Advertisement

Journal of Neurology

, Volume 263, Issue 7, pp 1274–1279 | Cite as

Analysis of nocebo effects of antiepileptic drugs across different conditions

  • Gaetano ZaccaraEmail author
  • Fabio Giovannelli
  • Filippo Sean Giorgi
  • Valentina Franco
  • Sara Gasparini
Review

Abstract

The aim of this study was to assess the nocebo effect in all randomised controlled trials (RCTs) exploring the effect of antiepileptic drugs (AEDs) in the clinical conditions in which these compounds have been studied with the exception of epilepsy. We searched for all double-blind, placebo-controlled trials performed in adult patients, testing AEDs in any clinical condition except epilepsy. The following data were extracted from the placebo arms: the number of randomized patients, the number of patients withdrawing because of adverse effects (AEs), and the number of patients with 11 predefined AEs (dizziness, ataxia/coordination abnormal, diplopia, somnolence, fatigue, headache, memory impairment, tremor, abnormal thinking, anxiety and depression). Outcome measures were the percentages of patients whithdrawing due to AEs and reporting the selected AEs. RCTs included in the analysis were grouped in six main categories of clinical conditions (pain, movement disorders, psychiatric disorders, substance abuse, obesity and binge eating disorders, and miscellanea). Proportions of patients with 95 % confidence intervals (CIs) have been calculated for all reported outcome measures. Thirteen AEDs were studied and the total number of selected RCTs was 157. Significant percentages of placebo-treated patients withdrawing due to AEs and with specific AEs were observed in several cases. Significant differences emerged across different conditions. Comparisons with results of a previous meta-analysis on all RCTs in patients with drug-resistant epilepsies showed that ataxia, diplopia and fatigue were significantly more frequent, and patients withdrawing were significantly less frequent, in placebo-treated epileptic patients. Significant differences have been identified in the AEDs-induced nocebo effect across different conditions. Placebo-treated epilepsy patients have significantly more frequent neurological AEs.

Keywords

Antiepileptic drugs Adverse effects Meta-analysis Placebo effects Nocebo effects 

Notes

Compliance with ethical standards

Ethical publication statement

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Funding

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. FG FSG and SG report no disclosures. VF is a former employee of Eisai s.r.l., Italy.

Supplementary material

415_2015_8018_MOESM1_ESM.pdf (46 kb)
Supplementary material 1 (PDF 46 kb)
415_2015_8018_MOESM2_ESM.pdf (27 kb)
Supplementary material 2 (PDF 26 kb)
415_2015_8018_MOESM3_ESM.pdf (20 kb)
Supplementary material 3 (PDF 19 kb)
415_2015_8018_MOESM4_ESM.doc (572 kb)
Supplementary material 4 (DOC 572 kb)
415_2015_8018_MOESM5_ESM.pdf (100 kb)
Supplementary material 5 (PDF 100 kb)
415_2015_8018_MOESM6_ESM.xls (71 kb)
Supplementary material 6 (XLS 71 kb)
415_2015_8018_MOESM7_ESM.pdf (13 kb)
Supplementary material 7 (PDF 13 kb)
415_2015_8018_MOESM8_ESM.pdf (29 kb)
Supplementary material 8 (PDF 29 kb)
415_2015_8018_MOESM9_ESM.pdf (10 kb)
Supplementary material 9 (PDF 10 kb)

