pharmacologic treatment of menopausal hot flashes: time course, duration, and predictors. Psychosom Med. 2015;77(2):167–75.CrossRefPubMedPubMedCentral
30.
Qu D, Zhang Z, Yu X, Zhao J, Qiu F, Huang J. Psychotropic drugs for the management of cancer-related fatigue: a systematic review and meta-analysis. Eur J Cancer Care (Engl). 2016;25(6):970–9.CrossRef
31.
Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson EE, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008;336(7651):999–1003.CrossRefPubMedPubMedCentral
32.
Hall KT, Lembo AJ, Kirsch I, Ziogas DC, Douaiher J, Jensen KB, et al. Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome. PloS One. 2012;7(10):e48135.CrossRefPubMedPubMedCentral
33.
Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta J-K. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry. 2008;65(2):220–31.CrossRefPubMed
34.
De La Fuente-Fernández R, Stoessl AJ. The biochemical bases for reward. Implications for the placebo effect. Eval Health Prof. 2002;25(4):387–98.CrossRef
35.
Kelley JM, Lembo AJ, Ablon JS, Villanueva JJ, Conboy LA, Levy R, et al. Patient and practitioner influences on the placebo effect in irritable bowel syndrome. Psychosom Med. 2009;71(7):789–97.CrossRefPubMedPubMedCentral
36.
Kaptchuk TJ, Shaw J, Kerr CE, Conboy LA, Kelley JM, Csordas TJ, et al. “Maybe I made up the whole thing”: placebos and patients’ experiences in a randomized controlled trial. Cult Med Psychiatry. 2009;33(3):382–411.CrossRefPubMedPubMedCentral
37.
Kerr CE, Shaw JR, Conboy LA, Kelley JM, Jacobson E, Kaptchuk TJ. Placebo acupuncture as a form of ritual touch healing: a neurophenomenological model. Conscious Cogn. 2011;20(3):784–91.CrossRefPubMedPubMedCentral
38.
Bishop FL, Jacobson EE, Shaw J, Kaptchuk TJ. Participants’ experiences of being debriefed to placebo allocation in a clinical trial. Qual Health Res. 2012;22(8):1138–49.CrossRefPubMedPubMedCentral
39.
Bishop FL, Jacobson EE, Shaw JR, Kaptchuk TJ. Scientific tools, fake treatments, or triggers for psychological healing: how clinical trial participants conceptualise placebos. Soc Sci Med. 2012;74(5):767–74.CrossRefPubMedPubMedCentral
40.
Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109 Suppl 1:S2–26. quiz S27.CrossRefPubMed
41.
42.
Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther. 1997;11(2):395–402.CrossRefPubMed
43.
Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344(21):1594–602.CrossRefPubMed
44.
45.
Schafer SM, Colloca L, Wager TD. Placebo-induced decreases in the neurologic pain signature do not always correspond with pain relief. In: Organization of Human Brain Mapping; June 14-18, 2015; Honolulu, Hawaii, USA. 14-18; Abstract #4272 6.
46.
Kirsch I. Response expectancy as a determinant of experience and behavior. Am Psychol. 1985;40(11):1189–202.CrossRef
47.
Albring A, Wendt L, Benson S, Nissen S, Yavuz Z, Engler H, et al. Preserving learned immunosuppressive placebo response: perspectives for clinical application. Clin Pharmacol Ther. 2014;96(2):247–55.CrossRefPubMed
48.
Stewart-Williams S, Podd J. The placebo effect: dissolving the expectancy versus conditioning debate. Psychol Bull. 2004;130(2):324–40.CrossRefPubMed
49.
Geers AL, Miller FG. Understanding and translating the knowledge about placebo effects: the contribution of psychology. Curr Opin Psychiatry. 2014;27(5):326–31.CrossRefPubMed
50.
Ritter W, Sussman E, Deacon D, Cowan N, Vaughan HG. Two cognitive systems simultaneously prepared for opposite events. Psychophysiology. 1999;36(6):835–8.CrossRefPubMed
51.
52.
Jensen KB, Kaptchuk TJ, Kirsch I, Raicek J, Lindstrom KM, Berna C, et al. Nonconscious activation of placebo and nocebo pain responses. Proc Natl Acad Sci U S A. 2012;109(39):15959–64.CrossRefPubMedPubMedCentral
53.
Jensen KB, Kaptchuk TJ, Chen X, Kirsch I, Ingvar M, Gollub RL, et al. A Neural mechanism for nonconscious activation of conditioned placebo and nocebo responses. Cereb Cortex N Y N 1991. 2015;25(10):3903–10.
54.
