Non-concealed placebo treatment for menopausal hot flushes: Study protocol of a randomized-controlled trial

Yiqi Pan, Ramona Meister, Bernd Löwe, Anne Winkelmann, Ted J Kaptchuk, Kai J Buhling, Yvonne Nestoriuc, Yiqi Pan, Ramona Meister, Bernd Löwe, Anne Winkelmann, Ted J Kaptchuk, Kai J Buhling, Yvonne Nestoriuc

Abstract

Background: Beneficial effects of placebos are high in double-blind hot flush trials. Studies in various conditions suggest that honestly prescribed placebos may elicit symptom improvement.

Objective: To determine whether open label placebo (OLP) treatment is efficacious in alleviating hot flushes among peri- and postmenopausal women.

Methods/design: In this assessor-blinded, randomized-controlled trial, n = 100 women experiencing five or more daily hot flushes of at least moderate severity and bothersomeness are assigned 1:1 to a 4-week OLP treatment or no treatment. To explore the duration and maintenance of placebo effects, the OLP group is randomized a second time to either discontinue or continue the OLP treatment for another 4 weeks. All participants receive a briefing about placebo effects and study visits at baseline, post-treatment (4 weeks), and follow-up (8 weeks, OLP group only). Qualitative interviews about subjective experiences with the OLP treatment are conducted. Primary outcomes are differences between the OLP and the no-treatment group in the hot flush composite score (frequency × severity), and bothersomeness of hot flushes as assessed with the Hot Flush Rating Scale at post-treatment. Secondary outcomes include hot flush frequency, health-related quality of life, global improvement, and the number of responders at post-treatment. Data are analyzed by fitting (generalized) linear mixed models. An exploratory analysis of maintenance and duration is performed including follow-up data.

Discussion: This trial will contribute to the evaluation of OLP treatments in clinical practice and further our understanding about the magnitude of placebo effects in hot flush treatments.

Trial registration: Clinicaltrials.gov, NCT03838523 . Retrospectively registered on February 12th, 2019. The first patient was enrolled on October 10th, 2018.

Keywords: Hot flashes; Hot flushes; Menopause; Non-hormonal treatment; Open-label placebo; Placebo effects.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schedule of enrolment, intervention, and assessment according to SPIRIT. Post post-treatment, wk week, FU follow-up, OLP open-label placebo, HFRS Hot Flush Rating Scale, WHQ Women’s Health Questionnaire, PGIC Patient Global Impression of Change, MRS Menopause Rating Scale, MHQ Menopause Health Questionnaire, AUDIT-C Alcohol Use Disorders Identification Test—Consumption, PHQ Patient Health Questionnaire, PSS Perceived Stress Scale, LOT-R Life Orientation Test—Revised, GASE Generic Assessment of Side Effects. Hot flushes are assessed ambulatory via the hot flush diary. *At baseline, health-related quality of life and expectations are assessed before and after the allocation, respectively. †The fourth study visit and the 8-week follow-up assessment takes place for the OLP 8wk and OLP 4wk groups only. ‡For the second allocation, the OLP group is further divided into the OLP 8wk and the OLP 4wk groups. §The interview is conducted at week 8 or later
Fig. 2
Fig. 2
Study design with hypothesized trends of hot flush score. SV study visit, OLP open-label placebo, wk week. The arrows represent the point in time of the first and second allocation. Circles represent placebo intake, squares represent no placebo intake. OLP 4wk and OLP 8wk are subgroups of the OLP group