References

  1. 1.
    Sullivan R, Behncke I, Purushotham A (2010) Why do we love medicines so much? An evolutionary perspective on the human love of pills, potions and placebo. EMBO Rep 11:572–578CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Murray D, Stoessl AJ (2013) Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions. Pharmacol Ther 140:306–318CrossRefPubMedGoogle Scholar
  3. 3.
    Finniss DG, Kaptchuk TJ, Miller F, Benedetti F (2010) Placebo effects: biological, clinical and ethical advances. Lancet 375:686–695CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Häuser W, Hansen E, Enck P (2012) Nocebo phenomena in medicine: their relevance in everyday clinical practice. Dtsch Arztebl Int 109:459–465PubMedPubMedCentralGoogle Scholar
  5. 5.
    Annoni M (2013) Highlights from the 2013 Science of Placebo thematic workshop. eCancer 7:346Google Scholar
  6. 6.
    Zaccara G, Giovannelli F, Schmidt D (2015) Placebo and nocebo responses in drug trials of epilepsy. Epilepsy Behav 43:128–134CrossRefPubMedGoogle Scholar
  7. 7.
    Amanzio M, Corazzini LL, Vase L, Benedetti F (2009) A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 146:261–269CrossRefPubMedGoogle Scholar
  8. 8.
    Zaccara G, Giovannelli F, Cincotta M, Loiacono G, Verrotti A (2015) Adverse events of placebo-treated, drug-resistant, focal epileptic patients in randomized controlled trials: a systematic review. J Neurol 262:501–515CrossRefPubMedGoogle Scholar
  9. 9.
    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Higgins JPT, Altman DG. (2008) Chapter 8: assessing risk of bias in included studies. Cochrane handbook for systematic reviews of interventions version 5.0.1 [updated September 2008]. Available at website: http://www.cochrane-handbook.org/. Accessed October 2015
  11. 11.
    Wallace BC, Schmid CH, Lau J, Trikalinos TA (2009) Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol 9:80CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Enck P, Klosterhalfen S, Weimer K et al (2011) The placebo response in clinical trials: more questions than answers. Philos Trans R Soc 366:1889–1895CrossRefGoogle Scholar
  13. 13.
    Mitsikostas DD, Mantonakis L, Chalarakis N (2014) Nocebo in clinical trials for depression: a meta-analysis. Psychiatry Res 215:82–86CrossRefPubMedGoogle Scholar
  14. 14.
    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 20:527–533CrossRefPubMedGoogle Scholar
  15. 15.
    Wang XQ, Lang SY, He MW, Zhang X, Zhu F, Dai W, Shi XB, Wan M, Ma YF, Chen YN, Yu SY (2014) High prevalence of headaches in patients with epilepsy. J Headache Pain 15:70CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hossain KJ, Nandi AK, Karim MR, Haque MM, Kamal MM (2012) Pattern of mental illness on substance abusers. Mymensingh Med J 21:251–258PubMedGoogle Scholar
  17. 17.
    Aichmüller C, Soyka M (2015) Fatigue in substance abuse disorders. Rev Med Suisse 11:927–930PubMedGoogle Scholar
  18. 18.
    Perucca P, Gilliam FG (2012) Adverse effects of antiepileptic drugs. Lancet Neurol 11:792–802CrossRefPubMedGoogle Scholar
  19. 19.
    Baker GA, Camfield C, Camfield P, Cramer JA, Elger CE, Johnson AL, Martins da Silva A, Meinardi H, Munari C, Perucca E, Thorbeke R (1998) Commission on outcome measurement in epilepsy, 1994–1997: final report. Epilepsia 39:213–231CrossRefPubMedGoogle Scholar
  20. 20.
    Sedgwick P, Greenwood N (2015) Understanding the Hawthorne effect. BMJ 351:h4672CrossRefPubMedGoogle Scholar
  21. 21.
    Perucca E, Kwan P (2005) Overtreatment in epilepsy: how it occurs and how it can be avoided. CNS Drugs 19:897–908CrossRefPubMedGoogle Scholar
  22. 22.
    Gilliam FG, Fessler AJ, Baker G, Vahle V, Carter J, Attarian H (2004) Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology 62:23–27CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Gaetano Zaccara
    • 1
    Email author
  • Fabio Giovannelli
    • 1
    • 2
  • Filippo Sean Giorgi
    • 3
  • Valentina Franco
    • 4
  • Sara Gasparini
    • 5
  1. 1.Unit of Neurology, San Giovanni di Dio Hospital, Department of MedicineFlorence Health AuthorityFlorenceItaly
  2. 2.Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA)University of FlorenceFlorenceItaly
  3. 3.Section of Neurology, Department of Clinical and Experimental MedicineUniversity of Pisa and Pisa University HospitalPisaItaly
  4. 4.C. Mondino National Neurological InstitutePaviaItaly
  5. 5.Department of Medical and Surgical SciencesMagna Graecia University of CatanzaroCatanzaroItaly

Personalised recommendations