Skip to main content

Advertisement

SpringerLink
Log in

Characterization of the adverse events profile of placebo-treated patients in randomized controlled trials on drug-resistant focal epilepsies

  • Review
  • Published:
Journal of Neurology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Murray D, Stoessl AJ (2013) Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions. Pharmacol Ther 140:306–318

    Article  CAS  PubMed  Google Scholar 

  2. 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

    PubMed  Google Scholar 

  3. 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

    Article  Google Scholar 

  4. Colloca L, Miller FG (2011) The nocebo effect and its relevance for clinical practice. Psychosom Med 73:598–603

    Article  PubMed Central  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. Papadopoulos D, Mitsikostas DD (2010) Nocebo effects in multiple sclerosis trials: a meta-analysis. Mult Scler 16:816–828

    Article  CAS  PubMed  Google Scholar 

  8. 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

    Article  PubMed  Google Scholar 

  9. 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

    PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  Google Scholar 

  11. Papadopoulos D, Mitsikostas DD (2012) A meta-analytic approach to estimating nocebo effects in neuropathic pain trials. J Neurol 259:436–447

    Article  PubMed  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. Guekht AB, Korczyn AD, Bondareva IB et al (2010) Placebo responses in randomized trials of antiepileptic drugs. Epilepsy Behav 17:64–69

    Article  CAS  PubMed  Google Scholar 

  14. 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

    CAS  PubMed  Google Scholar 

  15. 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]

  16. 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

    PubMed Central  PubMed  Google Scholar 

  17. 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

    Article  PubMed Central  PubMed  Google Scholar 

  18. 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

    Article  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. Benedetti F, Amanzio M (2013) Mechanisms of the placebo response. Pulm Pharmacol Ther 26:520–523

    Article  CAS  PubMed  Google Scholar 

  22. Benedetti F, Amanzio M (2011) The placebo response: how words and rituals change the patient’s brain. Patient Educ Couns 84:413–419

    Article  PubMed  Google Scholar 

  23. 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

    Article  PubMed  Google Scholar 

  24. 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

    CAS  PubMed  Google Scholar 

  25. 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

    Article  CAS  PubMed  Google Scholar 

  26. Colloca L, Benedetti F (2006) How prior experience shapes placebo analgesia. Pain 124:126–133

    Article  PubMed  Google Scholar 

  27. Rosenthal R (1966) Experimenter effects in behavioral research. Appleton Century Crofts, New York

    Google Scholar 

  28. Golomb BA, McGraw JJ, Evans MA et al (2007) Physician response to patient reports of adverse drug effects. Drug Saf 80:669–678

    Article  Google Scholar 

  29. 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

    Article  PubMed  Google Scholar 

  30. 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

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Ethical standard

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.

Author information

Authors and Affiliations

  1. Unit of Neurology Department of Medicine Florence Health Authority, San Giovanni di Dio Hospital, Via Di Torregalli n 3, 50143, Florence, Italy

    Fabio Giovannelli, Gaetano Zaccara & Massimo Cincotta

  2. Department of Neuroscience Psychology Pharmacology and Child Health (NEUROFARBA), University of Florence, Florence, Italy

    Fabio Giovannelli

  3. Department of Pediatrics, University of Chieti, Chieti, Italy

    Giulia Loiacono

  4. Department of Pediatrics, University of Perugia, Perugia, Italy

    Alberto Verrotti

Authors
  1. Fabio Giovannelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gaetano Zaccara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Massimo Cincotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giulia Loiacono
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alberto Verrotti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fabio Giovannelli.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table S1: PRISMA checklist (DOC 54 kb)

415_2014_7535_MOESM2_ESM.doc

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)

Table S3: Description of all double-blind, placebo-controlled studies included in this analysis (DOC 178 kb)

415_2014_7535_MOESM4_ESM.pdf

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-014-7535-0

Keywords

Search

Navigation