References

    1. Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort. Menopause. 2014;21(9):924–932. doi: 10.1097/GME.0000000000000196.
    1. Avis NE, Crawford SL, Greendale G, Bromberger JT, Everson-Rose SA, Gold EB, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175(4):531–539. doi: 10.1001/jamainternmed.2014.8063.
    1. Williams RE, Levine KB, Kalilani L, Lewis J, Clark RV. Menopause-specific questionnaire assessment in US population-based study shows negative impact on health-related quality of life. Maturitas. 2009;62(2):153–159. doi: 10.1016/j.maturitas.2008.12.006.
    1. Dibonaventura MD, Chandran A, Hsu MA, Bushmakin A. Burden of vasomotor symptoms in France, Germany, Italy, Spain, and the United Kingdom. Int J Women's Health. 2013;5(5):261–269. doi: 10.2147/IJWH.S39027.
    1. European Medicines Agency. Guideline on clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. 2005. . Accessed 22 Apr 2019.
    1. Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 2004;(4):CD002978.
    1. Grant M, Marbella A, Wang A, Pines E, Hoag J, Bonnell C, et al. Menopausal Symptoms: Comparative effectiveness of therapies. Rockville: Agency for Healthcare Research and Quality (US); 2015.
    1. Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SA, Brzyski R, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299(9):1036–1045. doi: 10.1001/jama.299.9.1036.
    1. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280(7):605–613. doi: 10.1001/jama.280.7.605.
    1. Sprague BL, Trentham-Dietz A, Cronin KA. A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 1999-2010. Obstet Gynecol. 2012;120(3):595–603. doi: 10.1097/AOG.0b013e318265df42.
    1. The North American Menopause Society Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause. 2015;22(11):1155–1172. doi: 10.1097/GME.0000000000000546.
    1. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295(17):2057–2071. doi: 10.1001/jama.295.17.2057.
    1. Brett KM, Keenan NL. Complementary and alternative medicine use among midlife women for reasons including menopause in the United States: 2002. Menopause. 2007;14(2):300–307. doi: 10.1097/01.gme.0000232031.84788.57.
    1. van der Sluijs CP, Bensoussan A, Liyanage L, Shah S. Women's health during mid-life survey: the use of complementary and alternative medicine by symptomatic women transitioning through menopause in Sydney. Menopause. 2007;14(3):397–403. doi: 10.1097/01.gme.0000236937.36078.f4.
    1. Buhling KJ, Daniels BV, Studnitz FS, Eulenburg C, Mueck AO. The use of complementary and alternative medicine by women transitioning through menopause in Germany: results of a survey of women aged 45-60 years. Complement Ther Med. 2014;22(1):94–98. doi: 10.1016/j.ctim.2013.12.004.
    1. Franco OH, Chowdhury R, Troup J, Voortman T, Kunutsor S, Kavousi M, et al. Use of plant-based therapies and menopausal symptoms: A systematic review and meta-analysis. JAMA. 2016;315(23):2554–2563. doi: 10.1001/jama.2016.8012.
    1. Drewe J, Bucher KA, Zahner C. A systematic review of non-hormonal treatments of vasomotor symptoms in climacteric and cancer patients. Springerplus. 2015;4(65):65. doi: 10.1186/s40064-015-0808-y.
    1. Borrelli F, Ernst E. Alternative and complementary therapies for the menopause. Maturitas. 2010;66(4):333–343. doi: 10.1016/j.maturitas.2010.05.010.
    1. Zhu X, Liew Y, Liu ZL. Chinese herbal medicine for menopausal symptoms. Cochrane Database Syst Rev. 2016;3:CD009023.
    1. Dodin S, Blanchet C, Marc I, Ernst E, Wu T, Vaillancourt C, et al. Acupuncture for menopausal hot flushes. Cochrane Database Syst Rev. 2013;7:CD007410.
    1. Saensak S, Vutyavanich T, Somboonporn W, Srisurapanont M. Relaxation for perimenopausal and postmenopausal symptoms. Cochrane Database Syst Rev. 2014;7:CD008582.
    1. Elkins GR, Fisher WI, Johnson AK, Carpenter JS, Keith TZ. Clinical hypnosis in the treatment of postmenopausal hot flashes: a randomized controlled trial. Menopause. 2013;20(3):291–298.
    1. Carmody JF, Crawford S, Salmoirago-Blotcher E, Leung K, Churchill L, Olendzki N. Mindfulness training for coping with hot flashes: results of a randomized trial. Menopause. 2011;18(6):611–620. doi: 10.1097/gme.0b013e318204a05c.
