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Adverse events of placebo-treated, drug-resistant, focal epileptic patients in randomized controlled trials: a systematic review

Abstract

Health-related quality of life of patients with epilepsy is heavily influenced by antiepileptic drug (AED) tolerability. However, an accepted method for precise assessment of AED-induced adverse events (AEs) has not yet been established. Assessment of tolerability and of the frequency of predefined AEs among drug-resistant epilepsy patients through an analysis of placebo-treated patients from randomized controlled studies (RCTs) performed in patients with partial onset epilepsies (POS) and evaluation of factors which may influence the occurrence of AEs in these patients are the objectives of this study. We searched all double-blind, placebo-controlled trials investigating any AED on adult patients with POS and extracted both for patients treated with placebo and for those treated with the active drug, number of patients, number of responders, number of patients withdrawing because of AEs, number of patients with AEs, and number of patients with 11 predefined AEs. We also explored the effect of multiple factors on AEs reporting. Seventy-nine RCTs were included in our study with 12,594 patients, 6,793 of whom randomized to placebo. In placebo-treated patients, overall responder rate was 15.2 %, proportion of placebo-treated patients withdrawing because of AEs was 3.9 %, and proportion of patients with AE was 60.3 %. The four most frequently reported AEs were headache (12.4 %) somnolence (8.6 %), dizziness (8.2 %), and fatigue (7.9 %). Several factors were found to influence these outcomes. Several factors influence AEs’ appearance in RCTs. Among the most important, we found the expectations of patients and doctors and their attitudes on the positive or negative effect of a drug.

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References

  1. Perucca E, Kwan P (2005) Overtreatment in epilepsy: how it occurs and how it can be avoided. CNS Drugs 19:897–908

    CAS  Article  PubMed  Google Scholar 

  2. Gilliam FG, Fessler AJ, Baker G et al (2004) Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology 62:23–27

    CAS  Article  PubMed  Google Scholar 

  3. Perucca E, Beghi E, Dulac O et al (2000) Assessing risk to benefit ratio in antiepileptic drug therapy. Epilepsy Res 41:107–139

    CAS  Article  PubMed  Google Scholar 

  4. Perucca P, Gilliam FG (2012) Adverse effects of antiepileptic drugs. Lancet Neurol 11:792–802

    CAS  Article  PubMed  Google Scholar 

  5. Baker GA, Camfield C, Camfield P et al (1998) Commission on outcome measurement in epilepsy, 1994–1997: final report. Epilepsia 39:213–231

    CAS  Article  PubMed  Google Scholar 

  6. Zaccara G, Cincotta M, Borgheresi A, Balestrieri F (2004) Adverse motor effects induced by antiepileptic drugs. Epileptic Disord 6:153–168

    CAS  PubMed  Google Scholar 

  7. 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 

  8. 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

    PubMed Central  Article  PubMed  Google Scholar 

  9. Higgins JP, Altman DG, Gotzsche PC et al (2011) The Cochrane collaboration’s tool for assessing risk of bias in randomized trials. BMJ 343:d5928

    PubMed Central  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  11. Rheims S, Perucca E, Cucherat M 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 

  12. Shukralla AA, Tudur-Smith C, Powell GA, Williamson PR, Marson AG (2011) Reporting of adverse events in randomised controlled trials of antiepileptic drugs using the CONSORT criteria for reporting harms. Epilepsy Res 97(1–2):20–29

    CAS  Article  PubMed  Google Scholar 

  13. Mula M, Schmitz B (2009) Depression in epilepsy: mechanisms and therapeutic approach. Ther Adv Neurol Disord 2:337–344

    PubMed Central  Article  PubMed  Google Scholar 

  14. Syvertsen M, Helde G, Stovner LJ et al (2007) Headaches add to the burden of epilepsy. Headache Pain 8:224–230

    Article  Google Scholar 

  15. Canevini MP, De Sarro G, Galimberti CA et al (2010) Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug-refractory epilepsy. Epilepsia 51:797–804

    CAS  Article  PubMed  Google Scholar 

  16. Carreno M, Gil-Nagel A, Sanchez JC et al (2008) Strategies to detect adverse effects of antiepileptic drugs in clinical practice. Epilepsy Behav 13:178–183

    CAS  Article  PubMed  Google Scholar 

  17. Pirio Richardson S, Farias ST, Lima AR 3rd et al (2004) Improvement in seizure control and quality of life in medically refractory epilepsy patients converted from polypharmacy to monotherapy. Epilepsy Behav 5:343–347

    Article  PubMed  Google Scholar 

  18. Thomas SV, Koshy S, Nair CR et al (2005) Frequent seizures and polytherapy can impair quality of life in persons with epilepsy. Neurol India 53:46–50

    Article  PubMed  Google Scholar 

  19. Deckers CL, Hekster YA, Keyser A et al (1997) Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects. Epilepsia 38:570–575

    CAS  Article  PubMed  Google Scholar 

  20. French JA, Krauss GL, Biton V et al (2012) Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology 79:589–596

    PubMed Central  Article  PubMed  Google Scholar 

  21. Enck P, Klosterhalfen S, Weimer K et al (2011) The placebo response in clinical trials: more questions than answers. Philos Trans R Soc 366:1889–1895

    Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  23. 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

    CAS  Article  PubMed  Google Scholar 

  24. 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 

  25. 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 

  26. Mitsikostas DD, Chalarakis NG, Mantonakis LI, Delicha EM, Sfikakis PP (2012) Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice. Eur J Neurol 19:672–680

    CAS  Article  PubMed  Google Scholar 

  27. 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

    CAS  Article  PubMed  Google Scholar 

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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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Correspondence to Gaetano Zaccara.

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Zaccara, G., Giovannelli, F., Cincotta, M. et al. Adverse events of placebo-treated, drug-resistant, focal epileptic patients in randomized controlled trials: a systematic review. J Neurol 262, 501–515 (2015). https://doi.org/10.1007/s00415-014-7391-y

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  • DOI: https://doi.org/10.1007/s00415-014-7391-y

Keywords

  • Antiepileptic drugs
  • Adverse effects
  • Side effects
  • Meta-regression
  • Placebo effects
  • Nocebo effects