Jensen K, Kirsch I, Odmalm S, Kaptchuk TJ, Ingvar M. Classical conditioning of analgesic and hyperalgesic pain responses without conscious awareness. Proc Natl Acad Sci U S A. 2015;112(25):7863–7.CrossRefPubMedPubMedCentral
55.
Eaves ER, Nichter M, Ritenbaugh C. Ways of hoping: navigating the paradox of hope and despair in chronic pain. Cult Med Psychiatry. 2016;40(1):35–58.CrossRefPubMedPubMedCentral
56.
Hsu C, Sherman KJ, Eaves ER, Turner JA, Cherkin DC, Cromp D, et al. New perspectives on patient expectations of treatment outcomes: results from qualitative interviews with patients seeking complementary and alternative medicine treatments for chronic low back pain. BMC Complement Altern Med. 2014;14:276.CrossRefPubMedPubMedCentral
57.
Lopez SJ, Snyder CR, Pedrotti J. Hope: many definitions, many measures. In: Positive psychological assessment: a handbook of models and measures. Washington: American Psychological Association; 2003. p. 91–107.CrossRef
58.
Averill J, Sundarajan L. Hope as rhetoric: cultural narratives of wishing and coping. In: Eliott J, editor. Interdisciplinary perspectives on hope. New York: Nova; 2005. p. 127–59.
59.
Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry. 2010;67(8):857–65.CrossRefPubMed
60.
Bergmann JF, Chassany O, Gandiol J, Deblois P, Kanis JA, Segrestaa JM, et al. A randomised clinical trial of the effect of informed consent on the analgesic activity of placebo and naproxen in cancer pain. Clin Trials Metaanal. 1994;29(1):41–7.PubMed
61.
Fiorillo CD, Tobler PN, Schultz W. Discrete coding of reward probability and uncertainty by dopamine neurons. Science. 2003;299(5614):1898–902.CrossRefPubMed
62.
Kaptchuk TJ. The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med. 2002;136(11):817–25.CrossRefPubMed
63.
Clark A. Surfing uncertainty: prediction, action and the embodied mind. New York: Oxford University Press; 2016.CrossRef
64.
Kirsch I. Response expectancy: An introduction. In: Kirsch I, editor. How expectancies shape experience. Washington: American Psychological Association; 1999. p. 3–13.CrossRef
65.
Dennett D. Consciousness Explained. Penguin: London; 1993.
66.
Clark A. Embodied prediction. In: Metzinger T, editor. Windt JM Open Mind 7(1). Frankfurt am Main: MIND Group; 2015.
67.
Costa VD, Tran VL, Turchi J, Averbeck BB. Dopamine modulates novelty seeking behavior during decision making. Behav Neurosci. 2014;128(5):556–66.CrossRefPubMed
68.
Guitart-Masip M, Bunzeck N, Stephan KE, Dolan RJ, Düzel E. Contextual novelty changes reward representations in the striatum. J Neurosci Off J Soc Neurosci. 2010;30(5):1721–6.CrossRef
69.
Winnicott DW. Through paediatrics to psycho-analysis: collected papers. 1st Brunner/Mazel ed. New York: Brunner/Mazel; 1992. p. 50.
70.
Sech SM, Montoya JD, Bernier PA, Barnboym E, Brown S, Gregory A, et al. The so-called “placebo effect” in benign prostatic hyperplasia treatment trials represents partially a conditional regression to the mean induced by censoring. Urology. 1998;51(2):242–50.CrossRefPubMed
71.
Goldenholz DM, Moss R, Scott J, Auh S, Theodore WH. Confusing placebo effect with natural history in epilepsy: a big data approach. Ann Neurol. 2015;78(3):329–36.CrossRefPubMedPubMedCentral
72.
Hull SC, Colloca L, Avins A, Gordon NP, Somkin CP, Kaptchuk TJ, et al. Patients’ attitudes about the use of placebo treatments: telephone survey. BMJ. 2013;347:f3757.CrossRefPubMedPubMedCentral
73.
Bishop FL, Aizlewood L, Adams AEM. When and why placebo-prescribing is acceptable and unacceptable: a focus group study of patients’ views. PLoS One. 2014;9(7):e101822.CrossRefPubMedPubMedCentral
74.
Barnhill A. Clinical use of placebos: still the physician’s prerogative? Hastings Cent Rep. 2012;42(3):29–37.CrossRefPubMed
Metadata
Title
Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial
Authors
Sarah Ballou
Ted J. Kaptchuk
William Hirsch
Judy Nee
Johanna Iturrino
Kathryn T. Hall
John M. Kelley
Vivian Cheng
Irving Kirsch
Eric Jacobson
Lisa Conboy
Anthony Lembo
Roger B. Davis
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Trials / Issue 1/2017
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-017-1964-x

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