    1. Ayers B, Smith M, Hellier J, Mann E, Hunter MS. Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial. Menopause. 2012;19(7):749–759. doi: 10.1097/gme.0b013e31823fe835.
    1. Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot flash studies. J Clin Oncol. 2001;19(23):4280–4290. doi: 10.1200/JCO.2001.19.23.4280.
    1. 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):167–175. doi: 10.1097/PSY.0000000000000143.
    1. Loprinzi CL, Sloan J, Stearns V, Slack R, Iyengar M, Diekmann B, et al. Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis. J Clin Oncol. 2009;27(17):2831–2837. doi: 10.1200/JCO.2008.19.6253.
    1. 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):2766–2772. doi: 10.1097/j.pain.0000000000000700.
    1. 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. doi: 10.1126/scitranslmed.3006175.
    1. 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. doi: 10.1371/journal.pone.0015591.
    1. 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):312–314. doi: 10.1159/000337053.
    1. Schaefer M, Harke R, Denke C. Open-label placebos improve symptoms in allergic rhinitis: A randomized controlled trial. Psychother Psychosom. 2016;85(6):373–374. doi: 10.1159/000447242.
    1. 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. doi: 10.1371/journal.pone.0192758.
    1. Locher C, Frey Nascimento A, Kirsch I, Kossowsky J, Meyer A, Gaab J. Is the rationale more important than deception? A randomized controlled trial of open-label placebo analgesia. Pain. 2017;158(12):2320–2328. doi: 10.1097/j.pain.0000000000001012.
    1. Mathur A, Jarrett P, Broadbent E, Petrie KJ. Open-label placebos for wound healing: A randomized controlled trial. Ann Behav Med. 2018.
    1. Hoenemeyer TW, Kaptchuk TJ, Mehta TS, Fontaine KR. Open-label placebo treatment for cancer-related fatigue: A randomized-controlled clinical trial. Sci Rep. 2018;8(1):2784. doi: 10.1038/s41598-018-20993-y.
    1. Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. doi: 10.1136/bmj.e7586.
    1. Hunter MS, Liao KL. A psychological analysis of menopausal hot flushes. Br J Clin Psychol. 1995;34(4):589–599. doi: 10.1111/j.2044-8260.1995.tb01493.x.
    1. Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab. 2012;97(4):1159–1168. doi: 10.1210/jc.2011-3362.
    1. Kroenke K, Spitzer RL, Williams JB, Lowe B. An ultra-brief screening scale for anxiety and depression: the PHQ-4. Psychosomatics. 2009;50(6):613–621.
    1. Bush K, Kivlahan DR, MB MD, Fihn SD, Bradley KA. The AUDIT Alcohol Consumption Questions (AUDIT-C). An effective brief screening test for problem drinking. Arch Internal Med. 1998;158(16):1789. doi: 10.1001/archinte.158.16.1789.
    1. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175–191. doi: 10.3758/BF03193146.
    1. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289(21):2827–2834. doi: 10.1001/jama.289.21.2827.
    1. Smith JA, Flowers P, Larkin M. Interpretative phenomenological analysis: Theory, method and research. London: SAGE Publications; 2009.
    1. Guttuso T, Jr, DiGrazio WJ, Reddy SY. Review of hot flash diaries. Maturitas. 2012;71(3):213–216. doi: 10.1016/j.maturitas.2011.12.003.
    1. Miller HG, Li RM. Measuring hot flashes: summary of a National Institutes of Health workshop. Mayo Clin Proc. 2004;79(6):777–781. doi: 10.1016/S0025-6196(11)62631-1.
    1. Butt DA, Deng LY, Lewis JE, Lock M. Minimal decrease in hot flashes desired by postmenopausal women in family practice. Menopause. 2007;14(2):203–207. doi: 10.1097/01.gme.0000235370.32103.4c.
    1. Hunter MS. The women's health questionnaire: A measure of mid-aged women's perceptions of their emotional and physical health. Psychol Health. 1992;7(1):45–54. doi: 10.1080/08870449208404294.
    1. Shin H, Shin HS. Measurement of quality of life in menopausal women: a systematic review. West J Nurs Res. 2012;34(4):475–503. doi: 10.1177/0193945911402848.
