Abstract
In epilepsy trials a substantial proportion of patients receiving placebo has some improvement or experience adverse events (AEs) which match those related to active drug. The characterization of factors influencing these responses is crucial for a better comprehension of study results and to improve design of new trials. Seventy-one placebo-controlled, double-blind trials in drug-resistant focal epilepsies has been selected. The effect of multiple factors on some outcome measures were explored using a meta-regression model. For subjective and objective AEs, risk difference (RD) was calculated and entered in an inverse variance-weighted linear meta-regression model as independent variable to evaluate the relationship with data reported in placebo-treated patients. The number of study arms influence the percentage of patients withdrawing because of AEs and the highest dose of the experimental drug used in each RCT correlates with withdrawal because of AEs and with subjective AEs. Higher titration speed is associated with lower percentages of responders and higher reporting of both objective and subjective AEs. The correlation between proportions of placebo-treated patients with subjective and objective neurological AEs and relative RD, was significant (P = 0.002 r = 0.364 and P < 0.001 r = 0.650, respectively). Efficacy and tolerability outcomes of the placebo groups are intrinsically tied to the trial methodology and to the outcomes observed in patients treated with the active drug. The correlation for objective and subjective AEs between RD and the placebo-treated patients suggest that investigators are influenced by factors which operate within each specific trial.
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References
Murray D, Stoessl AJ (2013) Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions. Pharmacol Ther 140:306–318
Perucca E (2012) What clinical trial designs have been used to test antiepileptic drugs and do we need to change them? Epileptic Disord 14:124–131
Enck P, Klosterhalfen S, Weimer K et al (2011) The placebo response in clinical trials: more questions than answers. Philos Trans R Soc Lond B Biol Sci 27(366):1889–1895
Colloca L, Miller FG (2011) The nocebo effect and its relevance for clinical practice. Psychosom Med 73:598–603
Amanzio M, Corazzini LL, Vase L, Benedetti F (2009) A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146:261–269
Rief W, Nestoriuc Y, von Lilienfeld-Toal A et al (2009) Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: a systematic review and meta-analysis. Drug Saf 32:1041–1056
Papadopoulos D, Mitsikostas DD (2010) Nocebo effects in multiple sclerosis trials: a meta-analysis. Mult Scler 16:816–828
Mitsikostas DD, Mantonakis LI, Chalarakis NG (2011) Nocebo is the enemy, not placebo. A meta-analysis of reported side effects after placebo treatment in headaches. Cephalalgia 31:550–561
Häuser W, Sarzi-Puttini P, Tölle TR, Wolfe F (2012) Placebo and nocebo responses in randomised controlled trials of drugs applying for approval for fibromyalgia syndrome treatment: systematic review and meta-analysis. Clin Exp Rheumatol 30(6 Suppl 74):78–87
Mitsikostas DD, Chalarakis NG, Mantonakis LI et al (2012) Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice. Eur J Neurol 19:672–680
Papadopoulos D, Mitsikostas DD (2012) A meta-analytic approach to estimating nocebo effects in neuropathic pain trials. J Neurol 259:436–447
Stathis P, Smpiliris M, Konitsiotis S, Mitsikostas DD (2013) Nocebo as a potential confounding factor in clinical trials for Parkinson’s disease treatment: a meta-analysis. Eur J Neurol 20:527–533
Guekht AB, Korczyn AD, Bondareva IB et al (2010) Placebo responses in randomized trials of antiepileptic drugs. Epilepsy Behav 17:64–69
Rheims S, Perucca E, Cucherat et al (2011) Factors determining response to antiepileptic drugs in randomized controlled trials. A systematic review and meta-analysis. Epilepsia 52:219–233
Zaccara G, Giovannelli F, Cincotta M, Loiacono G, Verrotti A (2014) Adverse events of placebo-treated, drug-resistant, focal epileptic patients in randomized controlled trials: a systematic review. J Neurol [Epub ahead of print]
Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Open Med 3:e123–e130
Wallace BC, Schmid CH, Lau J et al (2009) Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol 9:80
Brinkhaus B, Pach D, Lüdtke R et al (2008) Who controls the placebo? Introducing a placebo quality checklist for pharmacological trials. Contemp Clin Trials 29:149–156
Zaccara G, Perucca P, Gangemi PF (2012) The adverse event profile of pregabalin across different disorders: a meta-analysis. Eur J Clin Pharmacol 68:903–912
Zaccara G, Perucca P, Loiacono G, Giovannelli F, Verrotti A (2013) The adverse event profile of lacosamide: a systematic review and meta-analysis of randomized controlled trials. Epilepsia 54:66–74
Benedetti F, Amanzio M (2013) Mechanisms of the placebo response. Pulm Pharmacol Ther 26:520–523
Benedetti F, Amanzio M (2011) The placebo response: how words and rituals change the patient’s brain. Patient Educ Couns 84:413–419
Levine ME, Stern RM, Koch KL (2006) The effects of manipulating expectations through placebo and nocebo administration on gastric tachyarrhythmia and motion-induced nausea. Psychosom Med 68:478–486
Liccardi G, Senna G, Russo M et al (2004) Evaluation of the nocebo effect during oral challenge in patients with adverse drug reactions. J Investig Allergol Clin Immunol 14:104–107
Flaten MA, Simonsen T, Olsen H (1999) Drug-related information generates placebo and nocebo responses that modify the drug response. Psychosom Med 61:250–255
Colloca L, Benedetti F (2006) How prior experience shapes placebo analgesia. Pain 124:126–133
Rosenthal R (1966) Experimenter effects in behavioral research. Appleton Century Crofts, New York
Golomb BA, McGraw JJ, Evans MA et al (2007) Physician response to patient reports of adverse drug effects. Drug Saf 80:669–678
Rief W, Avorn J, Barsky AJ (2006) Medication-attributed adverse effects in placebo groups: implications for assessment of adverse effects. Arch Intern Med 166:155–160
Ben-Menachem E, Gabbai AA, Hufnagel A et al (2010) Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res 89:278–285
Acknowledgments
We are grateful to Valentina Franco for her contribution in doing bibliographic search. We also thank Andrea Messori and Dario Maratea for their help in performing statistical analyses. The authors received no funding for this study. FG is supported by a grant by “Ente Cassa di Risparmio di Firenze”.
Conflicts of interest
GZ has received speaker’s or consultancy fees from EISAI, Jansen-Cilag, Sanofi-Aventis, and UCB Pharma. AV received a grant by Viropharm. FG, MC and GL report no disclosures.
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Table S2: Drug doses used in RCTs of drug-resistant focal epilepsy which, according to SPC of various AEDs and clinical judgment, have been considered as recommended doses, and lower or higher than recommended (DOC 51 kb)
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Figure S1: Significant results of the meta-regression analysis for the outcome measures in placebo-treated patients (bubbles represent the inverse variance) (PDF 26 kb)
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Giovannelli, F., Zaccara, G., Cincotta, M. et al. Characterization of the adverse events profile of placebo-treated patients in randomized controlled trials on drug-resistant focal epilepsies. J Neurol 262, 1401–1406 (2015). https://doi.org/10.1007/s00415-014-7535-0
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DOI: https://doi.org/10.1007/s00415-014-7535-0