Interaction between drug and placebo effects: a cross-over balanced placebo design trial
Muhammad M Hammami, Eman A Al-Gaai, Syed Alvi, Muhammad B Hammami, Muhammad M Hammami, Eman A Al-Gaai, Syed Alvi, Muhammad B Hammami
Abstract
Background: The total effect of a medication is the sum of its drug effect, placebo effect (meaning response), and their possible interaction. Current interpretation of clinical trials' results assumes no interaction. Demonstrating such an interaction has been difficult due to lack of an appropriate study design.
Methods: 180 adults were randomized to caffeine (300 mg) or placebo groups. Each group received the assigned intervention described by the investigators as caffeine or placebo, in a randomized crossover design. 4-hour-area-under-the-curve of energy, sleepiness, nausea (on 100 mm visual analog scales), and systolic blood pressure levels as well as caffeine pharmacokinetics (in 22 volunteers nested in the caffeine group) were determined. Caffeine drug, placebo, placebo-plus-interaction, and total effects were estimated by comparing outcomes after, receiving caffeine described as placebo to receiving placebo described as placebo, receiving placebo described as caffeine or placebo, receiving caffeine described as caffeine or placebo, and receiving caffeine described as caffeine to receiving placebo described as placebo, respectively.
Results: The placebo effect on area-under-the-curve of energy (mean difference) and sleepiness (geometric mean ratio) was larger than placebo-plus-interaction effect (16.6 [95% CI, 4.1 to 29.0] vs. 8.4 [-4.2 to 21.0] mm*hr and 0.58 [0.39 to 0.86] vs. 0.69 [0.49 to 0.97], respectively), similar in size to drug effect (20.8 [3.8 to 37.8] mm*hr and 0.49 [0.30 to 0.91], respectively), and its combination with the later was larger than total caffeine effect (29.5 [11.9 to 47.1] mm*hr and 0.37 [0.22 to 0.64]). Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 [0.12 to 0.68] hr (P=0.007).
Conclusions: Drug and placebo effects of a medication may be less than additive, which influences the interpretation of clinical trials. The placebo effect may increase active drug terminal half-life, a novel mechanism of placebo action.
Trial registration: ClinicalTrials.gov identification number - NCT00426010.
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References
- 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:a1983. doi: 10.1136/bmj.a1938.
- Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344:1594–1602. doi: 10.1056/NEJM200105243442106.
- Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment. J Intern Med. 2004;256:91–100. doi: 10.1111/j.1365-2796.2004.01355.x.
- Moerman DE, Jonas WB. Deconstructing the placebo effect and finding the meaning response. Ann Intern Med. 2002;136:471–476.
- Fillingim RB, Price DD. What is controlled for in placebo-controlled trials? Mayo Clin Proc. 2005;80:1119–1121. doi: 10.4065/80.9.1119.
- Spiegel D, Harrington A. What is the placebo worth? The doctor-patient relationship is a crucial part of its value. BMJ. 2008;336:967–968. doi: 10.1136/.
- Oken BS. Placebo effects: clinical aspects and neurobiology. Brain. 2008;131:2812–2823. doi: 10.1093/brain/awn116.
- Miller FG, Wendler D, Swartzman LC. Deception in research on the placebo effect. PLoS Med. 2005;2:e262. doi: 10.1371/journal.pmed.0020262.
- Kienle GS, Kiene H. The powerful placebo effect: fact or fiction? J Clin Epidemiol. 1997;50:1311–1318. doi: 10.1016/S0895-4356(97)00203-5.
- Barfod TS. Placebos in medicine: Placebo use is well known, placebo effect is not. BMJ. 2005;330:45. doi: 10.1136/bmj.330.7481.45.
- McPherson K. Do patients' preferences matter? Yes, but to what extent is unclear. BMJ. 2008;337:a2034. doi: 10.1136/bmj.a2034.
- de Craen AJ, Kaptchuk TJ, Tijssen JG, Kleijnen J. Placebos and placebo effects in medicine: historical overview. J R Soc Med. 1999;92:511–515.
- Lotshaw SC, Bradley JR, Brooks LR. Illustrating caffeine's pharmacological and expectancy effects utilizing a balanced placebo design. J Drug Educ. 1996;26:13–24.
- Gundersen H, Specht K, Grüner R, Ersland L, Hugdahl K. Separating the effects of alcohol and expectancy on brain activation: an fMRI working memory study. Neuroimage. 2008;42:1587–1596. doi: 10.1016/j.neuroimage.2008.05.037.
- Cole-Harding S, Michels VJ. Does expectancy affect alcohol absorption? Addict Behav. 2007;32:194–198. doi: 10.1016/j.addbeh.2006.03.042.
- Kelemen WL, Kaighobadi F. Expectancy and pharmacology influence the subjective effects of nicotine in a balanced-placebo design. Exp Clin Psychopharmacol. 2007;15:93–101. doi: 10.1037/1064-1297.15.1.93.
- Green MW, Taylor MA, Elliman NA, Rhodes O. Placebo expectancy effects in the relationship between glucose and cognition. Br J Nutr. 2001;86:173–179. doi: 10.1079/BJN2001398.
- Pohl J, Frohnau G, Kerner W, Fehm-Wolfsdorf G. Symptom awareness is affected by the subjects' expectations during insulin-induced hypoglycemia. Diabetes Care. 1997;20:796–802. doi: 10.2337/diacare.20.5.796.
- Price DD. Assessing placebo effects without placebo groups: an untapped possibility? Pain. 2001;90:201–203. doi: 10.1016/S0304-3959(01)00265-2.
- Sayette MA, Breslin FC, Wilson GT, Rosenblum GD. An evaluation of the balanced placebo design in alcohol administration research. Addict Behav. 1994;19:333–342. doi: 10.1016/0306-4603(94)90034-5.
- Kirsch I, Moore TJ, Scoboria A, Nicholls SS. The emperor's new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment. 2002;5:23.
- Waring DR. The antidepressant debate and the balanced placebo trial design: an ethical analysis. Int J Law Psychiatry. 2008;31:453–462. doi: 10.1016/j.ijlp.2008.09.001.
- Krogsbøll LT, Hróbjartsson A, Gøtzsche PC. Spontaneous improvement in randomised clinical trials: meta-analysis of three-armed trials comparing no treatment, placebo and active intervention. BMC Med Res Methodol. 2009;9:1. doi: 10.1186/1471-2288-9-1.
- Mort JR, Kruse HR. Timing of blood pressure measurement related to caffeine consumption. Ann Pharmacother. 2008;42:105–110.
- Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology. 2004;176:1–29. doi: 10.1007/s00213-004-2000-x.
- Dickert N, Grady C. What's the price of a research subject? Approaches to payment for research participation. N Engl J Med. 1999;341:198–203. doi: 10.1056/NEJM199907153410312.
- Kamimori GH, Karyekar CS, Otterstetter R, Cox DS, Balkin TJ, Belenky GL, Eddington ND. The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. Int J Pharm. 2002;234:159–167. doi: 10.1016/S0378-5173(01)00958-9.
- McRae C, Cherin E, Yamazaki TG, Diem G, Vo AH, Russell D, Ellgring JH, Fahn S, Greene P, Dillon S, Winfield H, Bjugstad KB, Freed CR. Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry. 2004;61:412–420. doi: 10.1001/archpsyc.61.4.412.
- Preference Collaborative Review Group. Patients' preferences within randomised trials: systematic review and patient level meta-analysis. BMJ. 2008;337:a1864. doi: 10.1136/bmj.a1864.
- Waber RL, Shiv B, Carmon Z, Ariely D. Commercial features of placebo and therapeutic efficacy. JAMA. 2008;299:1016–1017. doi: 10.1001/jama.299.9.1016.
- Branthwaite A, Cooper P. Analgesic effects of branding in treatment of headaches. Br Med J (Clin Res Ed) 1981;282:1576–1578. doi: 10.1136/bmj.282.6276.1576.
- Schneider R, Grüner M, Heiland A, Keller M, Kujanová Z, Peper M, Riegl M, Schmidt S, Volz P, Walach H. Effects of expectation and caffeine on arousal, well-being, and reaction time. Int J Behav Med. 2006;13:330–339. doi: 10.1207/s15327558ijbm1304_8.
- Cavanna AE, Strigaro G, Monaco F. Brain mechanisms underlying the placebo effect in neurological disorders. Funct Neurol. 2007;22:89–94.
Source: PubMed