    1. Geisser ME, Clauw DJ, Strand V, Gendreau RM, Palmer R, Williams DA. Contributions of change in clinical status parameters to Patient Global Impression of Change (PGIC) scores among persons with fibromyalgia treated with milnacipran. Pain. 2010;149(2):373–378. doi: 10.1016/j.pain.2010.02.043.
    1. Guttuso T, Jr, Kurlan R, McDermott MP, Kieburtz K. Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101(2):337–345.
    1. Hauser GA, Potthoff P, Rosemeier PJ, Schneider HPG. Die Selbstbeurteilungs-Skala für klimakterische Beschwerden (Menopause Rating Scale II). J für Menopause. 1999;4:13-7.
    1. The North American Menopause Society. Menopause Health Questionnaire. Pepper Pike: NAMS; 2017.
    1. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav. 1983;24(4):385–396. doi: 10.2307/2136404.
    1. Klein EM, Brahler E, Dreier M, Reinecke L, Muller KW, Schmutzer G, et al. The German version of the Perceived Stress Scale - psychometric characteristics in a representative German community sample. BMC Psychiatry. 2016;16:159. doi: 10.1186/s12888-016-0875-9.
    1. Hunter MS, Chilcot J. Testing a cognitive model of menopausal hot flushes and night sweats. J Psychosom Res. 2013;74(4):307–312. doi: 10.1016/j.jpsychores.2012.12.005.
    1. Worsley R, Bell R, Kulkarni J, Davis SR. The association between vasomotor symptoms and depression during perimenopause: a systematic review. Maturitas. 2014;77(2):111–117. doi: 10.1016/j.maturitas.2013.11.007.
    1. Laferton JA, Kube T, Salzmann S, Auer CJ, Shedden-Mora MC. Patients' expectations regarding medical treatment: A critical review of concepts and their assessment. Front Psychol. 2017;8:233. doi: 10.3389/fpsyg.2017.00233.
    1. Haanstra TM, Hanson L, Evans R, van Nes FA, De Vet HC, Cuijpers P, et al. How do low back pain patients conceptualize their expectations regarding treatment? Content analysis of interviews. Eur Spine J. 2013;22(9):1986–1995. doi: 10.1007/s00586-013-2803-8.
    1. Hinz A, Sander C, Glaesmer H, Brahler E, Zenger M, Hilbert A, et al. Optimism and pessimism in the general population: Psychometric properties of the Life Orientation Test (LOT-R) Int J Clin Health Psychol. 2017;17(2):161–170. doi: 10.1016/j.ijchp.2017.02.003.
    1. Geers AL, Wellman JA, Fowler SL, Helfer SG, France CR. Dispositional optimism predicts placebo analgesia. J Pain. 2010;11(11):1165–1171. doi: 10.1016/j.jpain.2010.02.014.
    1. Pecina M, Azhar H, Love TM, Lu T, Fredrickson BL, Stohler CS, et al. Personality trait predictors of placebo analgesia and neurobiological correlates. Neuropsychopharmacology. 2013;38(4):639–646. doi: 10.1038/npp.2012.227.
    1. Rief W, Glombiewski JA, Barsky AJ. Generic Assessment of Side Effects: GASE Bern: Verlag Hans Huber; 2009 [cited 2019 April 22]. Available from: .
    1. Ziller V, Kalder M, Albert US, Holzhauer W, Ziller M, Wagner U, et al. Adherence to adjuvant endocrine therapy in postmenopausal women with breast cancer. Ann Oncol. 2009;20(3):431–436. doi: 10.1093/annonc/mdn646.
    1. 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. doi: 10.1136/bmj.f3757.
    1. Grady D, Macer J, Kristof M, Shen H, Tagliaferri M, Creasman J. Is a shorter hot flash diary just as good as a 7-day diary? Menopause. 2009;16(5):932–936. doi: 10.1097/gme.0b013e3181a4f558.
    1. Bell ML, Fairclough DL, Fiero MH, Butow PN. Handling missing items in the Hospital Anxiety and Depression Scale (HADS): a simulation study. BMC Res Notes. 2016;9(1):479. doi: 10.1186/s13104-016-2284-z.
    1. Feingold A. Effect sizes for growth-modeling analysis for controlled clinical trials in the same metric as for classical analysis. Psychol Methods. 2009;14(1):43–53. doi: 10.1037/a0014699.
    1. Kaptchuk TJ, Miller FG. Open label placebo: can honestly prescribed placebos evoke meaningful therapeutic benefits? BMJ. 2018;363:k3889. doi: 10.1136/bmj.k3889.
    1. Colloca L, Howick J. Placebos without deception: Outcomes, mechanisms, and ethics. Int Rev Neurobiol. 2018;138:219–240. doi: 10.1016/bs.irn.2018.01.005.
    1. Kaptchuk TJ. Open-label placebo: Reflections on a research agenda. Perspect Biol Med. 2018;61(3):311–334. doi: 10.1353/pbm.2018.0045.
    1. Kelley JM, Kraft-Todd G, Schapira L, Kossowsky J, Riess H. The influence of the patient-clinician relationship on healthcare outcomes: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2014;9(4):e94207. doi: 10.1371/journal.pone.0094207.
    1. Buchel C, Geuter S, Sprenger C, Eippert F. Placebo analgesia: a predictive coding perspective. Neuron. 2014;81(6):1223–1239. doi: 10.1016/j.neuron.2014.02.042.
    1. Henningsen P, Gundel H, Kop WJ, Lowe B, Martin A, Rief W, et al. Persistent physical symptoms as perceptual dysregulation: A neuropsychobehavioral model and its clinical implications. Psychosom Med. 2018;80(5):422–431. doi: 10.1097/PSY.0000000000000588.
    1. Ongaro G, Kaptchuk TJ. Symptom perception, placebo effects, and the Bayesian brain. Pain. 2019;160(1):1–4. doi: 10.1097/j.pain.0000000000001367.
    1. Kirsch I. Response expectancy and the placebo effect. Int Rev Neurobiol. 2018;138:81–93. doi: 10.1016/bs.irn.2018.01.003.
    1. Jensen KB. What is minimally required to elicit placebo effects? Int Rev Neurobiol. 2018;138:181–199. doi: 10.1016/bs.irn.2018.01.008.
    1. Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci. 2015;16(7):403–418. doi: 10.1038/nrn3976.
    1. Wiech K. Deconstructing the sensation of pain: The influence of cognitive processes on pain perception. Science. 2016;354(6312):584–587. doi: 10.1126/science.aaf8934.
    1. Eaves ER, Sherman KJ, Ritenbaugh C, Hsu C, Nichter M, Turner JA, et al. A qualitative study of changes in expectations over time among patients with chronic low back pain seeking four CAM therapies. BMC Complement Altern Med. 2015;15:12. doi: 10.1186/s12906-015-0531-9.
    1. 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. doi: 10.1007/s11013-009-9141-7.
    1. Mattingly C. The paradox of hope: Journeys through a clinical borderland. Berkeley and Los Angeles, California: University of California Press; 2010.
    1. Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol. 2008;59:565–590. doi: 10.1146/annurev.psych.59.113006.095941.
    1. Locher C, Nascimento AF, Kossowsky J, Meyer A, Gaab J. Open-label placebo response – Does optimism matter? A secondary-analysis of a randomized controlled trial. J Psychosom Res. 2019;116:25-30.
    1. Hrobjartsson A, Kaptchuk TJ, Miller FG. Placebo effect studies are susceptible to response bias and to other types of biases. J Clin Epidemiol. 2011;64(11):1223–1229. doi: 10.1016/j.jclinepi.2011.01.008.
    1. Archer DF, Sturdee DW, Baber R, de Villiers TJ, Pines A, Freedman RR, et al. Menopausal hot flushes and night sweats: where are we now? Climacteric. 2011;14(5):515–528. doi: 10.3109/13697137.2011.608596.
    1. Mann E, Hunter MS. Concordance between self-reported and sternal skin conductance measures of hot flushes in symptomatic perimenopausal and postmenopausal women: a systematic review. Menopause. 2011;18(6):709–722. doi: 10.1097/gme.0b013e318204a1fb.
    1. 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(1):234. doi: 10.1186/s13063-017-1964-x.
    1. Fassler 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. doi: 10.1186/1741-7015-8-15.
    1. Lynoe N, Mattsson B, Sandlund M. The attitudes of patients and physicians towards placebo treatment--a comparative study. Soc Sci Med. 1993;36(6):767–774. doi: 10.1016/0277-9536(93)90037-5.
    1. Colloca L, Enck P, DeGrazia D. Relieving pain using dose-extending placebos: a scoping review. Pain. 2016;157(8):1590–1598. doi: 10.1097/j.pain.0000000000000566.
    1. Sandler AD, Glesne CE, Geller G. Children's and parents' perspectives on open-label use of placebos in the treatment of ADHD. Child Care Health Dev. 2008;34(1):111–120.
    1. Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev. 2012;9:CD007244.
    1. Benedetti F, Carlino E, Piedimonte A. Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects. Lancet Neurol. 2016;15(7):736–747. doi: 10.1016/S1474-4422(16)00066-1.
    1. Blease C, Colloca L, Kaptchuk TJ. Are open-label placebos ethical? Informed consent and ethical equivocations. Bioethics. 2016;30(6):407–414. doi: 10.1111/bioe.12245.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren